DETAILED ACTION
Applicant’s response filed January 22, 2026 has been received and entered into the application file. All arguments have been fully considered. Claims 1-19 are currently pending. Claims 1-9, 11-13 and 15-19, are currently amended.
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
WITHDRAWN REJECTION(S)
Claim Rejections - 35 USC § 103
RE: Rejection of Claims 1-15 and 17-19 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over McNiece, in view of Boehar, Fukuhara, Yong and Martinez:
Applicant’s amendment submitted 1/22/2026 has amended claim 1 to now require the isolation step is conducted over a time period of no greater than 5 hours. Claims 1 and 18 have been amended to further define the demethylation agent comprises one or more of 5-aza-2'- deoxycytidine, dimethylsulfoxide, chelerythrine chloride, retinoic acid or salts thereof, 2-amino-4- (ethylthio)butyric acid, procainamide, and procaine.
It is noted that, although McNiece teaches exposing the CD271+ MSC precursors to 5-azacytidine to induce skeletal and cardiac muscle differentiation ([0069]), McNiece does not further disclose the 5-azacytidine is 5-aza-2’-deoxycytodine as recited in amended claims 1 and 18. It is further noted that McNiece does not explicitly teach the time-period for isolation of CD271+ MSC precursors.
Therefore, due to the claim amendments the rejection under 35 U.S.C. 103(a) has been withdrawn, however the amendments have necessitated a new ground of rejection, as set forth below.
RE: Rejection of Claim 16 under pre-AIA 35 U.S.C. 103(a) as obvious over McNiece, in view of Boehar, Fukuhara, Yong and Martinez, and further in view of Ghodsizad:
For the reasons discussed immediately above, the rejection of claims 1-15 and 17-19 over McNiece, in view of Boehar, Fukuhara, Yong and Martinez is withdrawn, and thus the rejection of claim 16 that is based on the same basis is likewise withdrawn. However, the amendment submitted 1/22/2026 has necessitated new grounds of rejection, as set forth below.
NEW GROUND(S) OF REJECTION, NECESSITATED BY AMENDMENT
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-15 and 17-19 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over McNiece et al., (WO 2009/140452, previously cited; IDS 6/23/2023) (“McNiece”), in view of Shiota et al., (Experimental Cell Research 313 (2007) 1008-1023; see PTO-892) (“Shiota”), Mund et al., (Cancer Res 2005; 65: (16), August 15, 2005, pages 7086-7090; see PTO-892) (“Mund”), (Boehar et al., (Journal of the American College of Cardiology, vol. 56, No. 16, 2010, pages 1287-1297; previously cited) (“Boehar”), Fukuhara et al., (Cell Transplantation, Vol. 13, pp. 741-747, 2004; previously cited) (“Fukuhara”) and Yong et al., (British Journal of Haematology, 1996, 94, 40-47; previously cited) (“Yong”) and Martinez et al., (Bone Marrow Transplantation 24, 1273-1278 (1999), Abstract; previously cited) (“Martinez”), as evidenced by Miltenyi Biotec CD271 MicroBead Kit, retrieved from the internet, 5 pages, see PTO 892) (“Miltenyi Biotec CD271 MicroBead Kit”), Miltenyi Biotec MACS Cell Pre-Enrichment for flow sorting and analysis (Information Brochure, 10 pages, retrieved from the internet, see PTO-892) (“MACS”) and Miltenyi Biotec How to Isolate Cells in 3 Easy Steps using MACS MicroBeads (You Tube demonstration retrieved from the internet, see PTO-892) (“Miltenyi Biotec You Tube”).
McNiece is directed to a culture system and methods that provide stem cells isolated from bone marrow for use in transplantation. The desired stem cell population is isolated using antibodies to select for cells having a phenotype of CD271+, CD105-. McNiece teaches isolation of mesenchymal stem cell precursors using magnetic cell selection with an antibody to CD271, i.e., CD271+ MSC precursors (claims 1-6; paragraphs [0011], [0013], [0018]-[0019], [0050]-[0052], [0065] and [00131]).
Regarding claim 1, McNiece’s claims 8-10, 13, 15-18, 21 and 29-33 claim the following treatment methods:
8. A method of repairing and regenerating tissue in an animal comprising: isolating stem cells from bone marrow of an animal; isolating, culturing, and expanding non-adherent stem cells; and, transferring the non-adherent stem cells into the animal.
