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 .
DETAILED ACTION
Applicant’s response filed 11/24/2025 has been received and entered into the application file. All arguments have been fully considered. Claims 14, 18, and 21-27 are currently pending. Claims 14 and 18 are currently amended. Claims 21-27 are new. Claims 1-13, 15-17, 19-20 are cancelled.
REJECTION(S) WITHDRAWN
Claim Rejections - 35 USC § 112
RE: Rejection of Claim 20 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite:
Applicant’s amendment submitted 11/24/2025 has cancelled claim 20, thus obviating the previous rejection of claim 20.
Claim Rejections - 35 USC § 102
RE: Rejection of Claim(s) 1-2, 5-6 and 8-11 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Takeuchi et al., (US 2017/0130184):
Applicant’s amendment submitted 11/24/2025 has cancelled claims 1-2, 5-6 and 8-11, thus obviating the previous rejection of claims 1-2, 5-6 and 8-11.
Claim Rejections - 35 USC § 103
RE: Rejection of Claim(s) 3, 7, 12, 14 and 20 under 35 U.S.C. 103 as being unpatentable over US ‘184;
Rejection of Claim(s) 4 under 35 U.S.C. 103 as being unpatentable over US ‘184, in view of Horvathy;
Rejection of Claim(s) 13 under 35 U.S.C. 103 as being unpatentable over US ‘184, in view of Leotot;
Rejection of Claim(s) 15 and 17-19 under 35 U.S.C. 103 as being unpatentable over US ‘184, and further in view of Robinson; and
Rejection of Claim(s) 16 is rejected under 35 U.S.C. 103 as being unpatentable over US ‘184, and further in view of Zeng:
The rejections have been withdrawn in view of Applicant’s amendment submitted 11/24/2025.
However, new grounds of rejection are set forth below in view of Applicant’s amendment.
NEW GROUND(S) OF REJECTION, NECESSITATED BY AMENDMENT
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 26 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 26 depends directly from claim 14 and recites the hydrogel is an alginate gel. However, claim 14 already recites gelating the alginate solution to form the hydrogel. Thus, claim 26 fails to further limit claim 14.
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.
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.
Claim(s) 14, 18, and 21-27 are rejected under 35 U.S.C. 103 as being unpatentable over Takeuchi et al., (US 2017/0130184, previously cited) (“US ‘184”), in view of Robinson et al., (Acta Biomaterialia 36 (2016) 86-98; previously cited) (“Robinson”).
Regarding claims 14 and 27, US ‘184 is directed to a hollow microfiber scaffold and methods of preparation wherein the microfiber scaffold comprises:
(1) one or more cell-adhesive layers having a cell-adhesive hydrogel, e.g., fibrin gel (i.e., fibrin polymer),
(2) an outer shell layer having a high-strength hydrogel, e.g., alginate gel, that covers the outer periphery of the cell-adhesive layer that is positioned farthest from the center axis among the one or more cell-adhesive layers, and
(3) a cell layer (adherent cells [0087], [0091]) that covers the inner periphery of the cell-adhesive layer that is positioned closest to the center axis among the one or more cell-adhesive layers, and wherein the outer diameter of the hydrogel ranges from 20 µm to 500 µm ([0010-]-[0017], [0083] and [0087]).
US ‘184, at paragraph [0115], teaches the use of the device shown in FIG. 5 for preparing the multilayered scaffold, wherein:
a cell suspension is injected from a line for introducing the cell suspension to form a laminar flow (which reads on flowing the suspension including an adherent cell);
a solution for preparing a cell-adhesive hydrogel (e.g., fibrin gel) is injected from a solution introducing line for preparing a cell-adhesive hydrogel to form a laminar flow of the solution for preparing a cell-adhesive hydrogel that covers the outer periphery of the laminar flow of the cell suspension (which reads on forming a fibrin polymer on an inner surface of a hydrogel);
solution for preparing a high-strength hydrogel, e.g., alginate gel, is injected from a solution introducing line for preparing a high-strength hydrogel to form a laminar flow of the solution for preparing the high-strength hydrogel that covers the outer periphery of the laminar flow of the solution for preparing the cell-adhesive hydrogel (which reads on flowing an alginate solution around a suspension including adherent cells);
the aggregation of the adherent cells, cell-adhesive hydrogel and high-strength hydrogel is passed through a region for gelling the solution for preparing the cell-adhesive hydrogel and the solution for preparing the high-strength hydrogel, and the solution for preparing the cell-adhesive hydrogel and the solution for preparing the high-strength hydrogel are respectively gelled. For example, gelling can be carried out by introducing the aggregate of the laminar flows formed into a gelling agent solution such as calcium ion solution, i.e., calcium chloride ([0124]) (which reads on gelating the alginate solution to form the hydrogel).
