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 .
DETAILED ACTION
The text of those sections of Title 35, U.S. Code not included in this action can be found
in a prior Office action.
This application is in response to the papers filed on October 30, 2025. Pursuant to the amendment filed on October 30, 2025, claims 1, 6-7, 9, 13-14, 16, 22-24, 26-27 and 31 are currently pending of which claims 9 and 16 have been amended. No claims have been cancelled or added.
Therefore, claims 1, 6-7, 9, 13-14, 16, 22-24, 26-27 and 31 are currently under examination to which the following grounds of rejection are applicable.
The Examiner is recommending applicants schedule an interview to discuss the standing rejections in order to move prosecution forward.
Response to Arguments
Withdrawn Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Rejections - 35 USC § 112
In view of Applicants’ amendment to the claims dated October 30, 2025, wherein claims 9 and 16 have been amended, the rejection to claims 9 and 16 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite are withdrawn.
Applicants’ arguments are moot in view of the withdrawn rejection. A response to any argument pertaining to a new or maintained rejection can be found below.
Maintained Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Rejections - 35 USC § 103
Claims 1, 6-7, 9, 13-14, 16, 23-24, and 26-27 remain rejected under 35 U.S.C. 103 as being unpatentable over Nagaya et al. (US2009/0053277A1; of record IDS filed on February 7, 2022) in view of Nakao et al. (Regenerative therapy 11 (2019): 34-40; of record IDS filed on February 7, 2022), Oyama et al. (US2019/0274300A1; of record IDS filed on February 7, 2022), and Lalu et al. (Stem cells translational medicine 7.12 (2018): 857-866) as evidenced by Lindsey et al. (American Journal of Physiology-Heart and Circulatory Physiology 314.4 (2018): H812-H838).
Claim 1 is directed to a method of treating acute ischemic heart in a subject in need thereof, comprising applying an effective amount of a mesenchymal stem cell sheet to the heart of the subject, wherein the mesenchymal stem cells are umbilical cord mesenchymal stem cells; and wherein the mesenchymal stem cell sheet is prepared by a method comprising the following step: a. culturing the mesenchymal stem cells in a thermo-sensitive petri dish pre-coated with adhesion matrix or serum; and wherein the effective amount of the mesenchymal stem cell sheet is a single-dose of one to four mesenchymal stem cell sheets, and wherein 2x 107 to 8x 107 mesenchymal stem cells are comprised in each of the sheets.
Regarding claim 1, Nagaya teaches a method of treating diseases related to cardiac tissue damage or cardiac insufficiency in a subject, comprising applying an effective amount of a mesenchymal stem cell sheet to the heart of the subject (“A method for treating heart failure in a patient, comprising transplanting a cell sheet for transplantation comprising mesenchymal stem cells to the heart of said patient.” (claim 6); “The mesenchymal stem cells may be readily prepared by collecting cells from the bone marrow, adipose tissue, or other tissue of the patient to be subjected to the transplant,” (0017)). Nagaya teaches wherein the mesenchymal stem cell sheet is prepared by a method comprising the following steps: a. culturing the mesenchymal stem cells in a thermo-sensitive petri dish pre-coated with adhesion matrix or serum (“Culture media such as α-MEM and DMEM supplemented with 10 to 15% autoserum or fetal bovine serum (FBS) and an antibiotic may be used in the invention.” (0018); “After the mesenchymal stem cells are seeded onto the temperature responsive culture dish and grown to confluence, the mesenchymal stem cell sheet can be prepared by changing the culturing temperature from 37° C. to 32° C. or lower to allow the cells detach from the culture dish.” (0019); “Because an enzyme treatment such as trypsinization is not necessary, this type of cell sheet retains the connection between cells and adhesion proteins” (0004)). The cells are released by temperature drop rather than by chemical/enzymatic means, and therefore the ECM is maintained. The reference teaches using a single mesenchymal stem cell sheet in transplantations (par 0055). In reference to cell number, Nagaya describes the start of culturing of the MSC sheets wherein the MSCs are seeded at a density of 7 x 105 in a 60 mm dish (21.5 cm2 area), and after 3 days the culture becomes confluent and are then detached for use (0031).