9. The method of claim 8, the isolated stem cells comprising at least one marker: c-kit+, CD271, CXCR4, CD 133, SCA-I, Tra-1-60, CD 44, CD 73, CD 90, CD 105 or Stro-1.
10. The method of claim 9, wherein the isolated stem cells have a CD271+, CD105- phenotype.
13. The method of claim 8, wherein the stem cells are obtained from allogeneic, autologous or syngeneic sources.
15. The method of claim 8, wherein the stem cells are transplanted into cardiac tissues.
16. A method of repairing and regenerating heart tissue in a patient comprising: isolating stem cells from a donor; isolating, culturing, and expanding non-adherent stem cells; and, transferring the non-adherent stem cells into the patient.
17. The method of claim 16, wherein the stem cells are isolated from any compartment of a donor comprising bone marrow, tissue, organs, fluids or combinations thereof.
18. The method of claim 16, wherein the isolated stem cells have a CD271+, CD 105- phenotype.
21. The method of claim 16, wherein the stem cells are obtained from allogeneic, autologous, heterologous, syngeneic or combinations thereof.
29. A method of engrafting stem cells into a patient in need thereof, comprising: isolating stem cells from a donor; isolating, culturing, and expanding non-adherent stem cells; and, engrafting the stem cells into the patient.
30. The method of claim 29, wherein the stem cells are cultured ex-vivo under conditions as non-adherent stem cells in the presence or absence of growth or differentiation factors.
31. The method of claim 29, wherein the donor cells are syngeneic, allogeneic, xenogeneic, autologous, heterologous, or combinations thereof.
32. The method of claim 29, wherein the stem cells are isolated from any compartment of a donor comprising bone marrow, tissue, organs, fluids or combinations thereof.
33. The method of claim 32, wherein the stem cells are cardiac stem cells.
Therefore, McNiece’s disclosed methods encompass isolating CD271+ mesenchymal stem cell precursors (MSCs) from bone marrow of a subject, expands the stem cells in non-adherent culture in the presence of differentiation factors, and thereafter administers the stem cells to cardiac tissues thus engrafting the stem cells into the patient for repairing and regenerating heart tissue, thus treating myocardial tissue damage.
Further, regarding claim 1 and the limitation “…treating ischemic or myocardial tissue damage…” and the specifically recited diseases and disorders in claim 10, it is noted that McNiece (paragraph [0083] and claim 15) specifically uses the CD271+ stem cells in a method of repairing and regenerating tissue, as well as specifically transplanting into cardiac tissues of patients suffering from cardiac disease or disorders such as myocarditis, angina, congenital heart disease, coronary heart disease (atherosclerosis) and chronic heart failure, thus meeting the limitations of claims 1 and 10.
Regarding claim 1 and the newly amended limitation directed to the isolation step being conducted over a time period of no greater than 5 hours, it is noted that McNiece does not comment on the time period for isolation. However, McNiece employs Miltenyi Biotec’s MACS cell separation device ([00126]) for isolation of the CD271+ precursor cells from the bone marrow MNC cells (BM MNCs) obtained from AllCells LLC ([00125]).
Miltenyi Biotec CD271 MicroBead Kit evidences preparation of CD271+ cells from BM MNCs as set forth at steps 1-9 of 2.2 Magnetic labeling (page 2/5). Steps 1-9 include 10-minute centrifugation step (2), incubation for 15 minutes (5), 5-minute incubation (6), additional 10-minute centrifugation step (7), followed by cell suspension in 500 µl of buffer prior to proceeding to magnetic separation (9). Thus, the labeling step comprises a time period of approximately 45 minutes.
MACS evidences the Miltenyi MACS process is a time-saving magnetic separation process conducted on high-speed cell sorters that reduces processing time from 7 hours to 1.4 hours (page 2, left col).
Miltenyi Biotec You Tube, further evidences the processing time for magnetic cell separation using Miltenyi Biotec MACS process.
Thus, McNiece’s disclosed Miltenyi Biotec’s MACS cell separation is considered to read on a time period of approximately 2.5 hours (i.e., of no greater than 5 hours), absent evidence to the contrary, thus meeting the limitation of claim 1.
