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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Status of claims
Claims 1-2, 4-5, 7-10, and 13-14 are pending and under exam. Claims 3, 6, 11-12, and 15 are cancelled.
WITHDRAWN REJECTIONS
Claim Rejections - 35 USC § 112
Claim 11 required the second structure to have a fiber shape which was unclear. The rejection has been rendered moot pursuant to cancellation of the claim.
Claim Rejections - 35 USC § 102
Claims 1-3, 5, and 13-14 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim et al (Biofabrication. 2017 Mar 23; hereinafter "Kim"; See PTO-892).
The rejection is withdrawn following Applicant amendments to indicate that the preparation step includes a positioning step in which the second structure is positioned on a substrate to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, and 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. It is submitted that Kim did not teach the recited methods.
Claim Rejections - 35 USC § 103
Claim 4 was rejected under 35 U.S.C. 103 as being unpatentable over Kim et al (Biofabrication. 2017 Mar 23; hereinafter "Kim"; See PTO-892) in view of Hong et al (Tissue Eng Regen Med. 2017 Jul 3; hereinafter "Hong;" See PTO-892).
Claims 6, 8, 11, and 15 were rejected under 35 U.S.C. 103 as being unpatentable over Kim et al (Biofabrication. 2017 Mar 23; hereinafter "Kim"; See PTO-892) 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The rejection is withdrawn following Applicant amendments to indicate that the preparation step includes a positioning step in which the second structure is positioned on a substrate to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, and 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. New rejections are set forth below.
MAINTAINED REJECTION
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 is 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 the shell is gel-like and the shell is dissolved by using a dissolving agent. It is pointed out that the specification neither defines “gel-like” nor points the properties or examples or any other guidance of deriving what the gel-like shell encompasses. As such the metes and bounds of this claim are still unclear. Pursuant to the indefiniteness about the composition of shell, the metes and bounds of the dissolving agent is also unclear.
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 are rejected under 35 U.S.C. 101 because they were directed to a law of nature judicial exception.
Regarding claims 9-10: The claims are directed to two structures – first and second, where, the first structure contains first tissue and second structure comprises second tissues wherein the structures are stacked. It is noted that the first and second structures are muscle and adipose tissues.
The claim is directed to a composition of matter, which is a statutory category of invention
(Step 1: YES).
The claim is then analyzed to determine whether it is directed to any judicial exception. The claim is directed to a structure containing a first tissue and second structure containing second tissue. The claimed structure encompasses many naturally occurring structures such as the endocardium or myocardium. It is known that the pericardium comprises three layers of muscle tissue and an epicardial adipose tissue. (see for example Krishnan et al, FIG. 1 (See PTO-892 of 08/25/2025)). Further Rienks et al taught that “The cardiac extracellular matrix (ECM) is a complex architectural network consisting of structural and nonstructural proteins, creating strength and plasticity.” (See Rienks et al Abstract). The cardiac extracellular matrix reads on the claimed molded matrix. The myocardium and endocardium comprise layered muscle tissue with aligned fibers and the cardiac extracellular matrix. This reads on the claimed 3D tissue composite, comprising: a multiple number of sheet-shaped first structures containing first tissues and comprising a molded matrix component. The epicardial adipose tissue reads on the second structure containing second tissues, wherein the multiple number of first structures are stacked; wherein the second structure has an elongated shape that is controlled to be positioned to extend along a first direction in the one of the multiple number of first structures. It is submitted that the claim describes a naturally occurring product. Thus, the claim recites at least one exception, which may be termed a product of nature. (Step 2A prong 1: YES). Krishnan clearly shows multiple layers of muscle fibers and fat in direct contact with each other as required by claim 10.
The claim is then analyzed to determine if additional elements integrates the
judicial exception into a practical application. The claim recites no additional elements
and is limited to the structures comprising two different kinds of tissues. (Step 2A prong 2: NO). Therefore, the claim is directed to a law of nature judicial exception.
The claim is patent ineligible.
Regarding claim 13-14: It is known that muscles are fibrous in nature and therefore have number of pores. For example Borg et al taught that “[t]he cardiac interstitium represents a system of diverse extracellular matrix (ECM) components organized into a complex, three-dimensional network that surrounds the cellular components of the heart” (See Borg et al Abstract). Given the orientation of various structures of the heart, it is conceivable that some pores are orthogonal to the muscle pores as required by claims 13 and 14. Similar analysis as claims 9-10 stands.
The claims are patent ineligible.
Response to Claim Amendments and Arguments: Applicants have amended the claims to indicate an artificially produced 3D tissue. Applicants indicated that the terms "artificially produced 3D tissue" clarify that the embodiments of the invention according do not encompass a product of nature. Applicants’ amendments and arguments have been considered but are not found persuasive.
It is submitted that the claimed composition is not sufficiently different from naturally existing counterpart under Myriad. As explained above and evidenced by Krishnan et al and Rienks et al, the natural cardiac tissue – including myocardium, endocardium and epicardial adipose tissue exhibits the same layered muscle fibers, the extracellular matrix and elongated adipose tissue as required by the claim. The ECM forms a 3D scaffold forming the interstitial spaces (pores) along the fiber direction, corresponding to the “molded matrix” and “openings” As such the claim reads on naturally occurring entities and therefore is directed to a product of nature.
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, and 7 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).
Regarding claims 1-2, 5 and 7: 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 recognize 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.
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 claim 7: The teachings of Kim in view of Selimović are disclosed above. Selimović taught that “to degrade hydrogels, the hydrophilic backbone of the polymer chains can be broken down as a result of hydrolysis or enzyme activity.” (See Selimović p. 3 last para).
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).
Regarding claim 4: The teachings of Kim in view of Selimović 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 Hon 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).
Claims 8 -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 claim 8: The teachings of Kim in view of Selimović are set forth above. Sakaguchi taught “When a vascular bed having a channel for perfusing a medium, etc., into the gel is fabricated, the gel may be mixed with the cells before fabrication.” (See Sakaguchi (US9617519B2), col. 4, lines 60-65). Sakaguchi further taught that “For example, when the object is the regeneration of the myocardial tissue or a method for evaluating the myocardial function, cells used include one type or combinations of two types or more of myocardial cells, cardiac myoblasts, myoblasts, mesenchymal stem cells, vascular endothelial, cells, vascular endothelial progenitor cells, fibroblasts, bone marrow-derived cells, and adipose-derived cells, and their types are not limited in any way.” (See Sakaguchi (US9617519B2), col. 5, lines 1-15). 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. The person would have had reasonable expectation of success in view of results of Sakaguchi, for example FIG. 10, showing outline of vascular network construction induced during the fabrication of a multilayered cell sheet using a vascular bed.
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.
Conclusion
No claim is free of art.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
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/JAGAMYA NMN VIJAYARAGHAVAN/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633