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 .
Priority
The instant application is a continuation of PCT/JP2020/041662 (filed 11/09/2020). Acknowledgement is made of Applicants’ claim for priority to Japanese Application No. JP2019-203477 (filed 11/08/2019).
Response to Amendment
The amendment filed on 08/20/2025 has been received and added into the application file.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 1-4 and 7-8 under 35 U.S.C. § 101:
The cancellation of claim 4 renders the rejection thereof moot.
The amendment to claim 1 reciting a method of preparing an injectable pharmaceutical composition and requiring limitations defining said method is effective to obviate the remaining rejections of record.
The rejections are withdrawn.
RE: Rejection of claims 1-9 under 35 U.S.C. § 103 over Noguchi and Sakamoto, et al. (each separately):
The cancellation of claims 4 and 9 renders the rejections thereof moot.
The amendment to claim 1 reciting a method of preparing an injectable pharmaceutical composition and requiring limitations defining said method is effective to obviate the remaining rejections of record.
The rejections are withdrawn.
RE: Rejection of claims 10-16 under 35 U.S.C. § 103 over Noguchi and Sakamoto, et al., each in view of Schmuck, et al.:
The amendment to claim 10 requiring the steps of suspending the sheet-shaped cell culture in a liquid to form a suspension and repeatedly sucking and discharging the suspension through a syringe is effective to obviate the rejections of record.
Thus, the rejections are withdrawn.
However, in the interest of compact prosecution, and as the Schmuck, et al. disclosure is referenced in the new grounds of rejection as necessitated by amendment herein, Applicants’ arguments regarding the instant rejections as they pertain to Schmuck, et al. will briefly be addressed:
Applicants assert while Schmuck, et al. teaches an embodiment in which cardiac fibroblast-derived extracellular matrices (CF-ECMs) are seeded with therapeutic cells, there is no disclosure of the use of therapeutic cells with the injectable CF-ECM composition and accompanying fragmentation protocol, disclosing use of therapeutic cells only with use of the CF-ECM “patch” formulation. Applicants further assert the dicing step disclosed in the fragmentation protocol risks damaging therapeutic cells (e.g., from physical stress of the cutting of the razor blade), and therefore would not be attempted by a person having ordinary skill in the art with the use of therapeutic cells.
Respectfully, these arguments are not found persuasive.
In par. 0100, Schmuck, et al. clearly teaches the use of therapeutic cells with the injectable formulations of CF-ECMs, and thus with the accompanying fragmentation protocol: “…intact CF-ECM scaffolds can be used as a therapeutic agent in treating damaged cardiac tissue or ischemic limb injury, even in the absence of therapeutic cells. Thus, injectable CF-ECM fragment formulations can be used as a stand-alone therapy, or can be seeded with therapeutic cells for transplantation. In use as a therapeutic cell delivery platform, the CF-ECM fragments can be paired with any adherent cell type. Adherent cells rapidly attach to CF-ECM and can be delivered to the diseased myocardium (or any organ/tissue) by needle and syringe or needle tipped catheter…” Schmuck, et al. clearly states the injectable formulations can be seeded with adherent cells, e.g., myoblasts; further, the disclosure of delivery to diseased myocardium by needle and syringe or needle-tipped catheter clearly refer to the CF-ECM and attached adherent cells as being injected into the myocardium; this can be contrasted with the CF-ECM “patch” formulation as being placed onto areas of infarction (e.g., par. 0106).
Further, as Schmuck, et al. clearly teaches injectable formulations of CF-ECM seeded with therapeutic cells, a person having ordinary skill in the art would not be discouraged by the risk of potentially damaging a mere portion of therapeutic cells to be injected.
RE: Rejection of claims 17-20 under 35 U.S.C. § 103 over Noguchi and Sakamoto, et al., each in view of Schmuck, et al., each further in view of Rao, et al.:
The cancellation of claim 19 renders the rejection thereof moot.
The amendment to claim 17 requiring the steps of suspending the sheet-shaped cell culture in a liquid to form a suspension and repeatedly sucking and discharging the suspension through a syringe is effective to obviate the rejections of record.
Thus, the rejections are withdrawn.
RE: Rejection of claims 1-4 and 6-9 on the ground of nonstatutory double patenting over U.S. Patent No. 11,395,863 and copending Application No. 18/767,567:
The cancellation of claims 4 and 9 renders the rejections thereof moot.
The amendment to claim 1 reciting a method of preparing an injectable pharmaceutical composition and requiring limitations defining said method is effective to obviate the remaining rejections of record.