Further regarding claim 1 and the limitation directed to exposing the isolated CD271+ MSCs to a demethylation agent to initiate differentiation among the MSC precursor cells, it is noted that, McNiece at [0069] teaches differentiation is induced by culturing in the presence of 5-azacytidine, i.e., a demethylation agent (instant specification [0068]). McNiece teaches differentiation of the non-adherent stem cells and expression of the cardiogenic markers α-sarcomeric actinin and Nkx2.5 (myocardial lineage) after culture in cardiac inducing conditions ([0029]-[0030] and [0134]; Figures 5 and 6). McNiece at [0087] teaches the CD271+ stem cells can be cultured and differentiated for purposes of treatment and Example 2 of McNiece ([0135]) further teaches administering the differentiated stem cells into the hearts of mice following myocardial infarct demonstrating the cells promoted treating the ischemic cardiac tissue. Thus, McNiece teaches exposing the isolated CD271+ MSC precursors to a demethylation agent to initiate differentiation into myocardial lineage prior to administering to a patient. The only difference between McNiece and the instant claim is that McNiece does not further comment on the 5-azacytidine demethylation agent being 5-aza-2’-deoxycytidine.
However, Shiota is directed to myogenic differentiation of bone marrow-derived MSC progenitors, including differentiation to cardiomyocytes (Abstract). Shiota induced cardiomyocytic differentiation under the same conditions as differentiation to skeletal myoblasts, which employed 5-aza-2’-deoxycytidine (page 1015, left and right columns), and Mund is directed to characterization of demethylation effects by 5-Aza-2’-deoxycytidine and acknowledges that 5-aza-2’-deoxycytidine and 5-azacytidine are closely related compounds and both function as DNA demethyltransferase inhibitors (Abstract and Introduction, page 7086, left col).
Thus, taking into hand the teachings of Shiota and Mund, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute 5-aza-2’-deoxycytidine for 5-azacytidine since both are known demethylation agents and Shiota has shown that 5-aza-2’-deoxycytidine is effective for initiating differentiation of MSC precursors into myocardial lineages. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of azacytidine demethylation agent for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Substitution of one element for another known in the field is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
As to claim 1 and the limitation directed at “parenterally administering to a patient a therapeutically effective amount of isolated CD271+ mesenchymal stem cell (MSC) precursors”, it is noted that, although claims 8, 16 and 29 of McNiece do not further claim the cells are administered parenterally, McNiece (paragraphs [00100] and [00101]) further teaches administering the cells parenterally as a pharmaceutical composition in a suitable carrier including physiological saline, for example.
Thus, McNiece does render obvious parenteral administration, that is, McNiece teaches the limitation required by claim 1 and as this limitation is found in one reference it is held that parenteral administration is within the scope of the teachings of McNiece, and thus renders the invention of claim 1 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to parenterally administer the pharmaceutical composition comprising the therapeutic CD271+ mesenchymal stem cell (MSC) precursors.
Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by McNiece.
McNiece ([0093]) further teaches the therapeutically effective amount administered to a host will be determined on an individual basis and will be based, at least in part, on consideration of the individual's size, the severity of symptoms to be treated, and the results sought. McNiece ([0096]) teaches the stem cells will be administered in a single dose in the range of 105 -108 cells per kg body weight, preferably in the range of 106 -107 cells per kg body weight. This dosage may be repeated daily, weekly, monthly, yearly, or as considered appropriate by the treating physician.
Further regarding claim 1 and the amended limitation “…parenterally administering to the heart of a patient multiple doses in increasing concentrations of a composition comprising at least one cytokine to form a chemotactic gradient…”, although McNiece teaches the administered therapeutic stem cells can be obtained by inducing mobilization using cytokines such as granulocyte colony-stimulating factor (G-CSF) ([0074]), or transformed with nucleic acids coding for growth factors and/or cytokines to aid in cell differentiation ([0088]), McNiece does not further teach parenterally administering to the heart of a patient multiple doses in increasing concentrations of a composition comprising at least one cytokine to form a chemotactic gradient.
