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 .
Status of the Application
Applicant’s remarks and amendment submitted on 10/14/2025 are acknowledged.
Claims 1 and 3-21 are pending.
Claim 1 is amended.
Claim 2 is canceled.
Claims 10-21 are withdrawn as indicated below.
Claims 1 and 3-9 have been examined on the merits.
Applicant’s election of Group I, claims 1 and 3-9, drawn to a multicellular construct, in the response filed on 10/14/2025, is acknowledged.
Claims 10-21 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention. Claims 1 and 3-9 are under consideration and are being examined herein to the extent they are directed to the elected invention.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
Specification
The abstract of the specification is objected to as it contains more than 150 words. Applicant is reminded of the proper language and format for an abstract of the disclosure. The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words. It is important that the abstract not exceed 150 words in length since the space provided for the abstract on the computer tape used by the printer is limited. Appropriate correction is required.
Priority
This application, U.S. Application number 17/778269, is a national stage entry of International Application Number PCT/JP2020/042861 filed on 11/17/2020, which claims foreign priority under 35 U.S.C. 119(a)-(d) to JP 2019-210649 filed on 11/21/2019 and JP 2020-150816 filed on 09/08/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/19/2022, 03/11/2024, and 08/08/2024 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Drawings
The drawings submitted on 05/19/2022 have been reviewed and are accepted by the Examiner for examination purposes.
Claim Objections
Claim 5 is objected to due to the recitation of “wherein a ratio Tf/Tn of a thickness … is 7.5x10-3 or less”. To be consistent with standard claim language, it is suggested to change the recited phrase to “wherein the gelatin film has a thickness Tf and the gelatin nonwoven has a thickness Tn, and a ratio Tf/Tn is 7.5x10-3 or less”. Appropriate correction is required.
Claim Rejections - 35 USC § 103
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 of this title, 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.
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 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.
Claims 1, 4-5, and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Steinberg et al. (US 2014/0112973, 2014, cited in IDS).
Steinberg et al. teach a biocompatible/biodegradable gradient layer system (i.e. a scaffold) constituted by a layered composite comprising: at least one layer of fibers of biocompatible/biodegradable cross-linked polymer as well as at least one biocompatible//biodegradable support layer (layered on the surface of the fiber layer), wherein the fibers of biocompatible cross-linked polymer may be gelatin fibers (i.e. gelatin nonwoven containing gelatin as a main component); wherein the biocompatible support layer may comprise gelatin as a major component, of which a suitable form is film, sheet, foil or laminate; wherein the scaffold (biocompatible/biodegradable gradient layer system) is seeded with cells, thus forming a multicellular construct (Claims 1, 5, 6, 9, and 10; Examples 1 and 3, Fig. 2, paras 0028, 0043-44, 0059 and 0065); and wherein the multicellular construct is applied for medical purposes, such as engineering tissue and organs, preparing tissue scaffold, and dressing wound, as well as for testing the effect of substances on the cells or the multicellular construct (para 0098, claims 14-16). Steinberg et al. further teach the scaffold (biocompatible gradient layer system) is paced in a culture medium for culturing cells, being in a swelling form (page 21, para 00131, Fig. 2), and further teach that the fiber diameter is in the range from 1 nm to 500 mm (page 27, Claim 1). It is noted that the fibers’ diameter range taught by Steinberg et al. encompasses the claimed average diameter range of 10 - 400 mm recited in the instant claim 1, and it is applicable to a swelling form of gelatin fibers in gelatin nonwoven of Steinberg et al. Furthermore, the diameter is readily mortified and adjusted for optimizing functional properties of the multicellular construct for medical application. Thus, the claimed average diameter range recited in the claim would have been obvious over the teachings of Steinberg et al.
