DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicants’ response on 05/05/2026 has been received and entered.
Claims 5-10, 15, and 17-20 are pending, all of which have been considered on the merits.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 1-12 and 15-20 under 35 U.S.C. 112(b)
Claims 1-4, 11-12, and 16 have been cancelled thus rendering their rejection moot.
Regarding the term “additional growth factors” in claims 5-10, 15, and 17-20, amendments to the claims, specifying no growth factors are added to the cell culture medium, overcome the rejection of record.
Regarding the terms “allogenic” and “autologous” in claims 17, 18, and 20, amendments to the claims, specifying the cells are allogenic or autologous to the coagulated mammalian blood plasma, overcome the rejection of record.
The rejections over claims 5-10, 15, and 17-20 are thus withdrawn.
RE: Rejection of claims 1-4 under 35 U.S.C. 102 over La Puente et al.
Claims 1-4 have been cancelled, thus rendering their rejection moot.
RE: Rejection of claims 1-5, 10-12, and 19 under 35 U.S.C. 103 over La Puente et al.
Applicants amended independent claims 5 and 20 to require a proteolytic enzyme or anticoagulation agent selected from the group consisting of nattokinase, bromelain, and tissue plasminogen activator (tPA). The 3D matrix of La Puente et al is solubilized by collagenase. Additionally, La Puente et al does not disclose or render obvious the use of nattokinase, bromelain, or tPA.
The rejection over claims 5, 10, and 19 is withdrawn.
Claims 1-4 and 11-12 have been cancelled, thus rendering their rejection moot.
RE: Rejection of claims 1-5, 6, 10-12, and 19 under 35 U.S.C. 103 over La Puente et al in view of CINJ.
Applicants amended independent claims 5 and 20 to require a proteolytic enzyme or anticoagulation agent selected from the group consisting of nattokinase, bromelain, and tissue plasminogen activator (tPA). The 3D matrix of La Puente et al is solubilized by collagenase. Additionally, La Puente et al and CINJ do not disclose or render obvious the use of nattokinase, bromelain, or tPA.
The rejection over claims 5, 6, 10, and 19 is withdrawn.
Claims 1-4 and 11-12 have been cancelled, thus rendering their rejection moot.
RE: Rejection of claims 1-7, 10-12, and 19 under 35 U.S.C. 103 over La Puente et al in view of CINJ and TerumoBCT.
Applicants amended independent claims 5 and 20 to require a proteolytic enzyme or anticoagulation agent selected from the group consisting of nattokinase, bromelain, and tissue plasminogen activator (tPA). The 3D matrix of La Puente et al is solubilized by collagenase. Additionally, La Puente et al, CINJ, and TerumoBCT do not disclose or render obvious the use of nattokinase, bromelain, or tPA.
The rejection over claims 5-7, 10, and 19 is withdrawn.
Claims 1-4 and 11-12 have been cancelled, thus rendering their rejection moot.
RE: Rejection of claims 1-5, 8-12, 15, 17-20 under 35 U.S.C. 103 over La Puente et al in view of Jackson et al.
Applicants amended independent claims 5 and 20 to require a proteolytic enzyme or anticoagulation agent selected from the group consisting of nattokinase, bromelain, and tissue plasminogen activator (tPA). The 3D matrix of La Puente et al is solubilized by collagenase. Additionally, La Puente et al and Jackson et al do not disclose or render obvious the use of nattokinase, bromelain, or tPA.
The rejection over claims 5, 8-10, 15, and 17-20 is withdrawn.
Claims 1-4 and 11-12 have been cancelled, thus rendering their rejection moot.
RE: Rejection of claims 1-5, 10-12, 16, and 19 under 35 U.S.C. 103 over La Puente et al in view of Carrion et al.
Applicants traverse the rejection of record on the grounds that La Puente discloses cell culture media may be added to the mixture and cell culture media most often comprises growth factors.
In response, the argument has been considered but is not found convincing. La Puente discloses cell culture media may be added meaning adding media is not necessary. Thus in some embodiments the method of La Puente does not comprise adding cell culture media.
