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 02/25/2026 has been entered. Claims 1, 2, 4 – 19, 21, and new claims 22 and 23 are pending. Claims 3 and 20 have been canceled. Claims 1, 2, 4 – 9, 15 – 19, and 21 – 23 are under consideration.
Election/Restrictions
2. Applicant's election with traverse of Group I (claims 1 – 9 and 15 – 21) in the reply filed on 11/24/2025 is acknowledged. The traversal is on the ground(s) that there is no evidence of record to show that the claimed product can be made as the Office has alleged and search of all claims would not impose a serious burden on the Office. This is not found persuasive because the inventions of Group I and II are distinct as the invention of Group I is drawn to a method and the invention of Group II is drawn to a product and the product as claimed can be made by excising an organ from an organism by surgical methods as known in the art because Applicant’s specification broadly defines “three-dimensional cell tissue” on page 4, lines 25 – 26 as “three-dimensional cell aggregate” and further states that the use of “three-dimensional cell tissues include” biological tissue models of organs (page 4, lines 26 – 27 and page 5, lines 1 – 4). Additionally, organs excised from an organism would comprise the recited components of the invention of Group II as broadly defined in Applicant’s specification (page 5, lines 21 – 25; page 6, lines 9 – 14; page 7, lines 1 – 12 and 24 – 27; page 8, lines 1 – 5; page 9, lines 5 – 7). The lack of search burden argument is not found persuasive because the Restriction Requirement mailed 11/06/2025 set forth that the inventions of Group I and II are classified separately and would require a different field of search thus showing a search burden by examining all pending claims together.
The requirement is still deemed proper and is therefore made FINAL.
3. Claims 10 – 14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/24/2025.
Priority
4. This application claims priority to Japanese Application No. 2020-196310 filed 11/26/2020.
5. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Withdrawn Specification Objection
6. The objection to the specification for improper trade name or marker usage is withdrawn in view of Applicant’s amendment to the specification.
Withdrawn Claim Rejections
7. The rejection of claim 4 under 35 U.S.C. 112(d) is withdrawn in view of Applicant’s amendment to the claim.
8. The rejection of claims 3 and 20 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancellation of these claims.
9. The rejection of claims 1 – 2, 5 – 9, and 15 – 19 under 35 U.S.C. 102(a)(1) is withdrawn in view of Applicant’s amendment to claim 1.
10. The rejection of claims 4 and 21 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1.
11. The rejection of claims 3 and 20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 3 – 10, 12 – 13, 15 – 22 of copending Application No. 17434686 (reference application) is rendered moot in view of Applicant’s cancellation of these claims.
12. The rejection of claims 3 and 20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13 – 27 of copending Application No. 17777786 (reference application) is rendered moot in view of Applicant’s cancellation of these claims.
13. The rejection of claims 3 and 20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 11 of copending Application No. 18043507 (reference application) is rendered moot in view of Applicant’s cancellation of these claims.
14. The rejection of claims 3 and 20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 10 and 14 – 16 of copending Application No. 18171862 (reference application) is rendered moot in view of Applicant’s cancellation of these claims.
15. The rejection of claims 3 and 20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 18 of copending Application No. 18437415 (reference application) is rendered moot in view of Applicant’s cancellation of these claims.
16. The rejection of claims 3 and 20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 11 of copending Application No. 18774971 (reference application) is rendered moot in view of Applicant’s cancellation of these claims.
17. The rejection of claims 3 and 20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10 – 18 of copending Application No. 19298823 (reference application) is rendered moot in view of Applicant’s cancellation of these claims.
Maintained Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
18. Claims 1 – 2, 4 – 9, and 15 – 21 remain and claims 22 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 3 – 10, 12 – 13, 15 – 22 of copending Application No. 17434686 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by reference claim 1, 12, and 17. Although maintained, the rejection is revised in view of Applicant’s cancellation of claims 3 and 20 and addition of claims 22 and 23.
Reference claim 1 recites a method for producing a three-dimensional tissue construct, the method comprising: culturing cells in a culture liquid including: fragmented collagen components, that are not derived from a human, and that include collagen molecule aggregates, the fragmented collagen
components having: an average length of 5 μm to 50 μm, and an average diameter of 50 nm to 30 μm,
fibrin, and an aqueous medium, and mixing fibrinogen with thrombin before the culturing, wherein the fibrinogen and/or the thrombin has been mixed with the fragmented collagen components.
Reference claim 12 recites a method for producing a cell-containing
composition, the method comprising: mixing fibrinogen with fragmented collagen components to form a first fibrinogen mixture, and/or mixing thrombin with fragmented collagen components to form a first thrombin mixture, wherein the fragmented collagen components are not derived from a human, include collagen molecule aggregates, have an average length of 5 μm to 50 μm, and have an average diameter of 50 nm to 30 μm; mixing the first fibrinogen mixture with thrombin and/or mixing the first thrombin mixture with fibrinogen, so that the fibrinogen and the thrombin react to form a fibrin mixture that
includes fibrin and the fragmented collagen components; and arranging a first liquid droplet comprising at least the fibrin mixture, an aqueous medium, and cells and a second liquid droplet comprising at least an aqueous medium so that the first liquid droplet comes into contact with the second liquid droplet.