Nagaya does not teach where the MSCs are umbilical cord mesenchymal stem cells and wherein the culture plates are pre-coated with adhesion matrix or serum. Furthermore, Nagaya does not teach treating acute ischemic heart failure, but rather heart failure (par 0008). Lastly, Nagaya does not teach wherein 2x 107 to 8x 107 mesenchymal stem cells are comprised in each of the sheets.
Nakao teaches that MSC sheets can be derived from bone marrow, adipose tissue, and umbilical cord tissue (UC-MSC) in which the adhesion properties were similar across groupings and proliferation for umbilical cord derived MSCs was higher at day 5 in comparison to adipose derived MSCs (abstract; p 37, par 1-2; Figure 4A,B). In reference to the culture plate coatings, Nakao teaches culture plates coated with fetal bovine serum (FBS) wherein such coating enhanced cell attachment and proliferation in all cell types (abstract). Lastly, Nakao teaches culturing the stem cells until they reach confluency which was around 4.7 x 105 cells at day 5 wherein the cells were seeded at a density of 2 × 105 cells on 35-mm diameter temperature-responsive cell culture dishes (Sec. 2.2, 3.1; Fig. 4).
Nagaya and Nakao does not teach the total MSC comprised in each sheet as being 2x 107 to 8x 107 mesenchymal stem cells, and moreover treating acute ischemic heart failure.
Oyama teaches the method of using stem cell sheets that contain MSC for the treatment of “heart diseases (for example, myocardial lesions (cardiac infarction and traumatic heart disease), cardiomyopathy (dilated cardiomyopathy), myocardial ischemia and the like)” (0185, 0188). Furthermore, Oyama teaches the produced sheet-shaped cell culture may have an area preferably not less than approximately 10 cm2, and in reference to the cell density of the sheet it can be as dense 3.4×106 cells/cm2 (“In an embodiment, the “density capable of forming a sheet-shaped cell culture without substantial proliferation” is equal to or higher than the density at which the cells reach a confluent state, or is not less than the confluent density… 1.0×105 to 3.4×106 cells/cm2.” (0222-0223)). This calculates out to a MSC sheet that contains at least 3.4 x 107 cells per sheet (e.g, 10 cm2 x 3.4×106 cells/cm2). Lastly, Oyama teaches multiple layers of the MSC sheet, stating “The sheet-shaped cell culture may be a culture configured with a single cell layer (single layer), or may be configured with two or more cell layers (stacked (multilayer), for example, two layers, three layers, four layers, five layers, six layers, and so on).” (par 0072).
Lalu teaches that mesenchymal stem cells (MSCs) may be beneficial in treating both acute myocardial infarction (AMI) and ischemic heart failure (IHF), further stating, “A total of 668 citations were reviewed and 23 studies met eligibility criteria. Of these, 11 studies evaluated AMI and 12 studies evaluated IHF. There was no association between MSCs and acute adverse events. There was a significant improvement in overall LVEF [left ventricular ejection fraction (LVEF)] in patients who received MSCs (SMD 0.73, 95% CI 0.24–1.21). No significant difference in mortality was noted (Peto OR 0.68, 95% CI 0.38–1.22). Results from our systematic review suggest that MSC therapy for ischemic heart disease appears to be safe:” (abstract).
Lindsey provides evidence of the relationship of ischemia, infarction, and heart failure, “Ischemia occurs when blood flow to the myocardium is reduced (129). Ischemia of prolonged duration induces myocardial infarction (MI), and MI is a common cause of heart failure (295).”