Applicants further traverse the rejection of record on the grounds that a person of ordinary skill in the art would not have expected nattokinase to work equivocally with collagenase because nattokinase digests fibrogen whereas collagenase digests collagen.
In response, the argument has been considered but is not found convincing. While nattokinase and collagenase function by digesting different components of the 3D cell matrix, both enzymes can be used for the same purpose (i.e. digesting the matrix to separate cells). Thus the enzymes are interchangeable for the purpose of digesting a component of the cell matrix thereby allowing separation of cells from said matrix.
The rejection over claims 5, 10, and 19 is maintained.
Claims 1-4, 11-12, and 16 have been cancelled, thus rendering their rejection moot.
New/Maintained Rejections
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 5, 10, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over La Puente et al (US20220228124A1) PCT filled 06/15/2019 in view of Carrion et al (Tissue Eng Part C Methods, 2013).
La Puente et al disclose a method for producing a human plasma 3D culture matrix (See ¶0014). The method of La Puente comprises mixing peripheral blood plasma with biological cells to form a pre-mixture then mixing the pre-mixture with a cross-linker and a stabilizer (See ¶007). The peripheral blood plasma may be present in the mixture at a concentration between 30% and 50% v/v (See ¶0036). The culture matrix is formed by cross-linking of fibrinogen found naturally in plasma into fibrin using Thrombin, CaCl2, or Factor XIII (See ¶0014). The cross-linked matrix can be disrupted by chemical lysis to quantify growth factors found in the medium including EGF, IGF-1, HGF, and PDGF-AB (¶0060). La Puente et al further disclose a culturing method comprising covering the matrix in a serum-free media (See ¶0060). The method can be used to culture any suitable biological cells including stem cells (See ¶30). In an exemplary method, La Puente discloses culturing breast cancer cells in the 3D plasma culture matrix. The matrix is digested using collagenase in order to retrieve the cells for analysis by flow cytometry (See ¶0063).
Regarding claims 5 and 10: La Puente discloses a method for culturing biological cells, including stem cells, in a 3D human plasma culture matrix produced by cross linking fibrinogen using thrombin which reads on culturing and growing stem cells in a cell culture medium comprising coagulated mammalian blood plasma to produced cultured cells. The plasma may be present at a concentration between 30% and 50% v/v which reads on the culture medium comprises 5 to 70 vol. %. The 3D culture matrix of La Puente comprises EGF, IGF-1, HGF, and PDGF-AB which reads on the blood plasma includes one or more growth factors. Additionally, La Puente et al do not teach adding additional growth factors to the 3D culture matrix. Thus, the 3D culture matrix of La Puente et al does not comprise additional growth factors. In an exemplary method, La Puente discloses culturing breast cancer cell lines in the 3D human plasma culture matrix. The cells are collected from the culture matrix by digesting the matrix with collagenase which reads on releasing the cultured cells without use of trypsin.
La Puente does not disclose releasing the cultured stem cells from the 3D human plasma matrix.
Although La Puente does not teach releasing the stem cells from the plasma matrix, it would have been prima facie obvious to use collagenase to release stem cells from the plasma matrix. One would have been motivated to use collagenase to release stem cells from the plasma matrix of La Puente because La Puente teaches the plasma matrix can be digested using collagenase in order to isolate cells. There is a reasonable expectation of success because La Puente teaches collagenase can digest the 3D plasma matrix.
Additionally, La Puente do not teach resolubilizing the plasma matrix with nattokinase, bromelain, or tissue plasminogen activator.
Carrion et al teach a method of retrieving mesenchymal stem cells from a three-dimensional fibrin gel by treating the gel with nattokinase, a fibrinolytic enzyme. Treatment with nattokinase for 30 minutes results in dissolution of the gel and produces mesenchymal stem cells which are in a single-cell suspension (See abstract and Fig. 1).