However, Boehar is directed to methods of rebuilding damaged heart (myocardial) tissue. Boehar teaches that cytokine therapy is suggested as a noninvasive treatment option for ischemic heart disease since several cytokines are known to mobilize progenitor cells from the bone marrow to ischemic damaged tissue, thus contributing to myocardial regeneration (Abstract). Boehar specifically teaches the cytokine therapy is useful as an adjunctive treatment to cell therapy and notes the recruited cells also secrete angiogenic or anti-apoptotic factors that accelerate healing (page 1287, left col.). Boehar discloses cytokine agents such as Fibroblast growth factor (FGF), Vascular endothelial growth factor (VEGF), and Granulocyte colony-stimulating factor (GCSF) and specifically teaches that GCSF mobilizes progenitor cells from the bone marrow, and when administered after MI (myocardial infarct), GCSF stimulates production of several anti-apoptotic proteins, decreases cardiomyocyte death and limits infarct size (page 1288, right col, 2nd paragraph).
Fukuhara is directed to a study showing administering granulocyte colony-stimulating factor (G-CSF) improved infarcted cardiac function. Fukuhara teaches injecting a mouse model of myocardial infarction with GFP mouse-derived bone marrow cells (GFP-BMC) and 2 weeks later ligation of the left descending coronary artery was performed. G-CSF was administered intraperitoneally (parenterally) at a concentration of 200 µg/kg/day for 3 days prior to infarct (ligation) and 5 days after infarct (Group 1). Saline was injected in the control group (Group 2). Fukuhara teaches the administration of G-CSF promoted BMCs to migrate into the infarcted myocardial tissue and improved the survival rate (100%) as compared to the control group (50%) (Abstract).
Martinez is directed to a study of progenitor cell mobilization using G-CSF at two different concentrations of dosing to compare doses higher than 10 µg/kg/day. Specifically, Martinez administered group A dosing of 10 µg/kg/12 hours and group B dosing of 10 µg/kg/24 hours. Thus, group A received a 24-hour dose of 20 µg/kg as compared to group B dose of 10 µg/kg. The group A dosing resulted in increased peripheral leukocytes and lymphocyte counts, and the number of both nucleated and CD34+ cells was higher in group A. Martinez teaches the group A dosing was well tolerated and resulted in the collection of a higher number of progenitor cells (Abstract).
Yong further demonstrates G-CSF increases neutrophil migration across vascular endothelium (Summary) and Yong’s Figure 4(a) illustrates increasing the concentration of G-CSF results in increasing cell migration in a dose-dependent manner. Yong, like Martinez, demonstrates that administering increased concentrations of G-CSF results in increasing cell migration.
Therefore, given Boehar discloses cytokine agents such as Granulocyte colony-stimulating factor (GCSF) mobilizes progenitor cells from the bone marrow, and when administered to damaged myocardial tissue GCSF has the beneficial effect of stimulating production of several anti-apoptotic proteins, decreases cardiomyocyte death and limits infarct size and Fukuhara teaches parenteral administration of multiple doses of G-CSF promoted BMCs to migrate into the damaged myocardial tissue and improved the survival rate, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include parenterally administering multiple doses to the heart of a patient at least one cytokine, e.g., G-CSF to promote chemotactic migration of therapeutic progenitor cells to the damaged myocardial tissue.
The person of ordinary skill in the art would have been motivated to modify the method of McNiece to include parenterally administering to the heart of a patient at least one cytokine, e.g., G-CSF, as taught by Boehar and Fukuhara, for the predictable result of promoting chemotactic migration of therapeutic progenitor cells to the damaged myocardial tissue since doing so decreases cardiomyocyte death and limits myocardial tissue damage, thus meeting the limitation of claim 1.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Boehar and Fukuhara with McNiece because each of these teachings are directed at treating damaged myocardial tissue.
As to the limitation of administering the doses in increasing concentrations to form a chemotactic gradient, Martinez and Yong have demonstrated that increasing the concentrations of G-CSF results in increasing the amount of cells that are recruited to the site of tissue damage. The parameter of cytokine concentration is recognized as a results-effective variable which achieves the recognized result of promoting increased cell migration. Martinez specifically illustrates that cytokine dosing can be optimized to affect the concentration of migrated cells.
Therefore, it would therefore have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to modify the method of the prior art to optimize the cytokine dosing to administer increasing concentrations to form a chemotactic gradient to permit increased amounts of progenitor cells being recruited to the damaged myocardial tissue.