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Nagaya by utilizing umbilical cord MSCs based on Nakao teaching producing mesenchymal stem cell sheets with UC-MSCs. There would be a reasonable expectation of success in utilizing UC-MSC for mesenchymal stem cell sheets based on Nakao’s findings that UC-MSC share similar adhesion properties and proliferative properties with adipose MSCs when formed into sheets. Furthermore, there is motivation to modify the Nagaya teaching of using adipose MSCs based on the finding of Nakao showing a higher proliferation rate at day 5 of umbilical cord MSCs in comparison to adipose MSCs. Lastly, it would have been prima facie obvious to have modified the culture plates of Nagaya as being pre-coated with FBS based on the findings of enhanced cell attachment and proliferation for UC-MSCs as taught by Nakao.
In reference to treating acute ischemic heart failure, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of utilizing MSC sheets for a damaged heart as taught by Nagaya in view of Nakao and Oyama, but for acute ischemic heart failure because Nagaya teaches this in relation to myocardial infarction and Oyama teachings are in view of either myocardial ischemia and cardiac infarction which are related by reduced blood flow to the heart as evidenced by Lindsey.
Secondly, Lalu teaches that MSC are useful in treating both acute myocardial infarction (AMI), which is treated by the claimed method in Nagaya and Oyama, and ischemic heart failure (IHF) which the instant application is directed to.
Therefore, there would be a reasonable expectation of success of using the method taught by Nagaya in view of Nakao, Oyama, and Lalu of a MSC sheet for treating heart damage/diseases, in particular acute ischemic heart failure based on Nagaya teaching myocardial infarction-induced heart failure in mice as seen in Example 1, the conditions’ similarity in reduced blood flow to the heart, and it being shown that MSC can improve outcomes related to myocardial infarction (AMI) and ischemic heart failure (IHF) as seen by Lalu.
Furthermore, it would have been obvious to try in treating acute ischemic heart failure using the claimed method for the same reasons listed above, and wherein the animal model employed is in relation to the claimed condition. Despite the animal model of Nagaya being slightly different than the instant application’s provided example(s), it would remain obvious to try in treating this claimed condition based on the relationship it has with Nagaya’s heart failure model induced by myocardial infarction as they are related by reduced blood flow and are shown to be related by Lindsey, and lastly, Lalu makes it known that both conditions have been treated by MSCs.
In reference to the cell number of the MSC sheets, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the number of MSCs per sheet based on the reached confluency obtained. This value would be affected based on the variables related to culturing such as the general cell type, substrate, and media used, and furthermore the size of the sheet (length and thickness) required for the transplant site. Moreover, it can be seen that Oyama teaches the value of 3.4 x 107 cells per sheet which is encompassed by the claimed range of 2x 107 to 8x 107 mesenchymal stem cells, and therefore this range is obvious.
Regarding claims 6 and 7 , dependent on claim 1, the combined teachings of Nagaya, Nakao, Oyama, and Lalu render obvious claim 1. Moreover, Nagaya teaches wherein the mesenchymal stem cell sheet is applied by attaching it to the anterior or lateral wall of left ventricle of heart [claim 6]; and wherein the mesenchymal stem cell sheet is applied by attaching or implanting it to damaged or defective sites of the heart, or adjacent sites thereof [claim 7] (“Only rats having an infarct size of 25% or more of the entire left ventricle were used as the chronic heart failure model animals. In the MSC group, mesenchymal stem cell sheet was transplanted to the anterior surface of the scarred heart 4 weeks after coronary artery ligature.” (0027); “a mesenchymal stem cell sheet was prepared by culturing mesenchymal stem cells… and the cell sheet was applied to the surface of an infarct lesion in a myocardial infarction-induced chronic heart failure model rat, the mesenchymal stem cells were readily engrafted to the surface of the heart, gradually grew in situ, and formed thick tissue (about 600 μm) accompanied by angiogenesis.” (0022)).
Regarding claim 9, dependent on claim 1, the combined teachings of Nagaya, Nakao, Oyama, and Lalu render obvious claim 1. Moreover, Nagaya teaches the selection of MSCs based on cell surface markers such CD29 and CD90, and to prepare the MSC sheet, the stem cells are isolated and cultured for several passages. The reference describes that after 3-4 passages almost all the adherent cells expressed these markers and were negative for markers not associated with MSCs, i.e., CD34 and CD45 (0029, 0039).