Reference claim 17 recites a method for producing a three-dimensional tissue
construct, the method comprising: culturing cells in a culture liquid including: fragmented collagen components, which are not derived from a human, and that include collagen molecule aggregates, the fragmented collagen components having: an average length of 5 μm to 50 μm, and an average diameter of 50 nm to 30 μm, fibrin, and an aqueous medium, and mixing fibrinogen with thrombin before the culturing, wherein the fibrinogen and/or the thrombin has been mixed with the fragmented collagen components, wherein the culture liquid is in a form of liquid droplets, the cells include fibroblasts, and
a content of the fibroblasts is greater than or equal to 25% based on a number of whole
cells.
Therefore, reference claims 1, 12, and 17 are in essence a species of the generic invention of instant claim 1. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
19. Claims 1 – 2, 4 – 9, and 15 – 21 remain and claims 22 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13 – 27 of copending Application No. 17777786 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by reference claim 13 and 27. Although maintained, the rejection is revised in view of Applicant’s cancellation of claims 3 and 20 and addition of claims 22 and 23.
Reference claim 13 recites a method for producing a cell structure, comprising: a contact step of contacting cells comprising at least hepatocytes and vascular endothelial cells with extracellular matrix components in an aqueous medium; and a culture step of culturing the cells in contact with the extracellular matrix components, wherein the contact step is performed under conditions in which aggregation of the extracellular matrix components in an aqueous medium is restricted, and
wherein the culture step is performed under conditions suitable for culturing hepatic nonparenchymal
cells.
Reference claim 27 recites a method for producing a cell structure, comprising: mixing human hepatocytes, liver sinusoidal endothelial cells, and hepatic stellate cells to obtain a cell mixture, wherein proportions of a number of human hepatocytes, liver sinusoidal endothelial cells, and hepatic stellate cells, based on a total number of cells, are 60% or more, 5% to 35%, and 1% to 15%, respectively;
mixing a heparin solution and a collagen solution to obtain a heparin-collagen solution, wherein the heparin solution has a heparin concentration of 0.05 to 5.0 mg/ml, and the collagen solution has a collagen concentration of 0.1 to 1.0 mg/ml; forming a viscous component by mixing the heparin-collagen solution and the cell mixture; mixing the viscous component and a thrombin solution to obtain a cell suspension; mixing the cell suspension and a fibrinogen solution to form a fibrin gel; and
culturing the fibrin gel in a culture medium for hepatocytes to obtain the cell structure.
Therefore, reference claims 13 and 27 are in essence a species of the generic invention of instant claim 1. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
20. Claims 1 – 2, 4 – 9, and 15 – 21 remain and claims 22 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 11 of copending Application No. 18043507 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by reference claim 1. Although maintained, the rejection is revised in view of Applicant’s cancellation of claims 3 and 20 and addition of claims 22 and 23.
Reference claim 1 recites a method for producing a three-dimensional tissue body, comprising:
a step of obtaining a mixture by mixing a cationic substance and a fragmented extracellular matrix component with cells; and a step of culturing the cells after the step of obtaining the mixture. Therefore, reference claim 13 and 27 are in essence a species of the generic invention of instant claim 1. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
21. Claims 1 – 2, 4 – 9, and 15 – 21 remain and claims 22 and 23 are are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 10 and 14 – 16 of copending Application No. 18171862 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by reference claim 1. Although maintained, the rejection is revised in view of Applicant’s cancellation of claims 3 and 20 and addition of claims 22 and 23.
Reference claim 1 recites a method for producing a three-dimensional cell structure, the method comprising: preparing a mixture of a cationic substance, an extracellular matrix component, a
poly electrolyte, and a cell population including comprising a plurality of endothelial cells and
a plurality of mouse-derived stromal cells, which exclude mouse-derived endothelial cells;
collecting a cell aggregate from the mixture; and culturing a collected cell aggregate to obtain a three-dimensional cell structure. Therefore, reference claim 1 is in essence a species of the generic invention of instant claim 1. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
22. Claims 1 – 2, 4 – 9, and 15 – 21 remain and claims 22 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 18 of copending Application No. 18437415 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by reference claim 1. Although maintained, the rejection is revised in view of Applicant’s cancellation of claims 3 and 20 and addition of claims 22 and 23.
Reference claim 1 recites a method of producing three-dimensional cellular tissues, comprising:
obtaining a stromal cell-containing mixture comprising stromal cells, a cationic substance, an extracellular matrix component and a polyelectrolyte, or a stromal cell-containing mixture comprising stromal cells, a cationic substance and a fragmented extracellular matrix component; gelling the stromal cell-containing mixture to obtain a first gel composition comprising stromal cells; obtaining a target cell-containing mixture comprising target cells, a cationic substance, an extracellular matrix component and a polyelectrolyte, or a target cell-containing mixture comprising target cells, a cationic substance and a fragmented extracellular matrix component; placing the target cell-containing mixture in contact with the first gel composition; gelling the target cell-containing mixture to obtain a second gel composition comprising target cells; and incubating the first gel composition and the second gel composition to obtain three-dimensional cellular tissues. Therefore, reference claim 1 is in essence a species of the generic invention of instant claim 1. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
23. Claims 1 – 2, 4 – 9, and 15 – 21 remain and claims 22 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 11 of copending Application No. 18774971 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by reference claim 1 and 5. Although maintained, the rejection is revised in view of Applicant’s cancellation of claims 3 and 20 and addition of claims 22 and 23.
