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
This action is in response to the papers filed December 22, 2025.
Claim Amendments
Applicant’s amendments to the claims filed 12/22/2025 are acknowledged.
Claims 4-11, 16, and 19 are cancelled.
Claims 1-3, 12-15, 17-18, 20-21 are pending.
Claims 1-3, 12-15, 17-18, 20-21 are under examination.
Priority
The instant application 15/779,869 was filed on 05/30/2018. This application is a national stage of international application PCT/JP2016/085882 filed 12/02/2016, claiming priority based on Japanese patent application JP2015-236442 filed 12/03/2015.
While a certified copy of the foreign patent application JP2015-236442 is provided with the instant application, a certified English translation of said foreign patent application has not been provided.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 09/25/2025 has been considered.
Withdrawal of Prior Rejections/Objections
Rejections and/or objections not reiterated from the previous Office action mailed 09/25/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Applicant’s remarks filed 12/22/2025 have been carefully considered, but the arguments are not found persuasive in view of the new grounds of rejection set forth in this rejection. Furthermore, the arguments conflate the issue of plasma inactivation and platelet activation, which are different processes as explained in the 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.
Claims 1-3, 12-15, 17-18, 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Bochev et al. (2008) “Mesenchymal stem cells from human bone marrow or adipose tissue differently modulate mitogen-stimulated B-cell immunoglobulin production in vitro” Cell biology international, 32(4), 384-393; in view of Okura et al. “Therapeutic potential of human adipose tissue-derived multi-lineage progenitor cells in liver fibrosis” Biochemical and Biophysical Research Communications 456 (2015) 860–865 (first published 6 December 2014); Kakudo et al. (2008) “Proliferation-promoting effect of platelet-rich plasma on human adipose–derived stem cells and human dermal fibroblasts” Plastic and reconstructive surgery, 122(5), 1352-1360; and Ayache et al. (2006) “Comparison of proteomic profiles of serum, plasma, and modified media supplements used for cell culture and expansion” Journal of translational medicine, 4:40, 12 pages.
This rejection is newly applied, as necessitated by amendment.
Terms of art: Enzymatically-digested adipose tissue contains two major cell populations, a stromal vascular fraction (SVF) cell population and a cell population of mature adipocytes, wherein the SVF cell population is the heterogeneous cell population containing mesenchymal stem cells (MSCs). The stromal vascular fraction is a cell mixture consisting of preadipocytes, mature endothelial cells, endothelial progenitor cells, vascular smooth muscle cells, pericytes, parietal cells, macrophages, fibroblasts, and adipose-derived stem cells. The adipose-derived stem cell is a mesenchymal stem cell. See par. 27 of the instant specification.
Retronectin® is a registered trademark for a fibronectin fragment having both the cell adhesion domain and the heparin-binding domain. See par. 34 of the instant specification.
Plasma inactivation is a process of plasma treatment, e.g., heating at 56°C for 30 minutes, that prevents activation of the serum components, e.g., the complement system. The process is often referred to as “complement inactivation” and/or “heat inactivation.” See par. 47, 70 of the specification; see also pg. 9 of the “Ayache” disclosure.
Platelet activation is a process of platelet treatment, e.g., incubation with calcium chloride (CaCl2) and/or thrombin, that induces release of growth factors, e.g., platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-β, from the secretory granules, or α-granules, of the platelets. See pg. 1352-1353 of the “Kakudo” disclosure.
Prior art: Bochev teaches a method of producing a mesenchymal stem cell comprising:
subjecting human adipose tissue to enzymatic treatment to obtain a cell population, then
centrifuging the cell population to separate a sedimentary stromal vascular fraction, thereby obtaining a stromal vascular fraction containing a mesenchymal stem cell, and
culturing the obtained stromal vascular fraction containing a mesenchymal stem cell in the presence of fibronectin, thereby selectively proliferating the mesenchymal stem cell.
Bochev does not disclose that the stromal vascular fraction is obtained by an ex vivo culture or proliferation step prior to the step of culturing the obtained stromal vascular fraction containing a mesenchymal stem cell in the presence of fibronectin.