Given that La Puente et al teach a method for retrieving stem cells from a 3D plasma culture matrix comprising cross-linked fibrinogen by digesting the plasma matrix with collagenase and Carrion et al teach a method of retrieving stem cells from a 3D fibrin gel by treating the gel with the fibrinolytic enzyme nattokinase, it would have been prima facie obvious to substitute the collagenase of La Puente et al with nattokinase in the method of La Puente et al. One would have expected the nattokinase of Carrion et al to work equivocally with the collagenase of La Puente et al, for the purpose of isolating cells from the 3D plasma matrix, in the method of La Puente et al because Carrion et al teach nattokinase is a fibrinolytic enzyme and the 3D plasma matrix of La Puente et al is produced by cross-linking fibrinogen. Additionally, Carrion et al teach nattokinase treatment of a fibrin gel produces a single-cell suspension and La Puente et al is retrieving cells for use in flow cytometry which requires cells to be in a single cell suspension. While the two enzymes work by digesting different components of the 3D plasma matrix, both enzymes can be used for the purpose of digesting the matrix in order to isolate cells. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
Regarding claim 19: Following the discussion of claim 5 above, La Puente discloses a method for culturing stem cells in a 3D culture medium comprising human plasma, a cross-linking agent, and a stabilizer. La Puente discloses the cross-linking agent can be , CaCl2 which reads on comprising calcium. The plasma matrix of La Puente et al is produced by contacting a cross-linking agent (i.e. , CaCl2) which is a component of the medium. Therefore the plasma in the 3D plasma matrix of La Puente et al is coagulated by contact with the cell culture medium.
Claims 5-6, 10, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over La Puente et al (US20220228124A1) PCT filled 06/15/2019 in view of Carrion et al (Tissue Eng Part C Methods, 2013) and Rutgers University Cancer institute of New Jersey (Procedure for separating Plasma and Serum from whole blood, published 3/12/2010) herein referred to as CINJ.
The teachings of La Puente et al and Carrion et al are set forth above.
La Puente et al and Carrion et al render claims 5, 10, and 19 obvious.
Regarding claim 6: Following the discussion of claim 5 above, La Puente et al teach a method for culturing stem cells in a 3D matrix comprising cross-linked human plasma which reads on the plasma is from mammalian blood.
La Puente et al do not teach the plasma is from blood combined with an anticoagulant prior to coagulation.
CINJ discloses a standardized protocol for separating plasma from whole blood. The protocol teaches blood should be collected into a tube with an anticoagulant such as EDTA, Sodium citrate, or sodium heparin (See Sec. Separating plasma). The tube is then centrifuged and the plasma is collected from the tube (See Sec. Separation of Plasma).
Given that La Puente et al teach a method for culturing cells requiring plasma and CINJ teaches a protocol for isolating plasma, it would have been prima facie obvious to collect the plasma of La Puente et al using the protocol of CINJ. One would have been motivated to collect plasma for the method of La Puente et al by the method of CINJ because CINJ teaches a standardized method of collecting plasma. There is a reasonable expectation of success because CINJ teaches a standardized method for collecting plasma.
Claims 5-7, 10, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over La Puente et al (US20220228124A1) PCT filled 06/15/2019 in view of Carrion et al (Tissue Eng Part C Methods, 2013), Rutgers University Cancer institute of New Jersey (Procedure for separating Plasma and Serum from whole blood, published 3/12/2010) herein referred to as CINJ, and TerumoBCT (ACD-A SDS sheet, 2013).
The teachings of La Puente et al, Carrion et al, and CINJ are set forth above.
La Puente et al and Carrion et al render claims 5, 10, and 19 obvious.
La Puente et al, Carrion et al, and CINJ render claims 5-6, 10, and 19 obvious
Regarding claim 7: Following the discussion of claims 5 and 6 above, La Puente et al teach a method for culturing stem cells in a 3D matrix comprising cross-linked human plasma which reads on the plasma is from mammalian blood. CINJ teaches blood plasma is produced by collecting blood in a tube with an anticoagulant and centrifuging the blood to separate the plasma.
La Puente et al and CINJ do not teach using an anticoagulant comprising citric acid, dextrose, and water.
TerumoBCT teaches ACD-A is an anticoagulant used for separation and processing of blood components (See Section 1). ACD-A is composed of citric acid monohydrate, trisodium citrate dihydrate, dextrose monohydrate, and water (See Section 3).