Reference claim 1 recites a method of producing three-dimensional cellular tissues, comprising:
mixing stromal cells with a cationic substance, an extracellular matrix component and a polyelectrolyte;
removing a liquid portion from a mixture of the stromal cells, the cationic substance, the extracellular matrix component and the polyelectrolyte such that a cell aggregate is obtained; culturing the cell aggregate in a first medium such that a three-dimensional cellular tissue is obtained; and
culturing the three-dimensional cellular tissue in a second medium comprising
ascorbic acid and Transforming Growth Factor-β, wherein a thickness of the three-dimensional cellular tissue remains greater than 50 μm for at least 3 days after culturing the three-dimensional cellular tissue in the second medium comprising ascorbic acid and Transforming Growth Factor-β.
Reference claim 5 recites a method of producing three-dimensional cellular tissues, comprising:
mixing stromal cells with a cationic substance, an extracellular matrix component and a polyelectrolyte such that a first mixture is obtained; removing a liquid portion from the first mixture of the stromal cells, the cationic substance, the extracellular matrix component and the polyelectrolyte such that a first cell
aggregate is obtained; culturing the first cell aggregate in a first medium such that a first three-dimensional cellular tissue is obtained; disposing target cells on the first three-dimensional cellular tissue; mixing stromal cells with a cationic substance, an extracellular matrix component and a polyelectrolyte such that a second mixture is obtained; removing a liquid portion from the second mixture of the stromal cells, the cationic substance, the extracellular matrix component and the polyelectrolyte such that a second cell aggregate is obtained; disposing the second cell aggregate such that the second cell aggregate is in contact with target cells; and culturing the second cell aggregate in a second medium comprising ascorbic acid and Transforming Growth Factor- β such that a second three-dimensional cellular tissue is obtained, wherein a total thickness of the first three-dimensional cellular tissue, the target cells and the second three-dimensional cellular tissue remains greater than 50 μm for at least 3 days after culturing the second three-dimensional cellular tissue in the medium
containing ascorbic acid and Transforming Growth Factor- β.
Therefore, reference claim 1 and 5 are in essence each a species of the generic invention of instant claim 1. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
24. Claims 1 – 2, 4 – 9, and 15 – 21 remain and claims 22 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10 – 18 of copending Application No. 19298823 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by reference claim 10. Although maintained, the rejection is revised in view of Applicant’s cancellation of claims 3 and 20 and addition of claims 22 and 23.
Reference claim 10 recites a method of manufacturing three-dimensional hepatic tissue, comprising: causing a composition including cells and a hydrogel-forming substance to gel and embed the cells in the hydrogel; and culturing the cells embedded in the hydrogel, wherein the cells include hepatocytes and no hepatic stellate cells. Therefore, reference claim 10 is in essence a species of the generic invention of instant claim 1. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
Claim Interpretation
25. For the purpose of applying prior art, “glycosaminoglycan” of claims 7 and 17 is interpreted to include heparin based on Applicant’s specification at page 8, lines 7 – 8.
26. For the purpose of applying prior art, “the extracellular matrix component” claim 15 is interpreted as the “extracellular component” of claim 1.
Rejections Necessitated by Amendment
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.
27. Claim(s) 1, 4 – 9 and 21 – 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Matsusaki (JP-WO2017146124-A1; Filed 02/22/2017; Published 07/26/2018; previously cited), hereinafter Matsusaki in view of Gansau (Gansau, Jennifer, et. al. Journal of functional biomaterials 9.3 (2018): 43.), hereinafter Gansau in view of Jeon (Jeon, Oju, et al. Journal of controlled release 105.3 (2005): 249-259.), hereinafter Jeon in view of Duong (Duong, Haison, et. al. Tissue Engineering Part A 15.7 (2009): 1865-1876.), hereinafter Duong. A machine translation of the original document is provided. The translation was performed on 12/19/2025 of pages 4 – 33 of the original document.
Regarding claims 1, 2, 5, and 7, Matsusaki teaches a method for producing three-dimensional cell tissue comprising mixing normal human dermal fibroblasts (NHDF) (“cells” of claim 1), Tris-HCl buffer (“cationic substance” of claim 1), collagen (“extracellular matrix component” of claims 1, 5), and heparin (“polyelectrolyte” of claim 1 and “glycosaminoglycan” of claim 7), centrifuging the mixture to obtain a viscous mass (“gelling” of claim 1), and incubating the mixture (“incubating” of claim 1) to obtain a 3D cell tissue (page 26, 0043; page 27, 0045; page 28, 0046 – 0047; page 31, 0052 – 0053; page 32 – 33, 0055; page 34 – 35, 0059; page 36, 0061; page 43, 0076 – 0077; page 44, 0078 – 0079; page 45, 0080). Matsusaki does not teach adding thrombin and fibrinogen, “fibrin monomers are gelled”, or the concentrations of thrombin and fibrinogen of claim 1.