Nakao teaches the stem cell sheet is prepared from umbilical cord-derived stem cells that were passaged 4 times before being used in culturing for the MSC sheets, and therefore there is an expectation that sheet is primarily comprised only of this cell type, e.g. > 90% of cells are MSC (Sec. 2.1).
Nagaya and Nakao do not explicitly teach wherein the cell ratio of mesenchymal stem cells in the mesenchymal stem cell sheet is at least 90%.
Oyama teaches that the MSC sheet can comprise a single cell type or two different cell types at select ratios (0075).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have set a threshold of the cell ratio for the MSC cell sheet based on Nagaya teaching cell surface antigen analysis for the purity of mesenchymal stem cells. Furthermore, it would have been obvious to optimize both methods by setting a 90% threshold based on the combined teachings describing the mesenchymal stem cell sheet as mostly or completely containing only MSCs.
Regarding claim 13, dependent on claim 1, Nagaya teaches wherein the mesenchymal stem cell sheet is prepared by using mesenchymal stem cells with passage number of P2-P10 (“After 3 to 4 passages, the mesenchymal stem cells from adipose tissue were trypsinized to prepare a cellular suspension, which is seeded on a 60 mm temperature responsive dish” (0031)). Furthermore, Nakao teaches using UC-MSC after four passages (Sec. 2.1).
Regarding claim 14, dependent on claim 1, Nagaya teaches wherein the thickness of the mesenchymal stem cell sheet is 30-300 µm (“Also preferably, the stem cells on the cell sheet will grow in situ to form a layer with a thickness of 100 μm or more.” (0007)).
Regarding claim 16, dependent on claim 1, Nagaya teaches the MSCs are seeded at a density of 7 x 105 in a 60 mm dish (21.5 cm2 area) and after 3 days the culture becomes confluent and are then detached for use (0031).
Nakao teaches the MSCs were seeded at a density of 2 × 105 cells on 35-mm diameter temperature-responsive cell culture dishes wherein the umbilical cord-derived MSC reach 4.7 × 105 cells per dish at day 5. The area of a 35 mm petri dish is 8.8 cm2, and therefore it can be seen the density at confluency was around 5.34 x 104 cells/cm2.
Nagaya and Nakao do not teach the claimed cell density value at confluency, specifically wherein the cell density of the mesenchymal stem cell sheet is 1 x 105 to 5 x 107 cells/cm2.
Oyama teaches the cell density of the sheet can be as dense 3.4×106 cells/cm2 (“In an embodiment, the “density capable of forming a sheet-shaped cell culture without substantial proliferation” is equal to or higher than the density at which the cells reach a confluent state, or is not less than the confluent density… 1.0×105 to 3.4×106 cells/cm2.” (0222-0223)).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the density of the MSC sheet based on the reached confluency obtained based on the variables related to culturing such as the general cell type, substrate, and media used. Furthermore, it would be obvious to modify the Nagaya in view of Nakao by specifying the taught density at reached confluency is within the claimed range which is taught by Oyama for growing a MSC sheet.
Regarding claim 23, dependent on claim 1, Nagaya teaches wherein the mesenchymal stem cells in the mesenchymal stem cell sheet are autologous or allogeneic to the subject (“The patient's autologous somatic stem cells are particularly preferred from the standpoint of histocompatibility and the risk of infection during the transplantation procedure.” (0017)).
