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 .
Status of claims
Claims 1-2, 4-5, 7, 9-10, and 13-14 are pending and under exam. Claims 3, 6, 8, 11-12, and 15 are cancelled.
WITHDRAWN REJECTIONS
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 7 was rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth the subject matter which the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the applicant regards as the invention.
Claim 7 was rejected for not specifying the shape, or composition of shell part and dissolving the shell part. Additionally, it was not clear how the shell is dissolved and in what time frame.
Applicants amended the claims to recite that an elongated core part containing the second cells and a shell part that surrounds a periphery of the core part and includes hydrogel. Further applicants amended the claim to recite “a dissolving step in which the shell part is dissolved by adding a dissolving agent including enzyme, chelating reagent, or acid that dissolves the hydrogel”. Applicant’s amendments overcomes the outstanding rejection
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 9-10, and 13-14 were rejected under 35 U.S.C. 101 because they were directed to a law of nature judicial exception.
Applicants amended the claims to indicate that the first tissues are muscle tissues containing muscle fibers along the first direction, and the second tissues are adipose tissues, and wherein the second structure includes adipose tissues or adipose tissue mass having an elongated shape aligned in the first direction. Zhang et al taught that “[i]ntermuscular adipose tissue (IMAT) is a unique adipose depot interspersed between muscle fibers (myofibers) or muscle groups.” (See Zhang Abstract). Further Bertaso taught that “[e]picardial fat is the adipose tissue accumulated between the visceral pericardium and the myocardium, without a structure or fascia separating it from the myocardium and the epicardial vessels.” (See Bertaso, p. e18, col. 2, para 2). As such the claims do not read on naturally occurring compositions.
Claim Rejections - 35 USC § 103
Claims 1-2, and 5, were rejected under 35 U.S.C. 103 as being unpatentable over Kim et al (Biofabrication. 2017 Mar 23; hereinafter "Kim"; See PTO-892 of 8/25/2025) in view of Selimović et al (Polymers (Basel). 2012 Sep; hereinafter " Selimović;" See PTO-892).
Claims 9-10, and 13-14 were rejected under 35 U.S.C. 103 as being unpatentable over Kim et al (Biofabrication. 2017 Mar 23; hereinafter "Kim"; See PTO-892 of 8/25/2025) in view of Selimović et al (Polymers (Basel). 2012 Sep; hereinafter " Selimović;" See PTO-892) further in view of Sakaguchi et al (WO2012/036225; Published Mar 22, 2013; and related U.S. Patent published Apr 11, 2017; Hereinafter "Sakaguchi" See IDS filed 06/17/2022).
The rejections are withdrawn in view of the claim amendments and arguments. Particularly, Applicants’ claim amendments pointing out “a gelation step in which a liquid containing the first cells is gelled on the substrate to form the first structure that holds the second structure at least partially embedded inside.” Applicants further indicated that “the second cells being preadipocytes or adipocytes, wherein the second structure includes a cell mass of the second cells, the cell mass having an elongated shape.” New rejections for certain claims are set forth below.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENTS
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.
Claims 1-2, 5, 9-10 and 13-14, are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al (Biofabrication. 2017 Mar 23; hereinafter "Kim"; See PTO-892 of 8/25/2025) in view of Selimović et al (Polymers (Basel). 2012 Sep; hereinafter " Selimović;" See PTO-892) further in view of Sakaguchi et al (WO2012/036225; Published Mar 22, 2013; and related U.S. Patent published Apr 11, 2017; Hereinafter "Sakaguchi" See IDS filed 06/17/2022).
Regarding claims 1-2, and 5: Kim disclosed a method for assembling 3D tissue by layer-by-layer stacking of cell sheets formed on aligned nanofiber mesh. Kim also disclosed that human umbilical vein endothelial cells (HUVECs), human foreskin dermal fibroblasts, and skeletal muscle cells (C2C12) were cultured on the nanofiber mesh, and they formed confluent monolayers and could be handled as continuous cell sheets. (See Kim Abstract). As such Kim disclosed a method to form 3D tissue by stacking multiple layers of cell sheets and culturing the sheet of cells as required by the claim. It is noted that Kim taught that the preparation step includes a positioning step in which the second structure is positioned on a substrate to have an elongation direction along a first direction. However, Kim did not teach a gelation step in which a liquid containing the first cells is gelled on the substrate to form the first structure that holds the second structure.