Regarding claim 6, Matsusaski teaches 0.05 mg/mL of collagen in the mixture (page 27, 0045).
Regarding claim 8, Matsusaki teaches 0.05 mg/mL of heparin in the mixture (page 27, 0045).
Regarding claim 9, Matsusaki teaches centrifuging the mixture to obtain a viscous mass (page 28, 0047).
Matsusaki does not teach “further adding thrombin and fibrinogen” or “gelling the mixture” or “a thrombin concentration in the mixture is from 1 mg/mL to 40 mg/mL” and “a fibrinogen concentration in the mixture is from 0.5 mg/mL to 25 mg/mL” of claim 1 or “gelling comprises adding the thrombin to the mixture; and then adding the fibrinogen to the mixture to which the thrombin has been added, wherein the fibrin gel is formed to gel the mixture” of claim 4 or the fibrinogen and thrombin concentrations recited in claims 21 – 23. However, Matsusaki teaches the 3D cellular tissues produced by the method include biological tissues such as cartilage (page 12, para. 0020). Matsusaki teaches in the absence of polyelectrolyte and extracellular matrix, the tissue was thin and collapsed as the cells had low adhesion to each other (page 45, 0080; page 46, 0082). Matsusaki teaches the method is useful in the field of regenerative medicine and in pharmaceutical development (page 52).
Regarding “further adding thrombin and fibrinogen” and “gelling the mixture” of claim 1, Gansau teaches a method of preparing a three-dimensional fibrin-collagen- cell tissue comprising mixing cells, HEPES, collagen, thrombin (5 U/mL), and fibrinogen (final concentration of 50 mg/mL) to obtain a mixture and gelling the mixture (page 13, para. 1; Table 2; page 14, para. 2).
Regarding claim 4, Gansau teaches for encapsulation of the cells, chondrocytes were suspended in fibrinogen and collagen-thrombin was added to the fibrinogen to form the construct (page 14, para. 2).
Gansau does not teach “a thrombin concentration in the mixture is from 1 mg/mL to 40 mg/mL” or “a fibrinogen concentration in the mixture is from 0.5 mg/mL to 25 mg/mL” of claim 1 or the fibrinogen and thrombin concentrations recited in claims 21 – 23. However, Gansau teaches lower fibrin concentrations resulted in significant contraction of the hydrogel which was minimized for concentrations at or above 25 mg/mL (Figure 1a and b; page 9, last para.). Gansau teaches hydrogels, such as fibrin, offer a promising delivery vehicle to introduce cells into intervertebral disc (IVD) to regenerate damaged disc tissue as a potential treatment of low back pain but fibrin lacks extracellular matrix components (Abstract). Gansau teaches incorporation of ECM components can enhance the bioactivity of fibrin-based hydrogels, which may help advance the clinical potential of commercial cell and biomaterial ventures in the treatment of IVD regeneration (Abstract). Gansau teaches chondrocytes have been shown to retain their rounded morphology in fibrin hydrogels, inhibiting dedifferentiation and promoting matrix production (page 2, para. 3). Gansau teaches incorporation of ECM constituents into fibrin gels such as collagen have been shown to enhance matrix deposition by chondrocytes (page 2, para. 4). One would have been motivated to combine the teachings of Matsusaki and Gansau because both teach 3D cell constructs comprising collagen for regenerative medicine and Matsusaki teaches the tissue produced by the method includes cartilage and Gansau teaches incorporation of ECM components can enhance the bioactivity of fibrin-based hydrogels.
Regarding “a fibrinogen concentration in the mixture is from 0.5 mg/mL to 25 mg/mL” of claim 1 and “the fibrinogen concentration in the mixture is from 0.5 mg/mL to 10 mg/mL” of claim 23, Jeon teaches a method of forming fibrin gels with fibrinogen, thrombin, and heparin to deliver bFGF where the Group V fibrin gel contains 9.4 mg/mL fibrinogen and 33.3 U/mL of thrombin (Table 1; page 251, left col. last para.). Jeon teaches almost all of the bFGF was released from the Group V fibrin gel (Table 1; page 255, right col. para. 3). Jeon teaches as the thrombin content in the fibrin gels increased, the bFGF release rate significantly decreased and increased concentration of fibrinogen decreased the bFGF release rate (Abstract; Figure 3). Jeon teaches the fibrin gels may stabilize the bFGF activity (Abstract). Jeon teaches microvessel density was much higher in mouse ischemic limbs treated with bFGF-loaded fibrin gels that without treatment (Abstract; page 256, right col. para. 2; Figure 8). Jeon teaches the rate of bFGF release from fibrin gels can be controlled and that the bFGF delivery system has therapeutic potentials for angiogenesis (Abstract; page 257, right col. last para.). Jeon teaches bFGF has been known to stimulate the regeneration of tissues including cartilage and blood vessels (Abstract; page 249, right col. last para.; page 250, left col. para. 1). Jeon does not teach “a thrombin concentration in the mixture is from 1 mg/mL to 40 mg/mL” of claim 1 or the fibrinogen and thrombin concentrations recited in claims 21 and 22 or the thrombin concentration of claim 23. One would have been motivated to combine the teachings of Matsusaki, Gansau, and Jeon because each teach 3D cell constructs for regenerative medicine and Matsusaki teaches the tissue produced by the method includes cartilage and Gansau teaches incorporation of ECM components can enhance the bioactivity of fibrin-based hydrogels and Jeon teaches incorporation of bFGF into a fibrin gel that releases bFGF in vitro and in vivo and bFGF is known to stimulate the regeneration of tissues including cartilage and blood vessels.