Given that La Puente et al and CINJ teach a method for culturing cells in plasma which is produced by collecting blood in a tube with an anticoagulant and TerumoBCT teaches ACD-A is an anticoagulant solution used for separation and processing of blood components, it would have been prima facie obvious to substitute the anticoagulant of La Puente in view of CINJ with ACD-A. One would have expected ACD-A to work equivocally with the anticoagulant of La Puente in view of CINJ in the plasma separation method of La Puente in view of CINJ because TerumoBCT teaches ACD-A is an anticoagulant used for separation of blood products. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
Claims 5, 8-10, 15, and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over La Puente et al (US20220228124A1) PCT filled 06/15/2019 in view of Carrion et al (Tissue Eng Part C Methods, 2013) and Jackson et al (PMC, 2011).
The teachings of La Puente et al and Carrion et al are set forth above.
La Puente et al and Carrion et al render claims 5, 10, and 19 obvious.
Regarding claims 8, 9, 15, 17, 18, and 20: Following the discussion of claim 5 above, La Puente et al teach a method for culturing stem cells in a 3D matrix comprising cross-linked human plasma which reads on the plasma is from mammalian blood. The plasma may be present at a concentration between 30% and 50% v/v which reads on the culture medium comprises 5 to 70 vol. %. Additionally, the plasma matrix can be disgusted using collagenase (reads on a proteolytic enzyme) in order to retrieve the cells for analysis be flow cytometry.
La Puente et al do not teach the stem cells are mammalian muscle derived mesenchymal cells.
Jackson et al review therapeutic applications of muscle-derived stem cells (see abstract). Jackson et al teach human mesenchymal stem cells can be harvested from healthy muscle biopsies (See Sec. 2. Skeletal muscle-derived mesenchymal stem and progenitor cells).
Given that La Puente et al teach a method of culturing stem cells and Jackson et al teach human mesenchymal stem cells can be isolated from muscle biopsies, it would have been prima facie obvious to substitute the stem cells of La Puente et al with mesenchymal stem cells of Jackson et al which are isolated from skeletal muscle. Culturing mesenchymal stem cells from muscle cell would inherently require a step of placing the cells (reads on muscular extracts) in the culture medium. One would have expected the muscle derived stem cells of Jackson et al to grow in the culturing method of La Puente et al because Puente et al et al teach the method can be used to culture stem cells. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
Additionally, given that the muscle stem cells of Jackson are derived from human muscle and the plasma of La Puente is human plasma, the stem cells and plasma are inherently allogenic or autologous to one another.
Additionally, La Puente do not teach resolubilizing the plasma matrix with nattokinase, bromelain, or tissue plasminogen activator.
Carrion et al teach a method of retrieving mesenchymal stem cells from a three-dimensional fibrin gel by treating the gel with nattokinase, a fibrinolytic enzyme. Treatment with nattokinase for 30 minutes results in dissolution of the gel and produces mesenchymal stem cells which are in a single-cell suspension (See abstract and Fig. 1).
Given that La Puente et al teach a method for retrieving stem cells from a 3D plasma culture matrix comprising cross-linked fibrinogen by digesting the plasma matrix with collagenase and Carrion et al teach a method of retrieving stem cells from a 3D fibrin gel by treating the gel with the fibrinolytic enzyme nattokinase, it would have been prima facie obvious to substitute the collagenase of La Puente et al with nattokinase in the method of La Puente et al. One would have expected the nattokinase of Carrion et al to work equivocally with the collagenase of La Puente et al, for the purpose of isolating cells from the 3D plasma matrix, in the method of La Puente et al because Carrion et al teach nattokinase is a fibrinolytic enzyme and the 3D plasma matrix of La Puente et al is produced by cross-linking fibrinogen. Additionally, Carrion et al teach nattokinase treatment of a fibrin gel produces a single-cell suspension and La Puente et al is retrieving cells for use in flow cytometry which requires cells to be in a single cell suspension. While the two enzymes work by digesting different components of the 3D plasma matrix, both enzymes can be used for the purpose of digesting the matrix in order to isolate cells. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
Conclusion
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/MARISOL ANN O'NEILL/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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