DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s response filed 7/14/2026 has been received and entered into the application file. All arguments have been fully considered. Claims 14, 18, 21-25 and 27-29 are currently pending. Claims 14, 21-22, 24-25 and 27 are currently amended. Claims 28-29 are new. Claims 1-13, 15-17, 19-20 and 26 are cancelled.
Claim Objections
Upon further consideration of claim 27, it is noted that claim 27 is objected to because of the following informalities: given that claim 27 is an independent claim, it is suggested the claim reads as follows:
“A culture method comprising culturing [[the]] adherent cells inside [[the]] an alginate gel outer shell by using the scaffold produced by the method according to claim 14.”
Appropriate correction is appreciated.
REJECTION(S) WITHDRAWN
Claim Rejections - 35 USC § 112
RE: Rejection of Claim 26 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 has been cancelled, thus obviating the previous rejection of record.
REJECTION(S) MAINTAINED/UPDATED
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, 21-25 and 27-29 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”).
The rejection has been updated in view of Applicant’s amendment and further review of US ‘184. It is noted that newly amended limitations are addressed in the updated rejection.
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 (FIG. 5, #1) for introducing the cell suspension to form a laminar flow (which reads on flowing the suspension including adherent cells);
a solution for preparing a cell-adhesive hydrogel (e.g., fibrin-containing gel material) 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 (FIG. 5, #3) and further adheres the fibrin polymer on the alginate gel upon gelating the alginate solution with the gelling agent (which reads on adhering the fibrin polymer on an inner surface of an alginate gel outer shell);
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 fibrin hydrogel (which reads on flowing a flow of an alginate solution around a suspension including a fibrin hydrogel and adherent cells);
the aggregation of the adherent cells, cell-adhesive fibrin hydrogel solution and high-strength alginate hydrogel solution 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 (FIG. 5, #7). 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 and adhering the adherend cells to the adhered fibrin polymer).
Thus, the produced scaffold comprises (a) the alginate gel outer shell; (b) the adhered fibrin polymer hydrogel on the inner surface of the alginate gel outer shell and (c) the adherend cells adhered to the fibrin polymer hydrogel.
US ‘184, at paragraph [0103], teaches an embodiment wherein the cell-adhesive fibrin hydrogel layer contains an additional cell population that is different from the cells that compose the cell layer provided by cell suspension (FIG. 5, #1). For example, when the cell layer comprises vascular endothelial cells, the cell-adhesive fibrin hydrogel contains vascular smooth muscle cells that would cover the outside of the cell layer.
Thus, US ‘184 teaches flowing a flow of an alginate solution around a suspension that includes a mixture of adherent cells and a fibrin-containing material or a fibrin polymer, adhering the fibrin polymer on the inner surface of the alginate gel outer shell formed by gelating the alginate solution wherein the adherent cells adhere to the adhered fibrin polymer hydrogel.
US ‘184, at paragraph [0115], further teaches that the encapsulated cells are then cultured (as recited in claim 27) in the resulting microfiber scaffold. 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 cell-adhesive fibrin polymer hydrogel, comprising the second cell adherent population, further includes human platelet lysate.
However, Robinson teaches of assessing a human platelet lysate hydrogel for promoting endothelial cell and mesenchymal stem cell-directed neovascularization. Robinson teaches that platelet lysate is rich in a variety of endogenous growth factors, e.g., PDGF-BB, and has desirable mechanical properties that are beneficial for cell delivery. Robinson teaches that platelet lysate (PL) hydrogel had improved degradation properties as compared to fibrin-only hydrogels, thus providing improved sustained release of PDGF-BB for up to 20 days. Robinson teaches the platelet lysate hydrogel stimulated pro-angiogenic activity and promotes vascular regeneration (Abstract; page 87, left col, second and third full paragraphs; 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 platelet lysate improves endothelial cell sprout length, as compared to the fibrin-only gel, that platelet lysate hydrogel retains the nutritive properties of soluble platelet lysate, platelet lysate is a superior nutrient as compared to bovine serum supplementation, platelet lysate can be cross-matched to reduce risk of immunogenicity, platelet lysate avoids use of xenogeneic supplements (3.5 PL scaffold promotes invasion of both MSCs and ECs independently, page 92; 4. Discussion, left col, page 94).
Additionally, Robinson indicates that a number of biologic materials have been developed to promote cell delivery, including encapsulation with alginate or embedding cells in a hydrogel, however these materials lack the nutritive benefit that is intrinsic to the inclusion of platelet lysate and platelet lysate gel has improved mechanical properties as compared to fibrin-only hydrogels, and platelet lysate gel has improved growth factor release properties that is superior to fibrin-only hydrogels (page 94, right col, second and third paragraphs; page 96, left col, second paragraph).