Regarding “a thrombin concentration in the mixture is from 1 mg/mL to 40 mg/mL” of claim 1 and the fibrinogen and thrombin concentrations recited in claims 21 and 22 and the thrombin concentration of claim 23, Duong teaches various fibrin matrix formulations derived from fibrinogen at 2 – 50 mg/mL and thrombin at 2 – 100 U/mL in Table 1. Duong teaches 1 IU of thrombin is defined as the activity contained in 0.0853 mg of human thrombin and 1 mL of thrombin solution was mixed with 1 mL of fibrinogen solution (page 1866, left col. last para.). Therefore, Duong teaches fibrin gels where the thrombin concentration in the mixture is 0.853 mg/mL (10 units/mL) (claim 1 and 22), 1.7 mg/mL (20 units/mL) (claim 1 and 22), 4.265 mg/mL (50 units/mL) (claim 1 and 21) and 8.53 mg/mL (100 units/mL) (claim 1, 22, and 23)when the fibrinogen concentration is 2 – 17 mg/mL (claim 1, 22, and 23) (Table 1). Duong teaches changing the fibrinogen and thrombin concentrations in the final 3D fibrin matrix influenced cell proliferation and differentiation (Abstract). Duong teaches the stiffness of the fibrin gel increased with increasing fibrinogen concentration or increasing thrombin concentration and at 2 mg/mL fibrinogen the stiffness varied with increasing thrombin concentration (page 1868, left col. para. 1 and 3 and right col.). Duong teaches changing the fibrinogen concentrations had a greater effect on the stiffness than changing the thrombin concentrations (page 1869, right col.). Duong teaches cell proliferation in the different fibrin gels varied over time and morphology changed with the different fibrin gels (page 1871, left col. and right col. para. 1). Duong teaches the unique feature of fibrin is that it can be modified to create microstructures of different porosities and stiffness to simulate an environment that is optimized for cell growth and survival (page 1874, left col. last para.). Duong teaches biomaterials are essential for the advancement of tissue engineering because they can function as delivery vehicles for bioactive substances or cells (page 1865, left col.). Duong teaches the preferred materials should have mechanical and biochemical properties that are biocompatible, bioabsorbable, and biodegradable; furthermore, the materials should easily be manipulated and easily reproducible (page 1865, 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 Matsusaki regarding a method for producing three-dimensional cell tissue comprising mixing cells, a cationic substance, an extracellular matrix component and a polyelectrolyte to obtain a 3D cell tissue for regenerative medicine with the teachings of Gansau regarding a method of producing a fibrin-extracellular matrix hydrogel with cells encapsulated for regenerative medicine with the teachings of Jeon regarding a method of forming bFGF-fibrin gel with various concentrations of fibrinogen and thrombin for bFGF release for regenerative medicine with the teachings of Duong regarding a method of controlling the stiffness of fibrin gels by varying the concentrations of fibrinogen and thrombin to arrive at the claimed method of producing a three-dimensional cell tissue, the method comprising: obtaining a mixture comprising mixing cells, a cationic substance, an extracellular matrix component and a polyelectrolyte, and further adding thrombin and fibrinogen to obtain a mixture; gelling the mixture such that a gel composition comprising the cells, the cationic substance, the extracellular matrix component, the polyelectrolyte, and a fibrin gel, in which fibrin monomers are gelled, is obtained; wherein a thrombin concentration in the mixture is from 1 mg/mL to 40 mg/mL, and a fibrinogen concentration in the mixture is from 0.5 mg/mL to 25 mg/mL, and incubating the gel composition, thereby obtaining a three-dimensional cell tissue. Further, it would be obvious to adjust the concentrations of thrombin and fibrinogen to arrive at the claimed concentrations, since it is a result-effective variable dependent on the cell type and desired biomechanical properties of the gel. One would have been motivated to combine the teachings of Matsusaki, Gansau, Jeon, and Duong in a method of producing a 3D tissue customized for desired stiffness and growth factor release rate for regenerative medicine as Matsusaki teaches the method is useful in the field of regenerative medicine and in pharmaceutical development and Gansau teaches hydrogels, such as fibrin, offer a promising delivery vehicle to introduce cells into intervertebral disc to regenerate damaged disc tissue as a potential treatment of low back pain and incorporation of ECM components can enhance the bioactivity of fibrin-based hydrogels, which may help advance the clinical potential of commercial cell and biomaterial ventures in the treatment of IVD regeneration and Jeon teaches the bFGF delivery system has therapeutic potentials for angiogenesis and Jeon teaches bFGF has been known to stimulate the regeneration of tissues including cartilage and blood vessels and Duong teaches the unique feature of fibrin is that it can be modified to create microstructures of different porosities and stiffness to simulate an environment that is optimized for cell growth and survival and Duong teaches biomaterials are essential for the advancement of tissue engineering because they can function as delivery vehicles for bioactive substances or cells. One would have a reasonable expectation of success in combining the teachings as Matsusaki teaches the 3D cellular tissues produced by the method include biological tissues such as cartilage and Gansau teaches the cells proliferated in the gel with a fibrinogen concentration at or above 25 mg/mL and Gansau teaches chondrocytes have been shown to retain their rounded morphology in fibrin hydrogels, inhibiting dedifferentiation and promoting matrix production and Gansau teaches incorporation of ECM constituents into fibrin gels such as collagen have been shown to enhance matrix deposition by chondrocytes and Jeon teaches controlling the rate of release by varying the composition of the components and Duong teaches cell proliferation and morphology can be controlled by varying the concentrations of fibrinogen and thrombin where the stiffness of the fibrin gel increased with increasing fibrinogen concentration or increasing thrombin concentration and changing the fibrinogen concentrations had a greater effect on the stiffness than changing the thrombin concentrations.