Regarding the limitation about the gelatin fibers are welded to one another and the gelatin film is welded to some gelatin fibers recited in the claim 1, Steinberg et al. teach the gelatin fibers (as fibers of biocompatible cross-linked polymer) are crosslinked to each other (as indicated above) and the crosslinking is through covalent bonding or non-covalent bonding such as hydrogen bond and electrostatic interaction (page 6/para 0033, last 4 lines). Given the term “welded” is not defined in the claim or the specification, the crosslinked gelatin fibers of Steinberg et al. meet the requirement that gelatin fibers are welded to one another in the claim 1. Steinberg et al. are silent about whether the support layer (gelatin film) is welded to some of the gelatin fibers in the gelatin nonwoven. However, Steinberg et al. teach that the biocompatible/biodegradable support layer (gelatin film) preferably acts as a binder and/or as a structural support to fibers of biodegradable cross-linked polymer (gelatin fibers) to a create mechanically stable material/scaffold (para 0054, lines 4-7 from bottom). In view of the teachings of Steinberg et al., it would have been obvious to apply the gelatin film of Steinberg et al. as a binder to weld/bind some of the gelatin fibers in the gelatin nonwoven of Steinberg et al. for mechanically stabilizing gelatin fibers, thus creating a mechanically stable scaffold.
Regarding the limitations about the cells are present on the surface of and/or inside the gelatin nonwoven recited in the claims 1 and 7, Steinberg et al. teach that the cells are added to the scaffold (biocompatible and preferably biodegradable gradient layer system) prior to cross-linking (page 13: para 0083/lines 2-5 from bottom), which would allow the cells to enter the gelatin nonwoven in addition to being present on the surface of the gelatin nonwoven. Furthermore, Fig. 2 shows that the cells are present on the surface of and in the scaffold. Thus, the teachings of Steinberg et al. renders the claimed limitations to be obvious.
Regarding the claim 4, Steinberg et al. teach that the biocompatible support layer is in a suitable form of film, sheet, foil or laminate, and may comprise gelatin as a main component, which renders the claimed limitation gelatin film to be obvious, as indicated above. Steinberg et al. further teach the support layer may have a thickness of about 100 nm to about 5 mm, or preferably about 1 mm to about 250 mm (para 0059, lines 2 and 5-9 from bottom), which encompass the claimed thickness range of 0.80 mm -3.2 mm, thus rendering the claimed range to be obvious, in the absence of evidence of criticality. See MPEP 2144.05.
Regarding the claim 5, Steinberg et al. do not teach a ratio of a thickness of the gelatin film vs. a thickness of the gelatin nonwoven is 7.5x10-3 or less. However, Steinberg et al. teach the thickness of the support layer (gelatin film) can be in a range of about 1 mm to about 250 mm, as indicated above; and the thickness of the fiber layer (gelatin nonwoven) can be in a range of about 1 nm – about 5 mm or preferably a range of about 1 mm to about 1 mm (para 0043, lines 7-14). Adjusting a thickness of the gelatin film and a thickness of the gelatin nonwoven in the ranges taught by Steinberg et al. would have arrived at the claimed ratio of 7.5x10-3 or less. For example, if the gelatin film has a thickness of 1 mm (from the range of about 1 mm to about 250 mm) and the gelatin nonwoven has a thickness of 1 mm (from the range of about 1 nm – about 5 mm), a ratio of the gelatin film thickness vs. the gelatin nonwoven thickness is 1x10-3, which reads on the claimed ratio range “7.5x10-3 or less”. The claimed ratio range would have been obvious over the teachings of Steinberg et al., in the absence of evidence of criticality.
Regarding the claim 8, Steinberg et al. teach that the cells comprised in the multicellular construct include: stem cells, cardiomyocytes, hepatocytes, endothelial cells, and/or fibroblasts, and they are derived/isolated from a tissue, such as primary dermal fibroblasts (isolated from skin tissue) (para 0083: 2nd half of para 1 on page 13; para 0131/line 8; Claim 11).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Steinberg et al. (US 2014/0112973, 2014, cited in IDS), as applied to Claims 1, 4-5, and 7-8, further in view of Morinaga et al. (US 2006/0029639, 2006, cited in IDS).
The teachings of Steinberg et al. are described above.
Regarding the claim 6, Steinberg et al. teach crosslinking the gelatin nonwoven of gelatin fibers (fibers of biocompatible/biodegradable cross-linked polymer), as indicated above. Regarding the support layer (the gelatin film), it would have been obvious to crosslink the support layer (the gelatin film) of Steinberg et al. because Steinberg et al. teach the crosslinking improves mechanical strength of the layer (para 0042, lines 4-7 from bottom).