As an initial matter, it is pointed out that Kim disclosed that frames containing cell sheet on nanofiber mesh “were simply placed on the larger frames that contained different type of cell sheets. Small amount of matrigel (final thickness ∼15 mm) was dispersed between the cell sheets to form conformal contact and act as a glue as well as provide extra ECM for the cells.” (See Kim p. 2, col.2, 2nd para). As such it is pointed out that Kim recognized that hydrogels can be used between cell sheets to hold layers together and provide ECM support. It is also pointed out that Kim explicitly taught that hydrogel ECMs are advantageous to mimic the EC matric “To mimic a microvascular system in vitro, vasculogenesis of self-assembled endothelial cells imbedded in natural hydrogel ECM matrix (collagen, gelatin, matrigel, or fibrin) is considered as reliable technique” (See Kim p. 6, col. 1, last para).
Selimović taught crosslinking methods of hydrogels for generation of cell containing gel particles. (See Selimović Abstract). Selimović taught that “Cells can be encapsulated in the resulting gel structures simply by suspending them in the gel prepolymer solution. For example, using this method NIH-3T3 fibroblasts were encapsulated in a hydrogel based on methacrylated hyaluronic acid (See Selimović p. 4, last para).
As such it is pointed out that Kim taught that hydrogels are useful for holding layers of cell sheets and supporting cells. Forming cell-laden hydrogels by gelation of a liquid precursor and placing hydrogel on a substrate or mold before crosslinking are known methods in the art by the disclosure of Selimović. A skilled artisan would have found it obvious to replace the cell sheet formation method of Kim with more complete gelation step of Selimović as required by the claim. This would have resulted in a robust first structure for holding a second structure, ready for stacking and culturing.
It is also pointed out that Sakaguchi taught a method for manufacturing a multilayered cell sheet by fabricating a vascular bed that constructs a vascular network extending to the surface from a channel for perfusing a medium, the channel being embedded in a gel; and layering a cell sheet onto the vascular bed to construct a vascular network in the cell sheet. As such one of ordinary skill in the art would have found it obvious to layer two different layers of cells such as those taught in Kim in the 3D model taught by Sakaguchi. It is noted that Sakaguchi taught that two or more types of cells can be used and the type is not limited. As such a person of ordinary skill in the art would have substituted the first cells in the first structure as muscle cells and the second cells in the second structure to be adipocytes as required by the claim. The person would have recognized this as simple substitution of cell types taught by Kim.
Regarding claim 2: Kim disclosed culture of stacked cells (See Kim, p. 8, col.2, last para, Figure 5b).
Regarding claim 5: Kim disclosed that “Detachable cell sheets were formed, manipulated, and stacked after 3–4 days of monolayer culture using myoblasts(C2C12), human umbilical vein endothelial cells(HUVECs), and fibroblasts(HS68).” As such Kim disclosed culturing cells in a second structure (such as nanofiber) before stacking.
Regarding claims 9-10: As disclosed above, Kim disclosed an artificially produced 3D tissue composite comprising multiple number of sheet-shaped first structures containing first tissues and second structure containing second tissues, wherein the multiple number of first structures are stacked. Kim also disclosed that the second structure has an elongated shape. It is noted that Kim taught that the nanofiber meshes are on a rectangular-shape handling plexiglass frames (See Kim Sec 2.2, first para). Kim taught that the second structures can be aligned parallelly or perpendicularly relative to the first structures. Additionally, as indicated above, the first and the second structures can be chosen from myoblasts or muscle fibers and adipose tissues, as taught by Sakaguchi. As such one of ordinary skill in the art would have been motivated to use adipose cells (which are a type of adipose derived cells) and myoblasts to arrive at the claimed invention. It is further submitted that as evidenced by Figure 5 of Kim, it is disclosed that the cell layers are in contact with each other, as required by claim 10.