See Material and methods; see Section 2.1.2 on pg. 385-386.
Bochev teaches culturing the obtained stromal vascular fraction containing a mesenchymal stem cell in the presence of fibronectin. Bochev does not teach a “fibronectin fragment” as claimed.
However, prior to the effective filing date of the instantly claimed invention, Okura discloses a method comprising culturing a stromal vascular fraction obtained from enzymatically-digested human adipose tissue on Retronectin® (RN)-coated dishes (Sections 2.1-2.2). The stromal vascular fraction comprises human adipose tissue-derived multi-lineage progenitor cells (hADMPCs), and, after the culturing step, the expanded cell population demonstrated mesenchymal stem cell properties (Section 3.1). Accordingly, one of ordinary skill in the art would have understood that Okura teaches a step of culturing a stromal vascular fraction containing a mesenchymal stem cell in the presence of Retronectin® (a fibronectin fragment), thereby selectively proliferating the mesenchymal stem cell.
Therefore, one of ordinary skill in the art would have recognized that fibronectin, as taught by Bochev, and Retronectin® (a fibronectin fragment), as taught by Okura, are alternative matrix components and adherent cell culture supports, each suitable for the growth and expansion of mesenchymal stem cells derived from human adipose tissue. For these reasons, it would have been prima facie obvious to one of ordinary skill in the art to substitute fibronectin, as found in Bochev, with a fibronectin fragment, as found in Okura, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
The claims further recite a step of differentiating the obtained mesenchymal stem cell (claim 12), wherein the differentiation step is a culturing step in a medium containing a differentiation inducer that induces differentiation of a mesenchymal stem cell into another cell (claim 13). Likewise, Bochev further discloses a step of differentiating the mesenchymal stem cell obtained by culturing in a medium containing a differentiation inducer that induces differentiation of a mesenchymal stem cell into another cell (Sections 2.7-2.8, 3.4). Okura also discloses a step of differentiating the mesenchymal stem cell obtained by culturing in a medium containing a differentiation inducer that induces differentiation of a mesenchymal stem cell into another cell (Sections 2.4, 3.1).
Bochev and Okura do not teach using a xeno-free medium containing autologous platelet-poor plasma (PPP) in the culturing step as claimed. Rather, Bochev and Okura use a medium containing animal serum. In particular, Bochev cultures in the presence of fetal calf serum (FCS) (Section 2.1.2), and Okura cultures in the presence of fetal bovine serum (FBS) (Section 2.2).
However, prior to the effective filing date of the instantly claimed invention, Kakudo studied the proliferation potential of activated and nonactivated platelet-poor plasma (PPP) on human adipose-derived stem cells, and found that adding activated PPP promoted the proliferation of human adipose-derived stem cells. The term “activated platelet-poor plasma,” as found in Kakudo, refers to activation of the platelets within the plasma by incubation with calcium chloride (CaCl2) and thrombin, thereby inducing the release of growth factors, such as platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-β, from said platelets. See, e.g., Abstract; pg. 1352-1353; Figure 5 (top):
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Furthermore, autologous plasma was known to mitigate the risk of immune rejection or infection in a clinical application (Kakudo, pg. 1358).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the cell culture of Bochev, which used a medium supplemented with animal serum, by rather using a medium supplemented with autologous platelet-poor plasma, as taught by Kakudo, with a reasonable expectation of success because autologous platelet-poor plasma promotes the proliferation of human adipose-derived stem cells and/or mitigates the risk of immune rejection or infection in a clinical application.
A media supplemented with autologous plasma rather than animal serum, as suggested by Kakudo, is an “xeno-free” medium, as claimed, because the medium contains no component derived from a species different than the species of the MSC-donor.
Claims 1 and 12 recite that the autologous plasma is “inactivated.” Kakudo does not disclose plasma inactivation, as claimed.