Steinberg et al. do not teach using a physical crosslinking treatment, i.e. the dehydrothermal crosslinking, for crosslinking the gelatin nonwoven and the gelatin film, as required by the claim 6. However, Steinberg et al. teach a chemical crosslinking treatment for the crosslinking by using a chemical crosslinking agent (cross-linker), and expressively teach that glutaraldehyde is a desirable crosslinking agent for collagen or gelatin (para 0033: page 5/lines 4-5 from bottom, page 6/lines 22-23).
Morinaga et al. teach a similar biodegradable substrate (i.e. scaffold) for medical use, comprising: a biodegradable nonwoven fabric and a biodegradable filmy material that is placed on the surface of the nonwoven fabric, wherein the filmy material is in a film form; wherein the nonwoven fabric may be made of fibers/threads of gelatin or collagen; wherein the scaffold has improved ability for introducing cells into the inside of the scaffold, and cells are added to or cultured in the scaffold to form a multicellular construct; and wherein the invasion of cells into the scaffold and material permeability are not affected by the nonwoven fabric and it is possible to culture cells in three dimensions; and wherein the cells may be cells of cardiac muscles (i.e. cardiomyocytes) (Claims 2-4, 13-15, and 17; paras 0010, 0060, 0070, and 0075/page 7/last line, Fig. 3). Morinaga et al. further teach that the nonwoven fabric may be subjected to physical or chemical crosslinking treatment, wherein a crosslinking method of thermal dehydration (i.e. dehydrothermal crosslinking) is listed as an example of the physical crosslinking treatment; and Morinaga et al. specifically indicate that the physical crosslinking treatment is preferably thermal dehydration (i.e. dehydrothermal crosslinking), and the chemical crosslinking treatment is preferably crosslinking treatment with glutaraldehyde (para 0055).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to replace the chemical crosslinking treatment of glutaraldehyde with the physical crosslinking treatment of thermal dehydration (i.e. dehydrothermal crosslinking) for crosslinking each of the gelatin nonwoven and the gelatin film in the scaffold of Steinberg et al., because both crosslinking methods are well-established in the art and they are art-recognized equivalents for the same purpose of crosslinking gelatin, as supported by Morinaga et al. Substitution of one known element for another and the results of the substitution would have been predictable.
It is noted that Morinaga et al. further teach that fibers/threads in the nonwoven fabric is in a wet condition and not subjected to drying (i.e. fibers//threads are swollen fibers/threads), and the fibers/threads in the nonwoven fabric has a diameter of about 10-200 mm, which reads on the diameter range recited in the claim 1 (paras 0046 and 0047).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Steinberg et al. (US 2014/0112973, 2014, cited in IDS) in view of Morinaga et al. (US 2006/0029639, 2006, cited in IDS), as applied to Claims 1 and 4-8, further in view of Yoshida et al. (US 2007/0298235, 2007).
The teachings of Steinberg et al. and Morinaga et al. are described above.
Regarding the claim 3, Steinberg et al. further teach that the thickness of the layer of fibers (fibers of gelatin nonwoven) is in the range of about 1 nm – about 5 mm or preferably about 1 mm to about 1 mm (para 0043, lines 7-14). Morinaga et al. further teach that the thickness of the nonwoven fabric is in the range from several hundreds of mm to several mm (para 066). The thickness ranges taught by the cited prior art either encompass or overlap the claimed range “0.1 mm or more and 2.0 mm or less”, thus rendering the claimed range to be obvious. See MPEP 2144.05.
Steinberg et al. do not teach the gelatin nonwoven fiber layer has a basis weight in a range from of 10 g/m2 to 600 g/m2.
Yoshida et al. teach a non-woven fabric composed of fibers with a desirable strength, comprising glass fibers, organic fibers, and fibrous binder (paras 0008 and 0038/lines 1-4), wherein gelatin is listed as the fibrous binder (para 0044, lines 1 and 5).