28. Claim(s) 2 and 15 – 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Matsusaki (JP-WO2017146124-A1; Filed 02/22/2017; Published 07/26/2018; previously cited), hereinafter Matsusaki in view of Gansau (Gansau, Jennifer, et. al. Journal of functional biomaterials 9.3 (2018): 43.), hereinafter Gansau in view of Jeon (Jeon, Oju, et al. Journal of controlled release 105.3 (2005): 249-259.), hereinafter Jeon in view of Duong (Duong, Haison, et. al. Tissue Engineering Part A 15.7 (2009): 1865-1876.), hereinafter Duong as applied to claims 1, 5 – 9 and 21 – 23 above, and further in view of Scionti (Scionti, Giuseppe, et al. Journal of Biomedical Materials Research Part A 102.8 (2014): 2573-2582.), hereinafter Scionti.
Matsusaki in view of Gansau, Jeon, and Duong make obvious the limitations of claim 1 as set forth above. Matsusaki, Gansau, Jeon, and Duong do not teach further gelling one of agarose or pectin in the gel composition of claim 2. However, Matsusaki teaches the 3D cellular tissues produced by the method include biological tissues such as cartilage (page 12, para. 0020). Gansau teaches articular-derived chondrocytes have been proposed for intervertebral disc repair, and have been investigated in several clinical trials for cartilage and disc repair with some success (page 2, para. 2). Gansau teaches chondrocytes have been shown to retain their rounded morphology in fibrin hydrogels, inhibiting dedifferentiation and promoting matrix production (page 2, para. 3). Gansau teaches incorporation of ECM constituents into fibrin gels such as collagen have been shown to enhance matrix deposition by chondrocytes (page 2, para. 4).
Regarding claim 15 and 16, Matsusaski teaches collagen (claim 15) at a concentration of 0.05 mg/mL (claim 16) in the mixture (page 27, 0045).
Regarding claim 17 and 18, Matsusaki teaches heparin (“glycosaminoglycan” of claim 17) at a concentration of 0.05 mg/mL (claim 18) in the mixture (page 27, 0045).
Regarding claim 19, Matsusaki teaches centrifuging the mixture to obtain a viscous mass (page 28, 0047).
Regarding “agarose” of claim 2, Scionti teaches a method of producing a fibrin-agarose gel by adding agarose to fibrinogen and gelling the mixture (page 2574, left col. para. 4). Scionti teaches the hydration content of the fibrin-agarose gel could be varied resulting in varying the porosity, fiber density, and thickness (page 2575, right col. last para.; page 2576 left col. para. 1 – 2; Figure 2; Table I). Scionti teaches agarose content and hydration grade have an important effect on the biomechanical properties of the hydrogels and these properties should be controlled during the ex vivo fabrication process of human tissues (page 2578, right col. para. 1). Scionti teaches fibrin-agarose gels can be safely used as scaffolds for the regeneration of tissues but the potential for precise applications will depend on the biomechanical properties of the native tissue to be replaced, which should be matched by those of the artificial hydrogels (page 2580, right col.). Scionti teaches the adjustability of the biomechanical properties makes fibrin-agarose gels potential candidates for a good number of applications in tissue engineering (page 2581, left col. para. 1 – 3; Figure 11 and 12). Scionti teaches the use of agarose content above 0.5% could possibly contribute to the generation of hydrogels appropriate for cartilage regeneration and there have been studies where fibrin and agarose scaffolds are used for cartilage regeneration (page 2581, left col. para. 3). Scionti teaches hydrogels can be used as scaffolds for tissue engineering but most hydrogels are much weaker than native tissues from a mechanical viewpoint which limits their practical use in tissue engineering (page 2573, left col. para. 1). Scionti teaches new methods and techniques should be developed to improve the mechanical properties of fibrin hydrogels (page 2573, right col.).