Moreover, at the time of the claimed invention, one of ordinary skill in the art would have been motivated by routine practice to optimize the cytokine dosing regimen to include increasing concentrations to form a chemotactic gradient with a reasonable expectation for successfully promoting progenitor cell migration to the damaged myocardial tissue; thus, meeting the limitation of claim 1. Generally, differences in parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such parameter is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05).
Regarding claim 2: as set forth above, McNiece teaches the CD271+ cells are isolated from bone marrow mesenchymal cells and as disclosed in the instant specification at paragraph [0048], CD271 is synonymous with low affinity nerve growth receptor (NGFR). Thus, McNiece’s bone marrow cells are isolated from bone marrow mesenchymal cells that express low affinity nerve growth receptor (CD271).
Regarding claim 3: McNiece discloses the CD271+ stem cells are isolated from one or more allogeneic, autologous or syngeneic donor sources (paragraphs [0016] and [0022]), thus meeting the limitation of claim 3.
Regarding claims 4-8, it is first noted that McNiece teaches differentiation of the non-adherent stem cells and expression of the cardiogenic markers α-sarcomeric actinin and Nkx2.5 (myocardial lineage) after culture in cardiac inducing conditions ([0029]-[0030] and [0134]-[0135]; Figures 5 and 6).
McNiece teaches administering the same CD271+ stem cell population by the same parenteral administration as disclosed in the instant specification at paragraph [0136]-[0144], which CD271+ cells were shown to have a high degree of engraftment and being capable of differentiating into myocardial, vascular and endothelial lineages.
Thus, because McNiece teaches administering the same stem cell composition to as the claimed method, McNiece’s stem cells will necessarily differentiate to myocardial, vascular and endothelial lineages, as recited in claims 4-5, and thus comprise the markers recited in claims 6-8. The fact that McNiece carries out the same method steps as in the instant application means that any and all results of the method of McNiece, whether recognized at the time of publication or not, were inherently achieved by the reference method. MPEP 2112.02 (I)
Additionally, as discussed above at the rejection of claim 1, McNiece at [0069] teaches differentiation is induced by culturing in the presence of 5-azacytidine, i.e., a demethylation agent (instant specification [0068]). McNiece teaches differentiation of the non-adherent stem cells and expression of the cardiogenic markers α-sarcomeric actinin and Nkx2.5 (myocardial lineage) after culture in cardiac inducing conditions ([0029]-[0030] and [0134]; Figures 5 and 6).
Further regarding claim 6, it is additionally noted, McNiece teaches differentiation of the non-adherent stem cells and expression of the cardiogenic markers α-sarcomeric actinin and Nkx2.5 (myocardial lineage) after culture in cardiac inducing conditions ([0029]-[0030] and [0134]; Figures 5 and 6), thus meeting the limitation of claim 6.
Regarding claim 9: although McNiece does not further teach one or more chemotactic factors, growth factors or differentiation agents are further administered to the patient, it is noted that Boehar teaches several types of cytokines/growth factors that are beneficial for treating damaged myocardial tissue, including Fibroblast growth factor that is effective for stimulating angiogenesis (page 1287, right col, Fibroblast growth factor (FGF)) and Vascular endothelial growth factor (VEGF) that has the therapeutic benefit of protective and regenerative effects in cardiac tissue (page 1288, left col., 2nd paragraph).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include one or more growth factors, e.g., FGF or VEGF, known as beneficial agents for treating damaged myocardial tissue.
The person of ordinary skill in the art would have been motivated to modify the method of McNiece to include growth factor agents, as taught by Boehar, for the predictable result of promoting angiogenesis and regeneration of damaged myocardial tissue, thus meeting the limitation of claim 9.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Boehar and McNiece because each of these teachings are directed at treating damaged myocardial tissue.
Regarding claim 10, McNiece (paragraph [0083]) teaches the therapeutic mesenchymal stem cells are transferred or transplanted in a patient suffering from various cardiovascular diseases including coronary heart disease (atherosclerosis) and chronic heart failure, thus meeting the limitation of claim 10.
Regarding claim 11, it is noted that McNiece teaches the stem cell composition can be administered in a single dose ranging from 105 cells/kg of body weight to 108 cells per kg body weight (i.e., varying concentrations), which may be repeated daily, weekly, monthly, yearly, or as considered appropriate by the treating physician (paragraph [0095]), thus meeting the limitation of claim 11.