Regarding claim 24, Nagaya teaches wherein the mesenchymal stem cell sheet is prepared by a method comprising the following steps: b. detaching the mesenchymal stem cells from the thermo-sensitive petri dish by decreasing the temperature, wherein the mesenchymal stem cells are connected to each other by extracellular matrix (ECM) secreted by the cells, thereby obtaining said mesenchymal stem cell sheet (“After the mesenchymal stem cells are seeded onto the temperature responsive culture dish and grown to confluence, the mesenchymal stem cell sheet can be prepared by changing the culturing temperature from 37° C. to 32° C. or lower to allow the cells detach from the culture dish.” (0019); “Because an enzyme treatment such as trypsinization is not necessary, this type of cell sheet retains the connection between cells and adhesion proteins” (0004)). The cells are released by temperature drop rather than by chemical/enzymatic means, and therefore the ECM is maintained.
In further support, Nakao teaches this method of MSC sheet detachment, “cell types were able to be detached as monolayer cell sheets by reducing the temperature to 20 °C for 30 min …sheets gradually became detached from the walls of the temperature-responsive cell culture dishes and shrank (10-mm diameter) upon full detachment from the dishes…Furthermore, the retained cell–cell bonds provided cytoskeletal contractile force in the sheets” (Sec. 3.1).
Regarding claim 26, dependent on claim 1, Nagaya teaches wherein the adhesion matrix includes one or more of fetal bovine serum, autologous serum, collagen, gelatin, fibronectin, vitronectin, laminin, polyornithine and polylysine (“Culture media such as α-MEM and DMEM supplemented with 10 to 15% autoserum or fetal bovine serum (FBS)” (0018); “cultured on a conventional polystyrene culture dish or collagen sheet” (0030)). Furthermore, Nakao teaches the adhesion matrix as comprising FBS as seen in the claim 1 rejection above.
Regarding claim 27, dependent on claim 26, Nagaya teaches wherein the mesenchymal stem cell sheet has an upper surface not contacted with the petri dish and a basal surface contacted with the petri dish during the preparation process, and wherein the basal surface of the mesenchymal stem cell sheet is attached to damaged or defective sites of heart, or adjacent sites thereof, or wherein the basal surface of the mesenchymal stem cell sheet is attached to anterior or lateral wall of left ventricle of heart. (Figure 2; “the cultured cells adherent to the surface of the culture dish will spontaneously detach from the grafted surface by changing the temperature.” (0020); “Only rats having an infarct size of 25% or more of the entire left ventricle were used as the chronic heart failure model animals. In the MSC group, mesenchymal stem cell sheet was transplanted to the anterior surface of the scarred heart 4 weeks after coronary artery ligature.” (0027)).
Claims 1 and 22 remain rejected under 35 U.S.C. 103 as being unpatentable over Nagaya et al. (US2009/0053277A1; of record IDS filed on February 7, 2022) in view of Nakao et al. (Regenerative therapy 11 (2019): 34-40; of record IDS filed on February 7, 2022) Oyama et al. (US2019/0274300A1; of record IDS filed on February 7, 2022), and Lalu et al. (Stem cells translational medicine 7.12 (2018): 857-866) as evidenced by Lindsey et al. (American Journal of Physiology-Heart and Circulatory Physiology 314.4 (2018): H812-H838), and further in view of Tano et al. (Molecular Therapy 22.10 (2014): 1864-1871; provided in the Office Action dated June 05, 2024).
Regarding claim 1, the disclosure of Nagaya in view of Nakao, Oyama, and Lalu is applied as in the 35 U.S.C. 103 rejection above, the content of which is incorporated above, in its entirety.
Regarding claim 22, Nagaya teaches transplanting a mesenchymal stem cell sheet to the epicardial surface of the heart during thoracotomy (0021).
The Nagaya reference does not teach wherein the mesenchymal stem cell sheet is applied to the heart of the subject in combination with coronary artery bypass graft performed on the subject.