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 Matsusaki regarding a method for producing three-dimensional cell tissue comprising mixing cells, a cationic substance, an extracellular matrix component and a polyelectrolyte to obtain a 3D cell tissue for regenerative medicine with the teachings of Gansau regarding a method of producing a fibrin-extracellular matrix hydrogel with cells encapsulated for regenerative medicine with the teachings of Jeon regarding a method of forming bFGF-fibrin gel with various concentrations of fibrinogen and thrombin for bFGF release for regenerative medicine with the teachings of Duong regarding a method of controlling the stiffness of fibrin gels by varying the concentrations of fibrinogen and thrombin with the teachings of Scionti regarding a method of preparing fibrin-agarose gels for regenerative medicine to arrive at the claimed method wherein in the gel composition agarose is further gelled. One would have been motivated to combine the teachings of Matsusaki, Gansau, Jeon, Duong, and Scionti in a method of producing a 3D tissue customized for desired stiffness and growth factor release rate for regenerative medicine to repair cartilage as Matsusaki teaches the method is useful in the field of regenerative medicine and in pharmaceutical development and Gansau teaches hydrogels, such as fibrin, offer a promising delivery vehicle to introduce cells into intervertebral disc to regenerate damaged disc tissue as a potential treatment of low back pain and incorporation of ECM components can enhance the bioactivity of fibrin-based hydrogels, which may help advance the clinical potential of commercial cell and biomaterial ventures in the treatment of IVD regeneration and Jeon teaches bFGF has been known to stimulate the regeneration of tissues including cartilage and Duong teaches the unique feature of fibrin is that it can be modified to create microstructures of different porosities and stiffness to simulate an environment that is optimized for cell growth and survival and Duong teaches biomaterials are essential for the advancement of tissue engineering because they can function as delivery vehicles for bioactive substances or cells and Scionti teaches the adjustability of the biomechanical properties makes fibrin-agarose gels potential candidates for a good number of applications in tissue engineering and Scionti teaches new methods and techniques should be developed to improve the mechanical properties of fibrin hydrogels. One would have a reasonable expectation of success in combining the teachings as Matsusaki teaches the 3D cellular tissues produced by the method include biological tissues such as cartilage and Gansau teaches the cells proliferated in the gel with a fibrinogen concentration at or above 25 mg/mL and Gansau teaches chondrocytes have been shown to retain their rounded morphology in fibrin hydrogels, inhibiting dedifferentiation and promoting matrix production and Gansau teaches incorporation of ECM constituents into fibrin gels such as collagen have been shown to enhance matrix deposition by chondrocytes and Scionti teaches the use of agarose content above 0.5% could possibly contribute to the generation of hydrogels appropriate for cartilage regeneration and there have been studies where fibrin and agarose scaffolds are used for cartilage regeneration.
Applicant’s Arguments/ Response to Arguments
29. Applicant Argues: On page 10, last para. and page 11, Applicant asserts that the claimed invention provides an advantageous effect where the inclusion of fibrin gel achieves a thickness retention ratio of 80% or more and suppresses the decrease in tissue thickness over time compared to compositions without it. Applicant asserts that the claimed invention results in a calculated thickness retention ratio of three-dimensional cell tissues containing no fibrin gel is inferior to that when a fibrin gel is present. Applicant asserts the combination of Matsusaki and Kim would not have been obvious as the claimed invention provides advantageous effects that are not foreseeable from the cited references. On page 12, Applicant asserts that the claimed invention provides advantageous effects as compared to a composition not including a fibrin gel which cannot be foreseen based on the disclosures in the cited references. On page 12, Applicant asserts that the concentration ranges recited in claims 22 and 23 do not overlap with that in Kim and the claimed ranges provides advantageous effects that cannot be foreseen based on the disclosures.
Response to Argument: The previous anticipation and obviousness rejections of the claims using the teachings of Matsusaki and Kim have been withdrawn in view of Applicant’s amendment to claim 1. In the necessitated rejection set forth above, Matsusaki teaches a method for producing three-dimensional cell tissue comprising mixing cells, a cationic substance, an extracellular matrix component, and a polyelectrolyte and centrifuging the mixture to obtain a viscous mass and incubating the mixture to obtain a 3D cell tissue (page 26, 0043; page 27, 0045; page 28, 0046 – 0047; page 31, 0052 – 0053; page 32 – 33, 0055; page 34 – 35, 0059; page 36, 0061; page 43, 0076 – 0077; page 44, 0078 – 0079; page 45, 0080). Matsusaki does not teach adding thrombin and fibrinogen, “fibrin monomers are gelled”, or the concentrations of thrombin and fibrinogen of claim 1. However, Gansau teaches a method of preparing a three-dimensional fibrin-collagen- cell tissue comprising mixing cells, HEPES, collagen, thrombin (5 U/mL), and fibrinogen (final concentration of 50 mg/mL) to obtain a mixture and gelling the mixture (page 13, para. 1; Table 2; page 14, para. 2). Gansau teaches lower fibrin concentrations resulted in significant contraction of the hydrogel which was minimized for concentrations at or above 25 mg/mL (Figure 1a and b; page 9, last para.). Gansau teaches hydrogels, such as fibrin, offer a promising delivery vehicle to introduce cells into intervertebral disc (IVD) to regenerate damaged disc tissue as a potential treatment of low back pain but fibrin lacks extracellular matrix components (Abstract). Gansau teaches incorporation of ECM components can enhance the bioactivity of fibrin-based hydrogels, which may help advance the clinical potential of commercial cell and biomaterial ventures in the treatment of IVD regeneration (Abstract). Gansau teaches chondrocytes have been shown to retain their rounded morphology in fibrin hydrogels, inhibiting dedifferentiation and promoting matrix production (page 2, para. 3). Gansau teaches incorporation of ECM constituents into fibrin gels such as collagen have been shown to enhance matrix deposition by chondrocytes (page 2, para. 4). One would have been motivated to combine the teachings of Matsusaki and Gansau because both teach 3D cell constructs comprising collagen for regenerative medicine and Matsusaki teaches the tissue produced by the method includes cartilage and Gansau teaches incorporation of ECM components can enhance the bioactivity of fibrin-based hydrogels.