Yoshida et al. further teach that the weight of the non-woven fabric is preferably in the range of 50 to 300 g/m2, more preferably in the range of 100 to 150 g/m2; and when the weight of the non-woven fabric is less than 50 g/m2, the strength may be insufficient, and when it exceeds 300 g/m2, the strength is excessive and undesirable (para 0038, last 8 lines). Yoshida et al. teach a desirable non-woven fabric having a specific weight of around 100 g/m2 and a specific thickness of around 400 mm (i.e. 0.4 mm) (see last 3 lines of each of Examples 1-11). It is noted that the weight and thickness of the non-woven fabric taught by Yoshida et al. read on the claimed ranges for weight and thickness recited in the claim 3.
It would have been obvious to try maintaining the thickness and basis weight of the gelatin nonwoven suggested by Steinberg et al. and Morinaga et al., respectively, in the ranges of 0.1 mm - 2.0 mm and 10 g/m2 - 600 g/m2 for preparing a scaffold with a strength suitable for medical application, because it is well known in the art that a weight to surface area ratio of a nonwoven fabric affects its mechanic strength; and when it is too low, the strength may be insufficient, and when it is too high, the strength is excessive/undesirable, as supported by Yoshida et al. In addition, it is known in the art that a nonwoven fabric with thickness and basis weight falling into the claimed ranges possesses a desirable strength, as supported by Yoshida et al. Given thickness and basis weight of Yoshida et al. are applied to a nonwoven fabric involved with gelatin and there is a limited number of nonwoven fabric involved with gelatin in the art, one of ordinary skill in the art would have recognized that thickness and basis weight of Yoshida et al. may be tried out for identifying those suitable for the scaffold of Steinberg et al. for obtaining a desirable strength for medical application. See MPEP 2143 I.E., the rationale “obvious to try” supports a conclusion of obviousness when there is a finite number of identified and predictable solutions in the prior art, and choosing from such a finite number of identified and predictable solutions would have a reasonable expectation of success.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Steinberg et al. (US 2014/0112973, 2014, cited in IDS) in view of Morinaga et al. (US 2006/0029639, 2006, cited in IDS), as applied to Claims 1 and 4-8, further in view of Porrello et al. (US 2019/0203179, published on July 4, 2019, effective filing date: Aug. 25, 2017, cited in IDS).
The teachings of Steinberg et al. and Morinaga et al. are described above.
Regarding the claim 9, Steinberg et al. (para 0083: page 13/para 1) and Morinaga et al. (para 0075: page 7/last line) teach the cells are mature cardiomyocytes. They do not expressively teach the cardiomyocytes are differentiated from stem cells or somatic cells. However, Steinberg et al. teach cells comprised in the multicellular construct may be differentiated cells (page 12/para 0083: line 5).
It would have been obvious to one of ordinary skill in the art to seed and culture mature cardiomyocytes derived from cardiomyocytes differentiated from stem cells in the scaffold suggested by Steinberg et al. and Morinaga et al. for preparing a multicellular construct to be used for medical purpose or for testing the effect of substances on the cells. A person of ordinary skill in the art would have been motivated to do so, because Steinberg et al. expressively teach culturing mature cardiomyocytes and differentiated cells in their scaffold. One of ordinary skill in the art has a reasonable expectation of success at obtaining the mature cardiomyocytes differentiated from stem cells for seeding the cells and preparing a multicellular construct. This is because the techniques for obtaining mature cardiomyocytes derived from cardiomyocytes differentiated from stem cells have been well established in the art. In support, Porrello et al. teach differentiating cardiomyocytes from progenitor cells, such as human embryonic stem cells and induced pluripotent stem cells, and obtaining mature cardiomyocytes by culturing the cardiomyocytes in a cardiac cell maturation medium under conditions suitable for maturation of the cardiomyocytes (paras 0007, 0019-20).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claim is in condition for allowance.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Qing Xu, Ph.D., whose telephone number is (571) 272-3076. The examiner can normally be reached on Monday-Friday from 9:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau, can be reached at (571) 272-0614. Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to the receptionist whose telephone number is (571) 272-1600.
/Qing Xu/
Patent Examiner
Art Unit 1656