US ‘184, at paragraph [0115], further teaches that the encapsulated cells are then cultured (as recited in claim 27) in the resulting microfiber to form a cell layer that covers the inner periphery of the cell-adhesive layer. FIG. 6 shows a cross-sectional view of a microfiber obtained using the device of FIG. 5.
The only difference between US ‘184 and the instant claims is US ‘184 does not specifically teach the inclusion of human platelet lysate in the suspension including the adherent cells.
However, Robinson teaches of assessing a human platelet lysate hydrogel for promoting mesenchymal stem cell-directed neovascularization. Robinson teaches that platelet lysate (PL) hydrogel had similar properties to fibrin hydrogels, and was less susceptible to rapid degradation thus providing improved sustained release of PDGF-BB for up to 20 days. Robinson teaches the platelet lysate hydrogel stimulated pro-angiogenic activity by promoting MSC (mesenchymal stem cell) growth and teaches their experimental results support the use of platelet lysate hydrogel as a scaffold for MSC delivery to promote vascular regeneration (Abstract and page 91, left and right columns). Robinson teaches the addition of the platelet lysate component (50% by volume, claimed range overlaps the prior art range) resulted in an increase proliferative response in human MSCs, as compared to fibrin control alone (3.4 PL gel selectively promotes MSC proliferation, page 92; Fig. 4A). Robinson further teaches that, for cell therapy applications in a clinical setting, the platelet lysate (PL) hydrogel would serve as a scaffold for MSC delivery (2.1 Production of fibrinogen-rich platelet lysate hydrogels, page 87), 3.5 PL scaffold promotes invasion of both MSCs and ECs independently (page 92).
Therefore, given the intention of US ‘184 is providing a hydrogel scaffold for cultivation of mesenchymal stem cells and Robinson further teaches the inclusion of human platelet lysate improves the degradation properties of the cell-adhesive fibrin component, as well as further improving MSC growth, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further include platelet lysate in the hydrogel scaffold at a concentration of 50% by volume, in the cell-adhesive hydrogel layer.
The person of ordinary skill in the art would have been motivated to modify the cell-adhesive hydrogel layer of US ‘184 to include platelet lysate that promotes MSC cell growth and vascular regeneration, as taught by Robinson, for the predictable result of successfully promoting angiogenesis and MSC cell growth, thus meeting the limitation of claim 14.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of US ‘184 and Robinson because each of these teachings are directed at tissue engineering methods.
Further regarding claim 14 and the limitation the temperature is 37°C, it is noted that US ‘184 ([0115]) teaches producing the scaffold at a temperature of 37°C, thus meeting the limitation of claim 14.
Regarding claim 18, Robinson teaches the platelet lysate at a concentration of 50% (2.1 Production of fibrinogen-rich platelet lysate hydrogels, page 87). In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Regarding claim 21, US ‘184 at paragraph [0091] teaches mesenchymal stem cells, thus meeting the limitation of claim 21.
Regarding claims 22-23, US ‘184 teaches the aggregation of the adherent cells, cell-adhesive hydrogel and high-strength hydrogel is passed through a region for gelling the solution for preparing the cell-adhesive hydrogel and the solution for preparing the high-strength hydrogel, and the solution for preparing the cell-adhesive hydrogel and the solution for preparing the high-strength hydrogel are respectively gelled. For example, gelling can be carried out by introducing the aggregate of the laminar flows formed into a gelling agent solution such as calcium ion solution, i.e., calcium chloride ([0115] and [0124]), thus meeting the limitations of claims 22-23.
Regarding claim 24, US ‘184 teaches formation of a tubular structure ([0099]), thus meeting the limitation of claim 24.