The rejections are withdrawn.
New Grounds of Rejection
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, 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.
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 1-3, 5-8, 10-13, 15-18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Schmuck, et al. (US 2019/0111113), as evidenced by Chaturvedi, et al. (PLoS One. 2015) and Germani, et al. (Am J Pathol. 2003).
Schmuck, et al. teaches compositions and methods using an engineered cardiac fibroblast-derived 3-dimensional extracellular matrix for use in the treatment of cardiac disease or ischemic disease or injury (Abstract).
Regarding claim 1: Schmuck, et al. teaches a method to produce a cardiac fibroblast-derived engineered extracellular matrix (CF-ECM) composition, wherein cardiac fibroblasts are cultured for 7 to 15 days, then removed as a sheet and incubated with 2 mM EDTA in PBS at 37°C until they lift off the plate surface (par. 0088); the resulting sheets are then denuded of cells in a series of washes, followed by subsequent storage of the resulting decellularized engineered CF-ECM (pars. 0090, 0091). Further disclosed is an embodiment wherein CF-ECM is seeded with myoblasts as therapeutic cells for the treatment of ischemic limb injury (par. 0032).
As Chaturvedi, et al. discloses that myoblasts secrete and organize their own matrix glycoproteins to create a localized extracellular matrix microenvironment (Abstract. PLoS One. 2015), the denuded CF-ECM sheets seeded with myoblasts resulting in CF-ECM comprising myoblasts that have secreted and organized their own extracellular matrix reads on the forming a sheet-shaped cell culture containing myoblast cells connected to an extracellular matrix so that the extracellular matrix is on an outer surface of the sheet-shaped cell culture limitation recited in claim 1.
Schmuck, et al. also teaches a fragmentation protocol to produce injectable compositions of CF-ECM (par. 0092), wherein fragmented CF-ECM is suspended in isotonic injectable solution (par. 0094); this reads on the method of preparing an injectable pharmaceutical composition limitation recited in claim 1. Schmuck, et al. teaches small fragments of CF-ECM are produced via dicing with a razor blade, scalpel, or scissors and suspended in isotonic buffer and passed through an 18-gauge needle attached to a syringe 15-20 times, wherein the resulting suspension is subsequently passed through a 21-gauge needle attached to a syringe 15-20 times followed by repeating this step with a 24-gauge needle, then a 27-gauge needle (par. 0093); this reads on the crushing the sheet-shaped cell culture containing the myoblasts cells connected to the extracellular matrix into fragments by (i) suspending the sheet-shaped cell culture containing the myoblasts cells connected to the extracellular matrix in a liquid to form a suspension and (ii) repeatedly sucking and discharging the suspension containing the sheet-shaped cell culture through a syringe; and suspending the fragments resulting from the crushing in a solution to form the injectable pharmaceutical composition limitation recited in claim 1.
Schmuck, et al. further discloses injectable CF-ECM fragment formulations can be used as a stand-alone therapy, or seeded with therapeutic cells for transplantation, wherein the CF-ECM fragments can be paired with any adherent cell type, as adherent cells rapidly attach to the CF-ECM and can be delivered to diseased myocardium (or any organ/tissue) by needle and syringe or needle tipped catheter (par. 100). Schmuck, et al. does not explicitly teach myoblasts as the therapeutic cell type for use with injectable CF-ECM compositions.
However, Schmuck, et al. teaches delivery of CF-ECM comprising adherent cells (e.g., myoblasts) increases cell retention in targeted tissue (par. 0100); it is also disclosed myoblasts are therapeutic for ischemic limb injury (par. 0032). Schmuck, et al. further teaches fragmenting the CF-ECM for an injectable composition increases the surface area over 40 times, potentially resulting in increased therapeutic efficacy (par. 0099).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have seeded the CF-ECM sheets with myoblasts for use with the injectable CF-ECM composition taught by Schmuck, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would be motivated to do so for the reasons taught by Schmuck, et al.; namely, increasing cell retention of therapeutic myoblasts in targeted tissues for ischemic limb injury, as well as the potential increased therapeutic efficacy. Further, as Schmuck, et al. discloses the use of injectable CF-ECM compositions comprising mesenchymal stem cells injected into the hearts of healthy rats (pars. 0141-0144), one skilled in the art would have a reasonable expectation of success in using injectable CF-ECM compositions comprising myoblasts for the less-invasive injection into an ischemic limb.
Lastly, Schmuck, et al. does not explicitly teach the CF-ECM comprising myoblasts as having a size of 100 µm to 500 µm, as required by the remaining limitation recited in claim 1.