Tano teaches that for clinical applications of MSC sheet therapy it would be reasonable to add MSC sheets coronary artery bypass grafting (CABG) due to the general efficacy of CABG alone not being satisfactory. The reference teaches that a meta-analysis describes addition of gene therapy (e.g. MSC sheet) in clinical trials increases therapeutic outcomes of CABG. In relation to convenience/accessibility, “MSC-sheet therapy can be readily integrated into ordinary CABG; immediately after completion of bypass grafting, surgeons can place MSC-sheets on the surface of target myocardial areas (no suture needed), and then close the chest as usual.” (p 1868, col 2, par 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Nagaya method by teaching the MSC sheet is applied in combination with CABG on a subject based on the motivation described by Tano wherein general outcomes for patients can be improved with the combination and the accessibility in doing so. Additionally, as described by Tano, the general outcome of CABG alone are not satisfactory so it would be obvious to try the combination to potentially improve outcomes.
Claims 1 and 31 remain rejected under 35 U.S.C. 103 as being unpatentable over Nagaya et al. (US2009/0053277A1; of record IDS filed on February 7, 2022) in view of Nakao et al. (Regenerative therapy 11 (2019): 34-40; of record IDS filed on February 7, 2022), Oyama et al. (US2019/0274300A1; of record IDS filed on February 7, 2022), and Lalu et al. (Stem cells translational medicine 7.12 (2018): 857-866) as evidenced by Lindsey et al. (American Journal of Physiology-Heart and Circulatory Physiology 314.4 (2018): H812-H838), and further in view of Matsuda et al. (US2007/0092492A1; provided in the Office Action dated June 05, 2024).
Regarding claim 1, the disclosure of Nagaya in view of Nakao, Oyama, and Lalu is applied as in the 35 U.S.C. 103 rejection above, the content of which is incorporated above, in its entirety.
Regarding claim 31, dependent on claim 30, Nagaya teaches a single MSC stem cell sheet that are seeded at a density of 7 x 105 in a round 60 mm dish (21.5 cm2 area) and after 3 days the culture becomes confluent and are then detached for use (0031). Furthermore, the stem cell sheet is capable of growing to a thickness of 600 µm, with the starting thickness being around 175 µm (Figure 3e).
Nagaya does not teach wherein the sheet diameter is between 15-55 mm.
Nakao teaches culturing MSCs in a round 35 mm petri dish wherein the diameter of the sheet shrank to 10 mm upon full detachment from the dishes, stating, “This occurred because of the loss of focal adhesion sites between the cell sheets and the cell culture dish surfaces. Furthermore, the retained cell–cell bonds provided cytoskeletal contractile force in the sheets.” (Sec. 3.1).
Oyama teaches in reference to the size or rather shrinkage of the detached sheet, “The sheet-shaped cell culture is known to shrink to a certain extent when detached from a culture substrate. The extent of such shrinkage differs depending on the kind of cells constituting the sheet-shaped cell culture, the content percentage of the cells, formation conditions of the sheet-shaped cell culture and the like. For example, in the case where a cell population containing skeletal myoblast cells is formed by sheet-formation cultivation, the shrink rate, for example, of the sheet diameter is approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, or approximately 80%.” (par 0209)
Nagaya in view of Nakao, Oyama, and Lalu do not teach the claimed sheet diameter as being between 15-55 mm, but teach a similar diameter of 10 mm while acknowledging that the diameters of the sheet shrinks after detachment. Furthermore, it remains unclear if the values described in this claim are before or after the detachment of the cultured stem cell sheet.
Matsuda teaches a single or multilayer stem cell sheet comprising mesenchymal stem cells wherein the length (diameter) is at least 1.5 cm (15 mm) and has a thickness of 50 µm per sheet (0127, 0188, 0191, 0298). Furthermore, the reference teaches that the stem cell sheet can shrink after detachment wherein some cases it may shrink up to 80% which would impact the diameter size. Matsuda describes the reasons are related to “the kind of cells constituting the sheet-shaped cell culture, the content percentage of the cells, formation conditions of the sheet-shaped cell culture and the like”. (0209).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the Nagaya method by using a smaller diameter size of the MSC sheet based in view of the tissue damage size being treated, and basing the size on the shrinkage that may occur after detachment as described by Nakao, Oyama, and Matsuda that is stated as being dependent upon cell type amongst other variables.