Regarding claim 13-14: Kim disclosed using “highly porous, electrospun PCL nanofibers” “using rigid frames and used to culture cells.” (See Kim p. 9, col. 1, para 2). The pores read on the gaps in the frame as claimed in claim 13. Additionally, Kim taught “Two layers of cell sheet were stacked in parallel (figure 5(a)) and three layers of cell sheet were assembled in perpendicular manner (figure 5(b)) to verify three dimensional nano-topographic influences among the layers, inspired by a former research to describe the orthogonally aligned cellular stimulus among cell sheet layers” (See Kim p. 8, col 1 end to col. 2, first para). This reads on the requirements of claim 14, that the opening of one of two adjacent first structures is at a position different from that of the opening of the other of the two adjacent first structures in a second direction orthogonal to the first direction and a stacking direction of the first structure.
Response to Claim Amendments and Arguments
Applicants have amended the claims to recite that the first cells are myoblasts and second cells are preadipocytes or adipocytes. Applicants further amended the claims to recite that the second structure is at least partially embedded in the first structure. Applicants also amended the claims to recite that the second structure includes a cell mass of the second cells, the cell mass having an elongated shape. Applicants argued that “combination [of the cited prior art] does not disclose at least that the second structure includes a cell mass of the second cells, having an elongated shape, wherein the second cells are preadipocyte or adipocyte, and that the second structure is positioned on a substrate such that an elongation direction of the cell mass is along a first direction, according to Claims 1 and 9, as amended.” Applicants claim amendments and arguments have been carefully considered, but are not persuasive.
It is noted that Kim taught stacking multiple layers of detached cell sheet, by nesting “different sizes of rigid frames by assembling cell sheets with smaller laser-cut rigid frames to larger ones, inspired by assembling the Russian Matryoshka nesting dolls” (See Kim p. 3, col. 2, first para). It is noted that the nesting as taught by Kim reads on the claimed embedding of the second structure within the first structure. Further, Figure 1 demonstrated that the nanofiber mesh is rectangular or square in shape. This reads on the elongated shape as required by the claim. As such the claims are still obvious over the cited art.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Kim et al (Biofabrication. 2017 Mar 23; hereinafter "Kim"; See PTO-892 of 8/25/2025) in view of Selimović et al (Polymers (Basel). 2012 Sep; hereinafter " Selimović;" See PTO-892), and further in view of Hong et al (Tissue Eng Regen Med. 2017 Jul 3; hereinafter "Hong;" See PTO-892) and Sakaguchi et al (WO2012/036225; Published Mar 22, 2013; and related U.S. Patent published Apr 11, 2017; Hereinafter "Sakaguchi" See IDS filed 06/17/2022).
Regarding claim 4: The teachings of Kim, in view of Selimović and Sakaguchi, are disclosed above. Kim did not teach a 3D tissue composite wherein the first structures are stacked such that both end portions of the first structures are fixed with anchors. Instead, Kim used a nesting structure of the frames to guide alignment. (See Kim Abstract). However, one of ordinary skill in the art would have readily come up with a means to anchor the first structure as claimed in order to aid stacking. For example, Hong taught use of guide rods for on the stacking rig to layer tissue sheets. (See Hong p. 274, col. 2, para 2). It would have been easily conceivable for a person or ordinary skill in the art to use an anchor for fixing the first structure as taught by Hong. The person would have reasonable expectation of success especially as Hong taught that “even without training, less than 2 min were required for manual stacking of 11 layers of the tissue sheets.” (See Hong p. 274, col. 2, para 2).
Claim Objections
Claim 7 appears free of art and may be allowable if written in independent form.
Conclusion
Claim 7 appears free of art.
No claim is 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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/JAGAMYA NMN VIJAYARAGHAVAN/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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