However, when the only difference between a claimed product and prior art is the size and proportion of the product, the claimed product is not patentably distinct from the prior art. See MPEP 2144.04(IV)(A); In Gardner v. TEC Syst., Inc., 725 F.2d 1338, 220 USPQ 777 (Fed. Cir. 1984), cert. denied, 469 U.S. 830, 225 USPQ 232 (1984).
Thus, the limitations of claim 1 are rendered obvious by Schmuck, et al.
Regarding claims 2-3, 7: It is known in the art that myoblasts secrete vascular endothelial growth factor (VEGF), as evidenced by Germani, et al. (“Expression of VEGF and its receptors during myogenic differentiation.” Fig 5B). Thus, the injectable CF-ECM composition comprising myoblasts of Schmuck, et al. reads on the wherein the fragments secrete at least one factor that promotes angiogenesis limitation recited in claim 2, the wherein the at least one factor that promotes angiogenesis is VEGF limitation recited in claim 3, as well as the wherein the fragments further secrete the cytokine VEGF limitation recited in claim 7.
Regarding claim 5: It is set forth above the CF-ECM taught by Schmuck, et al. are denuded of cells before seeded with therapeutic cells; thus, the injectable CF-ECM composition comprising myoblasts of Schmuck, et al. comprises only myoblasts. This reads on the wherein the myoblast cells are a most abundant cell type in the sheet-shaped cell culture and are present in the sheet-shaped cell culture at a content ratio of 60% or more limitation recited in claim 5.
Regarding claim 6: Following the above discussion, Schmuck, et al. teaches the myoblasts as skeletal myoblasts (par. 0032); this reads on the wherein the sheet-shaped cell culture is derived from skeletal muscle limitation recited in claim 6.
Regarding claim 8: Following the above discussion, the injectable CF-ECM composition comprising myoblasts that have secreted and organized their own extracellular matrix of Schmuck, et al. reads on the wherein the extracellular matrix is also present between the myoblast cells of the sheet-shaped cell culture limitation recited in claim 8.
Regarding claim 10: It is set forth above Schmuck, et al. teaches a method wherein myoblasts are seeded onto CF-ECM denuded of cells (pars. 0032, 0090, 0091), which reads on the seeding myoblasts cells on a substrate limitation recited in claim 10; it is additionally set forth above the fragmentation protocol taught by Schmuck, et al. for producing an injectable CF-ECM composition comprising said myoblasts (pars. 0093, 0100) reads on the remaining limitations recited in claim 10.
Regarding claim 11: Schmuck, et al. does not explicitly teach the CF-ECM comprising myoblasts as producing fragments having a size of 100 µm to 500 µm, as required by the limitation recited in claim 11. However, when the only difference between a claimed product and prior art is the size and proportion of the product, the claimed product is not patentably distinct from the prior art. See MPEP 2144.04(IV)(A); In Gardner v. TEC Syst., Inc., 725 F.2d 1338, 220 USPQ 777 (Fed. Cir. 1984), cert. denied, 469 U.S. 830, 225 USPQ 232 (1984).
Regarding claim 12: Schmuck, et al. does not teach sucking and discharging the suspension through the syringe 4-6 times, as required by the limitation recited in the instant claim. However, the exact number of times a suspension might be passed through a syringe would have been routinely optimized by a person having ordinary skill in the art. Schmuck, et al. clearly teaches the step of passing the CF-ECM suspension through a syringe in the fragmentation protocol is provided in a number effective to allow the CF-ECM fragments to pass through a catheter without clogging it while still readily binding to cells and retaining function as a seeded material (par. 0096); this means the conditions to achieve the ideal size of CF-ECM fragments were result effective variables. Result effective variables would be optimized by routine experimentation by one having ordinary skill in the art. Furthermore, differences in size will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such size is critical. See MPEP 2144.05(II)(A).
Regarding claim 13: Schmuck, et al. does not teach the substrate as having an area of 1 cm2 to 200 cm2, as required by the limitation recited in the instant claim. However, when the only difference between a claimed product and prior art is the size and proportion of the product, the claimed product is not patentably distinct from the prior art. See MPEP 2144.04(IV)(A); In Gardner v. TEC Syst., Inc., 725 F.2d 1338, 220 USPQ 777 (Fed. Cir. 1984), cert. denied, 469 U.S. 830, 225 USPQ 232 (1984).