Response to Applicants’ Arguments filed on October 30, 2025 as they apply to the rejection of claims under 35 USC § 103.
Starting on page 6 of the remarks filed on October 30, 2025 Applicants essentially argue the following:
“The treatment of acute ischemic heart failure is different from those of other ischemic heart diseases….With respect to the differences, acute ischemic heart failure is caused by acute myocardial infarction or unstable angina leading to widespread acute myocardial ischemia and necrosis, the onset would be sudden and acute (within hours to days), and the treatment goals are life-saving and hemodynamic stabilization, in which urgent revascularization (such as PCI and stent implantation) is the core;… That is, none of the references are directed to acute ischemic heart failure, which indicates that the treatment of acute ischemic heart failure with MSC sheet is not disclosed and taught by the prior art.
“The single-dose of the present MSC sheets is non-obvious in view of the prior arts… As discussed above, none of the prior arts teaches the treatment of acute ischemic heart failure. Although Oyama teaches the cell number of cell sheet, those skilled in the art cannot expect a single-dose for the treatment of acute ischemic heart failure. For example, Guo et al. Stem Cell Res Ther 11, 19 (2020) discloses that "A single cell sheet is too thin to support long-term beneficial effects without vascularization in the hypoxic pathological condition of MI. To overcome such critical issues, cell sheets are often overlapped" (see page 3, paragraph 6). The present application verified that one cell sheet can be used for the treatment of acute ischemic heart failure.”
In response to these arguments, they have been fully considered but are not persuasive due to the following reasons:
Regarding the first presented argument, the Nagaya reference teaches treating heart failure as stated in paragraph 0006 without specifying that the condition is specifically acute ischemic heart failure. The reference then further specifies the type of heart failure is that caused/induced by myocardial infarction (other name: heart attack) (par 0041).
The reference describes the outcome of the mice model wherein the produced mesenchymal stem cell sheet was applied to the surface of an infarct lesion in a myocardial infarction-induced chronic heart failure model rat, the mesenchymal stem cells were readily engrafted to the surface of the heart, gradually grew in situ, and formed thick tissue (about 600 μm) accompanied by angiogenesis, further stating, “The grown mesenchymal tissue contained newly formed vessels, myocardial cells, and undifferentiated mesenchymal cells. More specifically, the grown mesenchymal tissue contained multiple vascular structures, indicating that the mesenchymal stem cells in the sheet were able to induce neovascularization. It is believed that this capability enables the construction of thick tissue. These results indicate that the mesenchymal stem cells in the sheet grow in situ, induce cardiac muscle and neovascularization, and differentiate into cardiac muscle, vascular endothelium, and the vascular smooth muscle cells.”
Despite the method and condition differences presented by Applicant of acute ischemic heart failure and myocardial infarction, it can be seen that it would be obvious to try in treating other forms of heart failure wherein blood flow to the heart is affected, i.e. acute ischemic heart failure, based on the improved outcomes that were observed in treating a form of a heart failure by Nagaya. Moreover, Oyama clearly states “The sheet-shaped cell culture is useful for treatment of various diseases, particularly diseases related to tissue abnormalities… Examples of tissues as targets for treatment include, but are not limited to, cardiac muscle, … In addition, examples of diseases as targets for treatment include, but are not limited to, heart diseases (for example, myocardial lesions (cardiac infarction and traumatic heart disease), cardiomyopathy (dilated cardiomyopathy), myocardial ischemia and the like)”(par 0185). Therefore, the step in treating ischemic heart diseases which are impacted by damaged cardiac tissues remains an obvious step based on the work done by Nagaya in repairing cardiac tissues and Oyama clearly teaching such disease can be treated with stem cell sheets. The Lindsey reference teaches the relationship between ischemia and infarction as being related to reduced blood flow to the heart, and therefore since the conditions are related there would obviousness to try in applying the method of Nagaya taught for myocardial infarction, but for acute ischemic heart failure due to this relationship.