Prior to the effective filing date of the instantly claimed invention, Ayache teaches that plasma is often heat inactivated, e.g., by heating at 56°C for 1 hour, when used as a cell culture supplement in order to inactivate the complement components and prevent the occurrence of complement mediated cell lysis. See, e.g., pg. 2, 9.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to further modify the cell culture of Bochev, by using inactivated plasma, as taught by Ayache, reasonable expectation of success because plasma is often inactivated, e.g., by heating at 56°C for 1 hour, when the plasma is used as a media supplement in cell culture, and the process inactivates the complement components in the plasma, thereby preventing the occurrence of complement mediated cell lysis.
The claims further recite that the plasma is contained at a concentration of 10% v/v or less (claims 1 and 12), 5% v/v or less (claims 17 and 20) or 2% or less (claims 18 and 21).
Kakudo teaches a cell culture containing 5% v/v of platelet-poor plasma (pg. 1354, right column; Figure 5, reproduced above), which lies within the ranges of claims 1, 12, 17 and 20.
Kakuda does not teach cell culture containing 2% v/v or less of platelet-poor plasma (pg. 1354, right column; Figure 5, reproduced above), as claimed in claims 18 and 21. However, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration 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). In this case, Kakudo teaches a cell culture containing 5% v/v of activated platelet-poor plasma (aPPP; pg. 1354, right column; Figure 5, reproduced above). In subsequent experiments, Kakuda performed cell cultures containing 1%, 5%, 10%, or 20% activated platelet-rich plasma (aPRP), where 1% aPRP improved proliferation of human adipose-derived stem cells relative to control (pg. 1354, right column; Figure 6). By lowering the aPRP concentration to 1% v/v and maintaining an improved cellular proliferation, one of ordinary skill in the art would have been led to lowering the concentration of aPPP from 5% v/v, as found in Kakuda, through routine experimentation. For these reasons, as it pertains to claims 18 and 21, the difference in plasma concentration between the claimed invention and Kakuda would have been prima facie obvious, absent a secondary consideration.
For these reasons, claims 1, 12-13, 17-18, 20-21 would have been prima facie obvious over the prior art.
Regarding claim 2, Retronectin®, as found in Okura, is a registered trademark for a fibronectin fragment having both the cell adhesion domain and the heparin-binding domain (par. 34 of the instant specification). For these reasons, and those provided above, the limitations of dependent claim 2 would have been prima facie obvious over the cited references.
Regarding claim 3, Bochev discloses the culturing step is performed in fibronectin-precoated well plates (Section 2.1.2 on pg. 385-386). Okura also discloses that the culturing step is performed on retronectin (RN)-coated dishes (Sections 2.2). For these reasons, and those provided above, the limitations of dependent claim 3 would have been prima facie obvious over the cited references.
Regarding claims 14-15, the stromal vascular fraction is a cell mixture consisting of preadipocytes, mature endothelial cells, endothelial progenitor cells, vascular smooth muscle cells, pericytes, parietal cells, macrophages, fibroblasts, and adipose-derived stem cells (par. 27 of the instant specification). Bochev does not disclose any step to remove any of preadipocytes, mature endothelial cells, endothelial progenitor cells, vascular smooth muscle cells, pericytes, parietal cells, macrophages, fibroblasts, or adipose-derived stem cells from the stromal vascular fraction prior to the step of culturing in the presence of fibronectin (Section 2.1.2). Okura does not disclose a step to remove any of preadipocytes, mature endothelial cells, endothelial progenitor cells, vascular smooth muscle cells, pericytes, parietal cells, macrophages, fibroblasts, or adipose-derived stem cells from the stromal vascular fraction prior to the step of culturing in the presence of a fibronectin fragment (Section 2.2). Since not one of the cell types recited in claims 14-15 are removed from the stromal vascular fraction prior to cell culture in Bochev or Okura, the stromal vascular fraction of the cited prior art would be reasonably expected to contain preadipocytes, mature endothelial cells, endothelial progenitor cells, vascular smooth muscle cells, pericytes, parietal cells, macrophages, fibroblasts and adipose-derived stem cells, as claimed in claims 14-15. For these reasons, and those provided above, the limitations of dependent claims 14-15 would have been prima facie obvious over the cited references.
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 JAMES J GRABER whose telephone number is (571)270-3988. The examiner can normally be reached Monday-Thursday: 9:00 am - 4:00 pm.
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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631