Therefore, given the intention of US ‘184 is providing a hydrogel scaffold for cultivation of mesenchymal stem cells and/or vascular endothelial cells ([0018], [0072], [0091]), and the cell-adhesive fibrin hydrogel can further include additional cell populations, and Robinson further teaches the inclusion of human platelet lysate promotes cell delivery, improves the release of endogenous growth factors and provides improved mechanical properties, as compared to fibrin-only hydrogels, that platelet lysate hydrogel promotes vascular regeneration, that platelet lysate is a superior nutrient as compared to bovine serum supplementation, platelet lysate has reduced risk of immunogenicity, and platelet lysate avoids xenogeneic contamination, 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 cell-containing fibrin hydrogel at a concentration of 50% by volume.
The person of ordinary skill in the art would have been motivated to modify the cell-containing fibrin hydrogel layer of US ‘184 to include platelet lysate since doing so provides the predictable result of promoting MSC and endothelial cell growth, promoting vascular regeneration, reducing immunogenicity and xenogeneic contamination, providing improved mechanical properties, as compared to fibrin-only gel, providing improved release of endogenous growth factors, as compared to fibrin-only gel, thus providing increased nutrients to the encapsulated cells, as taught by Robinson, thus meeting the limitation of claim 14.
It is noted that the combination of multiple products (cell delivery hydrogel materials) each known to have the same effect to produce a final product having the same effect is prima facie obvious. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). The combined effect of multiple cell delivery hydrogel materials, i.e., fibrin and platelet lysate, would have been expected to be greater than the effect of any one individually, as the effects would have been expected to be additive. The reason to combine the cell delivery hydrogel materials is to produce a product with improved mechanical properties. See KSR International Co v Teleflex 82 USPQ2d 1385 (US 2007) at page 1397.
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 28, FIG. 6 of US ‘184 teaches the alginate gel outer shell is formed in a spherical shape, thus meeting the limitation of claim 28.
Regarding claim 29, US ‘184 teaches a microfiber scaffold having a continuous luminal structure having a constant length (i.e., string shape) ranging from 1 mm to 100 cm ([0008], [0073] and [0086]) and FIG. 1 of US ‘184 shows the appearance of the produced microfiber having a string shape. Thus, it is considered that the alginate outer shell of the microfiber scaffold is formed in a string shape, which meets the limitation of claim 29.
Response to Remarks
Applicant has traversed the rejection on the grounds that Takeuchi (US ‘184) does not teach or suggest anything about the human platelet lysate recited in claim 14, and Robinson’s teaching would not have motivated one of ordinary skill in the art to arrive at flowing the suspension including a mixture of a human platelet lysate and adherent cells, as amended claim 14 currently recites, as discussed at Applicant’s remarks (pages 7-8).
In response to applicant's arguments against Takeuchi and 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 set forth above, the updated rejection notes that Takeuchi (FIG. 5 and [0103]) teaches an embodiment of the method for producing a scaffold wherein alginate solution is flowed around a suspension of a second population of adherent cells and a cell-adhesive hydrogel solution, i.e., fibrin polymer. The fibrin polymer material is adhered on an inner surface of the alginate gel outer shell formed by gelating the alginate solution with a calcium chloride solution. Takeuchi further teaches the first cell population (FIG. 5, #1) is adhered to the fibrin polymer layer.
The only difference between Takeuchi and the instant claims is Takeuchi does not specifically teach the cell-adhesive fibrin polymer hydrogel, which comprises the second population of adherent cells, further includes human platelet lysate. However, Robinson further teaches that human platelet lysate gels comprising adherent cells are excellent cell delivery scaffolds due to their mechanical properties and since the inclusion of human platelet lysate not only promotes cell delivery, but further provides additional cell nutrients that are not present in fibrin-only or alginate-only scaffolds, and the human platelet lysate can replace bovine serum supplementation thus removing xenogeneic contamination and reduce immunogenicity to the scaffold recipient. Robinson teaches platelet lysate improves the sustained-release of endogenous growth factors, as compared to fibrin-only hydrogels, and platelet lysate hydrogel promotes vascular regeneration. Thus, 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 cell-containing fibrin hydrogel since the combination of multiple products (cell delivery hydrogel materials) each known to have the same effect to produce a final product having the same effect is prima facie obvious. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). The combined effect of multiple cell delivery hydrogel materials, i.e., fibrin and platelet lysate, would have been expected to be greater than the effect of any one individually, as the effects would have been expected to be additive. The reason to combine the cell delivery hydrogel materials is to produce a product with improved mechanical properties. See KSR International Co v Teleflex 82 USPQ2d 1385 (US 2007) at page 1397.
As to Applicant’s remarks regarding newly amended limitations of claim 14, these limitations are addressed above in the updated rejection.
Conclusion
No claim is allowed. No claim is free of prior art.
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
Prosecution Insights