Regarding claim 25, US ‘184 teaches an outer diameter ranging from wherein the outer diameter of the hydrogel ranges from 20 µm to 500 µm ([0083]). In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Regarding claim 26, US ‘184 teaches an alginate gel ([0016]), thus meeting the limitation of claim 26.
Response to Remarks
It is initially noted that the previous rejections of record have been withdrawn in view of Applicant’s amendment.
However, as to Applicant’s remarks that the platelet lysate hydrogel disclosed by Robinson is prepared by freeze-thaw cycles, as discussed at Applicant’s remarks (page 5), it is noted that Applicant’s remarks have been fully considered, but are not found persuasive since Robinson is not relied upon for teaching the flowing of the suspension that includes the adherent cells since the cited reference to US ‘184 addresses this limitation. Robinson is relied upon for teaching the obvious modification to include human platelet lysate as a component of the hydrogel scaffold since Robinson teaches the human platelet lysate improves the degradation properties of the cell-adhesive fibrin component, as well as further improving MSC growth.
In response to applicant's arguments against Robinson individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
As to Applicant’s remarks regarding unexpected results related to cell proliferation when the platelet lysate is present at concentrations of 10% or more, as discussed at Applicant’s remarks (pages 6-7), Applicant’s remarks have been fully considered, but are not found persuasive in view of Robinson’s teaching that the inclusion of platelet lysate at a concentration of 50% improves MSC cell proliferation, and is thus an expected result.
As to Applicant’s remarks that Takeuchi (US ‘184) teaches fibrin gel as one material among many options and only exemplifies collagen, as discussed at Applicant’s remarks, page 7, Applicant’s remarks have been carefully considered, but are not found persuasive since US ‘184 teaches a specific grouping of cell-adhesive hydrogel components being:
Chitosan gel, collagen gel, gelatin, peptide gel, laminin gel, fibrin gel and mixtures thereof.
The fact that US ‘184 explicitly recognized that several different cell-adhesive components could be used, in this particular application, does not make the selection of any given cell-adhesive nonobvious. The cell-adhesive components in US ‘184 are a finite number of identifiable cell-adhesive materials that are well known in the cell culture arts.
As noted in KSR International Co. v Teleflex, Inc., 82 USPQ2d 1385, 1397 (U.S. 2007), “When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.”
As to Applicant’s remarks that Takeuchi (US ‘184) prepares the hydrogel scaffold by flowing four layers of laminar streams, as discussed at Applicant’s remarks (pages 7-8), it is noted that Applicant’s remarks have been considered, but are not found persuasive since the claims as currently written employ the transitional phrase “comprising”. The transitional term “comprising”, which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004) (“[L]ike the term ‘comprising,’ the terms ‘containing’ and ‘mixture’ are open-ended.”). “The word ‘comprising’ transitioning from the preamble to the body signals that the entire claim is presumptively open-ended.” Id. MPEP 2111.03
The claims as currently written do not exclude flowing four layers of laminar streams. The claims as currently written do not require the adhesive cell is flown as a layer separate from the innermost cell suspension.
It is further noted that US ‘184 prepares a hydrogel scaffold wherein the suspension including the adherent cells and cell-adhesive component is further covered by the alginate gel component.
As to Applicant’s remarks regarding the simplification of the manufacturing apparatus, as discussed at Applicant’s remarks (page 8), it is noted the instant claims are not directed to an apparatus.
Conclusion
No claim is allowed. No claims is free of prior art.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
Response to fibrin gel argument at page 7:
In response, regarding the disclosed possible cell types, Applicant is alleging that once an art becomes crowded and well-characterized, it becomes unpredictable. The fact that Crumpler explicitly recognized that many different cell types could be used, in this particular application, does not make the selection of any given cell type nonobvious.
As to the limitation to dermal fibroblasts, as discussed below at Claim Interpretations, the limitation directed to the source of the fibroblasts is considered to be a product-by-process limitation (i.e., the process by which the fibroblasts were made, i.e. obtained from the dermis of the subject). There is no indication in the instant specification that the source of the fibroblasts provides any physical, structural or functional difference as compared to fibroblasts from other sources. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.