Lalu provides a systematic review to evaluate the safety and efficacy of MSC therapies in patients with ischemic heart disease, specifically acute myocardial infarction (AMI) and ischemic heart failure (IHF). Applicant has stated in the Remarks that “acute ischemic heart failure is caused by acute myocardial infarction or unstable angina leading to widespread acute myocardial ischemia”, and therefore it can be seen that MSC therapies that have been used for treatment on AMI have a role in treating acute ischemic heart failure, this is further supported by Lalu describing MSC therapies for IHF which encompasses the claimed acute IHF. Altogether, there remains an obviousness rationale that these conditions can be treated similarly with the MSC taught by Nagaya in view of Nakao, Oyama, and Lalu, but for acute ischemic heart failure.
Lastly, in reference to the working example supplied in the instant Specification, “Example 6. Construction of animal model of heart failure, ” it is described, “In this example, a mouse model of ischemic heart failure is constructed by coronary artery ligation. In male C57BL/6 mice (approximately 12 weeks old), sutures are used to ligate the left anterior descending branch, which hinder the blood supply of the left ventricle myocardium and lead to myocardial cell apoptosis in the infarct area, resulting in decreased left ventricular ejection function, remodeling of the ventricular structure and eventually heart failure.” (par 00127); “The modeling method can simulate the course of acute ischemic heart failure to a good extent, with high modeling success rate and good stability.” (par 00136).
The working example supplied by Applicant is a model for heart failure, not specifically for acute ischemic heart failure. As such, applicants own working example agrees with the obviousness rationale that outcomes related to treating heart failure are expected to be the similar in treating acute ischemic heart failure. In reference to this specific murine model, Reichert et al. (Journal of visualized experiments: JoVE 122 (2017): 55353) teaches the same model, specifically a left anterior descending coronary artery ligation within mice as an approach to study IHD by mimicking human myocardial infarction (abstract), it is noted that ischemic heart disease (IHD) is also characterized as acute coronary syndrome (ACS). The reference further states, “The cause of ACS is the presence of a myocardial thrombosis due to the rupture of a coronary atherosclerotic plaque that blocks or reduces blood flow to the heart tissue. Therefore, there are clinical signs consistent with the presence of acute myocardial ischemia, such as myocardial infarction (MI).” (abstract). Altogether, based on Example 6 being a model for Heart Failure as evidenced by Reichert et al. and supported in the Specification as being for Heart Failure; and moreover stating the model can be used to simulate outcomes for acute ischemic heart failures, the obviousness rationales are maintained as the references teach treating heart failure with the claimed composition.
On page 8 of the Remarks Applicant describes the differences between the animal model of Nagaya with the instant application; however the model employed in the working example of instant application still is one that is applicable to heart failure, and then states outcomes are to be expected to be similar when treating for acute ischemic heart failure. Therefore, Nagaya’s method of treating heart failure is expected to follow the same logic that it can be used in treating acute ischemic heart failure despite differences in the animal model.
Regarding the second argument, the Applicant states “The present application verified that one cell sheet can be used for the treatment of acute ischemic heart failure.”, yet it the claim is directed the effective amount of the mesenchymal stem cell sheet is a single-dose of one to four mesenchymal stem cell sheets. Therefore, despite the inventor’s findings of one sheet sufficing the claims are directed to up to four sheets. Altogether, Nagaya teaches a single MSC sheet (par 0031) as well as Oyama who teaches they can contain a single layer or several (par 0072). In reference to the cellular density, the rejection above describes the sheets can be optimized in several ways to alter the total cell density, for example by changing the size of the sheet, using multiple layers, and changes in culture conditions.
Conclusion
Claims 1, 6-7, 9, 13-14, 16, 22-24, 26-27 and 31 are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. 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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/MICHAEL ANGELO RIGA/ Examiner, Art Unit 1634
/TERESA E KNIGHT/ Primary Examiner, Art Unit 1634