Regarding claim 15: Schmuck, et al. does not teach the myoblast cells seeded at a density of 7.1 x 105 cells/cm2 to 3.0 x 105 cells/cm2, as required by the limitation recited in claim 15. However, cell seeding density would have been routinely optimized by a person having ordinary skill in the art. Cell seeding density influences cellular processes such as proliferation and cell-cell communication, and optimal cell seeding densities can vary greatly even between donors of the same species; thus, cell seeding density is a result effective variable. Result effective variables would be optimized by routine experimentation by one having ordinary skill in the art. Furthermore, differences in cell seeding density will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such a density is critical. See MPEP 2144.05(II)(A). This renders obvious the limitations of claim 15.
Regarding claim 16: It is set forth above the CF-ECM taught by Schmuck, et al. are denuded of cells before seeded with therapeutic cells; thus, the injectable CF-ECM composition comprising myoblasts of Schmuck, et al. comprises only myoblasts. This reads on the wherein sheet-shaped cell culture contains myoblast cells at a content ratio of 60% or more limitation recited in claim 16.
Regarding claims 17-18, 20: It is set forth above Schmuck, et al. renders obvious the limitations recited in claim 1. This renders obvious most of the limitations recited in claim 17; excluded from this is the remaining administering the injectable pharmaceutical composition to the lower limb of the patient limitation recited in claim 17. Nor does Schmuck, et al. explicitly teach the administering as injecting the injectable pharmaceutical composition into the lower limb of a patient, as required by the limitation recited in claim 18, or as intramuscular administration of the injectable pharmaceutical composition, as required by the limitation recited in claim 20.
It would have been prima facie obvious to a person having ordinary skill in the art to have used the injectable CF-ECM composition comprising myoblasts of Schmuck, et al. to treat peripheral arterial disease in a lower limb of a patient by injecting said CF-ECM composition comprising myoblasts into the lower limb of the patient via intramuscular injection. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would be motivated to do so in order to treat peripheral arterial disease in a lower limb, as Schmuck, et al. discloses myoblasts as appropriate therapeutic cells for the treatment of ischemic limb injury (par. 0032), wherein the ischemic limb injury reads on peripheral arterial disease. Schmuck, et al. discloses the use of injectable CF-ECM compositions comprising mesenchymal stem cells injected into the hearts of healthy rats (pars. 0141-0144); thus, one skilled in the art would have a reasonable expectation of success in using injectable CF-ECM compositions for a less-invasive injection into an ischemic lower limb. Additionally, as intramuscular injections for administration of a therapeutic is a well-known technique in the art, one would have more than a reasonable expectation of success in injecting the CF-ECM comprising myoblasts intramuscularly.
This renders obvious the limitations of claims 17, 18, and 20.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Schmuck, et al. (US 2019/0111113), in view of Shahini, et al. (Stem Cell Res. 2018), as evidenced by Chaturvedi, et al. (PLoS One. 2015), Germani, et al. (Am J Pathol. 2003), and Benton, et al. (Adv Drug Deliv Rev. 2014).
The teachings, of Schmuck, et al. are set forth above.
Shahini, et al. teaches a protocol for the isolation of skeletal muscle progenitor cells (Abstract).
Regarding claim 14: It is set forth above the injectable CF-ECM composition comprising myoblasts of Schmuck, et al. renders obvious the method of claim 11. Schmuck, et al. does not teach the myoblasts seeded onto a substrate coated with a serum, a growth factor, a steroid drug, or any combination thereof, as required by the limitation recited in claim 14.
However, Shahini, et al. teaches culturing myoblasts onto tissue culture dishes coated with Matrigel, disclosing Matrigel as necessary for culturing myoblasts as the cells seeded on collagen do not spread or migrate well (“Note 4”; pg. 126). As evidenced by Benton, et al., Matrigel comprises laminin and collagen IV, as well as growth factors including fibroblast growth factor and epidermal growth factor (pg. 4; col. 2, par. 1.3); this reads on the wherein the substrate is coated with a growth factor limitation recited in the instant claim.
It would have been prima facie obvious to a person having ordinary skill in the art to have coated the denuded CF-ECM with Matrigel before seeding the myoblasts, as taught by Schmuck, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; one would be motivated to do so in order to maximize the spread and migration of myoblasts, as taught by Shahini, et al. Further, as the plating of myoblasts onto a surface coated with Matrigel is taught by Shahini, et al., one would have more than a reasonable expectation of success.
This renders obvious the limitations of claim 14.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GINA PRONZATI whose telephone number is (571)270-5725. The examiner can normally be reached Monday - Friday 9:00a - 5:00p ET.
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/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633