Regarding claim 12 and the limitation “wherein the CD271+ precursors are engrafted in a heart in vivo in infarct and border zones”, it is initially noted that, McNiece, at paragraph [0033], teaches the stem cells have a great capacity to integrate into a tissue and continue to proliferate resulting in regeneration of damaged tissue.
Moreover, McNiece teaches administering the same CD271+ stem cell population by the same intravenous administration as disclosed in the instant specification at paragraph [0136]-[0144], which CD271+ cells were shown to have a high degree of engraftment and being capable of differentiating into myocardial, vascular and endothelial lineages.
Thus, because McNiece teaches administering the same stem cell composition to as the claimed method, McNiece’s stem cells will necessarily differentiate myocardial, vascular and endothelial lineages, thus meeting the limitation of claim 12. The fact that McNiece carries out the same method steps as in the instant application means that any and all results of the method of McNiece, whether recognized at the time of publication or not, were inherently achieved by the reference method. MPEP 2112.02 (I)
Regarding claim 13, it is noted that McNiece, as evidenced by Kuci, differs from the instant invention in that the combined references do not specifically exemplify culturing the CD271+ mesenchymal precursor cells in the presence of media conditioned by heart derived stromal cells. However, McNiece discloses culturing cardiac stem cells in the presence of various growth factors in order to assess colony formation, specifically a combination of stem cell factor (rhSCF) and media conditioned by human heart stromal cells (HuHStr). McNiece shows that cardiac stem cells cultured in the presence of these specific growth factors produce the largest colonies and differentiated to a cardiac phenotype and upon transplanting the conditioned cells generated cells capable of engrafting ischemic cardiac tissue (Example 2, paragraphs [0135]-0145]. Therefore, given the intention of McNiece is to provide stem cells capable of differentiating to a cardiac lineage and engraft ischemic cardiac tissue for the purpose of repairing and regenerating damage cardiac tissue, it would have been obvious to one having ordinary skill in the art at the time of the invention to include conditioning of the CD271+ MSC precursors with media conditioned by human heart stromal cells (i.e. heart derived stromal cells), for the predictable result of successfully providing growth factors that promote differentiation to the cardiac lineage and generate cells capable of engrafting ischemic cardiac tissue, thus meeting the limitation of claim 13. One of ordinary skill in the art would have been motivated to culture the CD271+ mesenchymal precursor cells in the presence of media conditioned by heart derived stromal cells in order to promote differentiation to the cardiac lineage and generate cells capable of engrafting ischemic cardiac tissue. Thus, one would have had a reasonable expectation of successfully culturing the CD271+ mesenchymal precursor cells in the presence of media conditioned by heart derived stromal cells in the method of McNiece, as evidenced by Kuci.
Regarding claim 14, it is noted that claims 8, 16 and 29 of McNiece claim the non-adherent stem cells are isolated, expanded and administered to a patient, thus meeting the limitation of claim 14.
Regarding claim 15, it is noted that McNiece ([0093] and [0095]) teaches the stem cells can be administered by subcutaneous or other injection, including endoscopic retrograde injection or injection of the cells directly into cardiac tissue, thus meeting the limitation of claim 15.
Regarding claim 17, it is noted the combined prior art renders obvious treating a myocardial infarction by administering a first composition comprising bone marrow-derived CD271+ mesenchymal stem cell precursors prepared in a pharmaceutically acceptable carrier and administering a second composition comprising at least one cytokine, e.g. G-CSF, in a pharmaceutically acceptable carrier. Given the first and second compositions are delivered parenterally, it is considered the administered first and second compositions are provided in an applicator.
The combined prior art does not disclose a kit comprising the composition of claim 17. However, it would have been prima facie obvious to one having ordinary skill in the art at the time of the invention to collect these items into a single container (e.g., kit) for the predictable result of providing the composition in convenient packaging for distribution, thus meeting the limitation of claim 17. One of ordinary skill in the art would have been motivated to modify the composition of the prior art in order to provide the components in a manner that is convenient for saving time and provides easier distribution of the composition components; thus, one would have had a reasonable expectation of successfully collecting these items into a single container (e.g., kit) for the predictable result of providing the composition in convenient packaging for distribution.