Regarding the concentration ranges of fibrinogen and thrombin, Duong teaches various fibrin matrix formulations derived from fibrinogen at 2 – 50 mg/mL and thrombin at 2 – 100 U/mL in Table 1. Duong teaches 1 IU of thrombin is defined as the activity contained in 0.0853 mg of human thrombin and 1 mL of thrombin solution was mixed with 1 mL of fibrinogen solution (page 1866, left col. last para.). Therefore, Duong teaches fibrin gels where the thrombin concentration in the mixture is 0.853 mg/mL (10 units/mL), 1.7 mg/mL (20 units/mL), 4.265 mg/mL (50 units/mL), and 8.53 mg/mL (100 units/mL) when the fibrinogen concentration is 2 – 17 mg/mL (Table 1). Duong teaches changing the fibrinogen and thrombin concentrations in the final 3D fibrin matrix influenced cell proliferation and differentiation (Abstract). Duong teaches the stiffness of the fibrin gel increased with increasing fibrinogen concentration or increasing thrombin concentration and at 2 mg/mL fibrinogen the stiffness varied with increasing thrombin concentration (page 1868, left col. para. 1 and 3 and right col.). Duong teaches changing the fibrinogen concentrations had a greater effect on the stiffness than changing the thrombin concentrations (page 1869, right col.). Duong teaches cell proliferation in the different fibrin gels varied over time and morphology changed with the different fibrin gels (page 1871, left col. and right col. para. 1). Duong teaches the unique feature of fibrin is that it can be modified to create microstructures of different porosities and stiffness to simulate an environment that is optimized for cell growth and survival (page 1874, left col. last para.). Duong teaches biomaterials are essential for the advancement of tissue engineering because they can function as delivery vehicles for bioactive substances or cells (page 1865, left col.). Duong teaches the preferred materials should have mechanical and biochemical properties that are biocompatible, bioabsorbable, and biodegradable; furthermore, the materials should easily be manipulated and easily reproducible (page 1865, left col. para. 1). Therefore, it would be obvious to adjust the concentrations of thrombin and fibrinogen to arrive at the claimed concentrations, since it is a result-effective variable dependent on the cell type and desired biomechanical properties of the gel.
Applicant Argues: On page 13, Applicant asserts that the claims of application 17/434,686 and 17/777,786 do not recite also mixing a cationic substance and a polyelectrolyte with cells and an extracellular matrix component.
Response to Argument: The claims of application 17/434,686 and 17/777,786 broadly recite “an aqueous medium” and does not exclude additional components; claims 15 and 16 of ‘786 recites polyelectrolyte. The rejections are maintained.
Applicant Argues: On page 13 and 14, Applicant asserts that the claims of application 18/043,507 recite a method of producing a three-dimensional tissue body comprising mixing cells, a cationic substance, an extracellular matrix component and a polyelectrolyte. However, the claims do not recite gelling the mixture and incubating the gel composition. Applicant asserts the claims of application 18/171,862 do not recite gelling the mixture and incubating the gel composition.
Response to Argument: The claims of application 18/043,507 broadly recite “a three-dimensional tissue body” and the claims of application 18/171,862 broadly recite “a three-dimensional cell structure” and therefore the recited extracellular matrix component would not be in a liquid form for a 3D tissue but in a gel form. The rejections are maintained.
Applicant Argues: On page 14 and 15, Applicant asserts that If a "provisional" nonstatutory double patenting rejection is the only rejection remaining in an application having the earliest effective U.S. filing date (PCT filing date of the present application is November 26, 2021) (including any benefit claimed under 35 USC 120, 121, 365(c), or 386(c)) compared to the reference application(s), the examiner should withdraw the rejection in the application having the earliest effective U.S. filing date and permit that application to issue as a patent.
Response to Argument: As the provisional nonstatutory double patenting rejection is not the only rejection remaining, the rejections over reference applications 18437415, 18774971, and 18774971 are maintained.
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
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
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