As to the limitation requiring an instruction manual that follows the method of claim 1, it is noted that where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, such as instructions pertaining to the use of the product, the content of the printed matter will not distinguish it from the claimed product of the prior art. See In re Gulack, 703 F.2d 1381, 1385-86, 217 USPQ 401, 404 (Fed Cir. 1983).
Regarding claims 18 and 19, it is noted claims 8-10, 13, 15-16, 18, 21-22 and 29-31 of McNiece claim the following:
8. A method of repairing and regenerating tissue in an animal comprising: isolating stem cells from bone marrow of an animal; isolating, culturing, and expanding non-adherent stem cells; and, transferring the non-adherent stem cells into the animal.
9. The method of claim 8, the isolated stem cells comprising at least one marker: c-kit+, CD271, CXCR4, CD 133, SCA-I, Tra-1-60, CD 44, CD 73, CD 90, CD 105 or Stro-1.
10. The method of claim 9, wherein the isolated stem cells have a CD271+, CD105- phenotype.
13. The method of claim 8, wherein the stem cells are obtained from allogeneic, autologous or syngeneic sources.
15. The method of claim 8, wherein the stem cells are transplanted into cardiac tissues.
16. A method of repairing and regenerating heart tissue in a patient comprising: isolating stem cells from a donor; isolating, culturing, and expanding non-adherent stem cells; and, transferring the non-adherent stem cells into the patient.
18. The method of claim 16, wherein the isolated stem cells have a CD271+, CD 105- phenotype.
21. The method of claim 16, wherein the stem cells are obtained from allogeneic, autologous, heterologous, syngeneic or combinations thereof.
29. A method of engrafting stem cells into a patient in need thereof, comprising: isolating stem cells from a donor; isolating, culturing, and expanding non-adherent stem cells; and, engrafting the stem cells into the patient.
30. The method of claim 29, wherein the stem cells are cultured ex-vivo under conditions as non-adherent stem cells in the presence or absence of growth or differentiation factors.
31. The method of claim 29, wherein the donor cells are syngeneic, allogeneic, xenogeneic, autologous, heterologous, or combinations thereof.
As set forth above regarding claim 1, the combined prior art, renders obvious a method for treating ischemic or myocardial tissue damage comprising:
isolating CD271+ mesenchymal stem cell precursors from bone marrow of a subject over a time period of no greater than 5 hours,
exposing the isolated CD271+ mesenchymal stem cell precursors (MSCs) to a demethylation agent, wherein the demethylation agent comprises 5-aza-2’-deoxycytidine, wherein exposure to the demethylation agent initiates differentiation among the CD271+ MSC precursors into at least one lineage selected from:
myocardial, vascular, or endothelial lineages;
parenterally administering to the heart of a patient multiple doses in increasing concentrations of a composition comprising at least one cytokine to form a chemotactic gradient; and
parenterally administering to the patient a therapeutically effective amount of the isolated CD271+ MSC precursors that were exposed to the demethylation agent.
McNiece’s claims 8-10, 13, 15-16, 18, 21 and 29-31 do not further claim the stem cells are administered as a matrix-cell complex (claim 18), wherein the matrix of the matrix-cell complex is a scaffold comprising at least the CD271+ MSC precursors (claim 19).
However, it is noted that McNiece at [0102] teaches injectable formulations include agents which delay absorption, including gelatin (i.e., matrix).
Thus, McNiece does render obvious the CD271+ MSCs administered as a matrix-cell complex as a scaffold comprising at least the cells, that is, McNiece teaches the limitations required by the current claims and as all limitations are found in one reference it is held that administering the CD271+ MSCs as a matrix-cell complex as a scaffold comprising at least the cells is within the scope of the teachings of McNiece, and thus renders the invention of claims 18-19 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to administer the CD271+ MSCs as a matrix-cell complex as a scaffold comprising at least the cells. Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by McNiece.
Claim 16 is rejected under pre-AIA 35 U.S.C. 103(a) as obvious over McNiece, in view of Shiota, Mund, Boehar, Fukuhara, Yong and Martinez, as evidenced by Miltenyi Biotec CD271 MicroBead Kit”, MACS and Miltenyi Biotec You Tube, as applied to claims 1-15 and 18-19 above, and further in view of Ghodsizad et al., (Heart, 2009;95:27-35; previously cited) (“Ghodsizad”).
The teaching of McNiece, in view of Shiota, Mund, Boehar, Fukuhara, Yong and Martinez, as evidenced by Miltenyi Biotec CD271 MicroBead Kit, MACS and Miltenyi Biotec You Tube is set forth above.
Regarding claim 16, it is noted that McNiece does not further teach administering the CD271+ cells with stem cells other than CD271+ cells, myoblasts, myocytes, cardiomyoblasts, cardiomyocytes, or progenitors of myoblasts, myocytes, cardiomyoblasts, and/or cardiomyocytes. However, Ghodsizad is directed at cell-based methods for functional improvement after acute myocardial ischemia (MI). Ghodsizad teaches transplanting human cord blood-derived unrestricted somatic stem cells (USSCs) into acutely ischemic lateral wall of the left ventricle (LV). Transplantation of USSCs significantly improved LV function and prevented scar formation as well as LV dilation (Abstract).
Therefore, it is submitted that because each of the stem cell types disclosed by McNiece and Ghodsizad were known to individually promote cardiac repair after myocardial ischemia, it would further have been obvious to one having ordinary skill in the art to combine the umbilical cord blood-derived stem cells (USSCs) of Ghodsizad with the CD271+ MSCs of McNiece for the purpose of producing a composition that promotes cardiac repair after myocardial ischemia. Combination of multiple products (i.e., stem cells) each known to have the same effect to produce a final product having the same effect is prima facie obvious. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
The person of ordinary skill in the art would have been motivated to modify the stem cell composition of McNiece to include umbilical cord blood-derived stem cells (USSCs), as taught by Ghodsizad, for the predictable result of successfully promoting functional improvement and reduction in scar formation after myocardial ischemia, thus meeting the limitation of claim 16.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of McNiece and Ghodsizad because each of these teachings are directed at using stem cells to promote cardiac tissue repair.
Response to Arguments
Rejections under 35 USC 103:
As set forth above, the previous rejections of record have been withdrawn in view of Applicants amendment submitted 1/22/2026.
In response to Applicant’s remarks regarding the cited reference to McNiece and the newly amended limitation defining the demethylation agent, as discussed at Applicant’s remarks (page 7, second to fourth paragraphs), it is noted that Applicant’s remarks have been carefully considered, but are not found persuasive in view of the new ground of rejection set forth above, specifically addressing the newly amended limitation that the demethylation agent comprises one or more of 5-aza-2’-deoxycytidine, dimethylsulfoxide, chelerythrine chloride, retinoic acid or salts thereof, 2-amino-4-(ethylthio)butyric acid, procainamide, and procaine.
Applicant has further traversed the rejection of record on the grounds that McNiece does not provide an enabling disclosure for treating ischemic or myocardial tissue damage using CD271+ mesenchymal stem cell precursors, as discussed at Applicant’s remarks (page 7, last paragraph to page 8, first and second paragraphs). Applicant asserts that McNiece provided extremely limited discussion on why MSC precursors should be selected to perform the intended therapeutic function.
Applicant’s remarks have been fully considered, but are not found persuasive for the following reasons:
(1) McNiece’s intention is that of isolating stem cell precursors (Title and [0011]), specifically cells having a CD271+, CD105- phenotype ([0008], [00130]);
(2) McNiece at [0070] teaches precursor MSCs are preferably used since these MSC precursors are capable of differentiating into various mesenchymal lineages, including cardiac lineage ([00134]);
(3) McNiece’s claims 16-18 claim the following:
16. A method of repairing and regenerating heart tissue in a patient comprising: isolating stem cells from a donor; isolating, culturing, and expanding non-adherent stem cells; and, transferring the non-adherent stem cells into the patient.
17. The method of claim 16, wherein the stem cells are isolated from any compartment of a donor comprising bone marrow, tissue, organs, fluids or combinations thereof.
18. The method of claim 16, wherein the isolated stem cells have a CD271+, CD 105" phenotype.
Thus, McNiece discloses a method of repairing and regenerating heart tissue (i.e., treating myocardial tissue damage) in a patient comprising: isolating stem cells from a donor; isolating, culturing, and expanding non-adherent stem cells; and, transferring the non-adherent stem cells into the patient, wherein the stem cells are bone marrow-derived and the isolated stem cells have a CD271+, CD 105- phenotype (i.e., CD271+ MSC precursors).
Conclusion
No claim is allowed. No claim is free of the prior art.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633