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 10/02/2025 has been received and entered.
Claims 1-12 and 15-20 are pending, all of which have been considered on the merits.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 2 and 3 under 35 U.S.C. 112(b)
Amendments to the claims overcome the rejection of record. The rejection is withdrawn.
RE: Rejection of claim 15 under 35 U.S.C. 102 over Jalowiec et al (Tissue Engineering Part C: Methods, 2016).
Claim 15 has been amended to depend from claim 8. Jalowiec et al does not anticipate claim 8. Thus, the rejection is withdrawn.
RE: Rejection of claims 1-7, 11-12, and 15 under 35 U.S.C. 103 over Jalowiec et al (Tissue Engineering Part C: Methods, 2016) in view of Amable et al (PLOS One, 2014).
Applicants have amended independent claims 1 and 5 to recite the limitation that no additional growth factors are present in the cell culture medium. Additionally, applicants have traversed the rejection of record on the grounds that there is no motivation to combine the PRP of Jalowiec et al with the PRP of Amable et al because the PRP of Amable et al is depleted of calcium and fibrinogens and is therefore not capable of forming a gel. Applicants have further traversed claim 5 on the grounds that Amable et al does not teach or suggest “releasing the cultured cells without use of trypsin”.
In response, the arguments have been fully considered but are not convincing. The rejection of record does not suggest combining the PRPs of Jalowiec et al and Amable et al. Instead, Amable et al presents a rationale for using 10% PRP in a MSC culture medium.
Additionally, while the culture method of Amable et al uses trypsin, the rejection of record does not rely upon combining the culturing methods of Amable et al and Jalowiec et al. The method of Jalowiec et al does not use trypsin. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
However, both Jalowiec et al and Amable et al use a culture medium comprising FBS which reads on having additional growth factors. Therefore, the amendments to the claims overcome the rejection of record.
The rejection is therefore withdrawn.
RE: Rejection of claims 1-12, and 15 under 35 U.S.C. 103 over Jalowiec et al (Tissue Engineering Part C: Methods, 2016) in view of Amable et al (PLOS One, 2014) and further in view of Serteyn et al (US10633633B2).
Applicants’ amendments to independent claims 1 and 5 requiring the limitation that no additional growth factors are present in the cell culture medium overcome the rejection of record.
The rejection is withdrawn.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-12 and 15-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1-12 and 15-20: Claims 1-12 and 15-20 require a culture medium comprising coagulated blood plasma wherein the blood plasma includes one or more growth factors and no additional growth factors are present in the culture medium. The broadest reasonable interpretation of the term “blood plasma” can comprise platelet rich plasma (PRP) and platelet poor plasma (PPP). The growth factors present in PRP and PPP differ since platelets release growth factors. It is unclear whether the growth factors released by platelets, in PRP, are considered part of the plasma serum or “additional growth factors”.
Regarding claim 17: Claim 17 recites the limitation “the stem cells are allogenic or autologous”. It is unclear to what the stem cells are allogenic or autologous. For the purpose of compact prosecution the claim will be interpreted as requiring stem cells that are allogenic or autologous to the blood plasma.
Regarding claims 18 and 20: Claims 18 and 20 require the limitation of allogenic or autologous blood plasma. It is unclear to what the blood plasma is allogenic or autologous. For the purpose of compact prosecution, the claims will be interpreted as requiring blood plasma that is allogenic or autologous to the stem cells.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by La Puente et al (US20220228124A1) PCT filled 06/15/2019.
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 1-4: La Puente et al teach a 3D human plasma culture matrix, produced by cross linking fibrinogen, which reads on a 3D cell culture medium comprising coagulated mammalian blood plasma and a 3D substrate for 3D cell growth. 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. %, at least 10 vol. % and at most 60 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.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5, 10-12, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over La Puente et al (US20220228124A1) PCT filled 06/15/2019.
The teachings of La Puente et al are set forth above.
La Puente et al anticipates claims 1-4.
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.
Regarding claims 11 and 12: Following the discussion of claim 5 above, La Puente et al discloses the 3D plasma matrix can be digested with collagenase which reads on resolubilizing the coagulated mammalian plasma with a proteolytic enzyme.
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 1-5, 6, 10-12, 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 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 are set forth above.
La Puente et al anticipates claims 1-4 and renders obvious claims 5, 10-12, 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 1-7, 10-12, 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 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 are set forth above.
La Puente et al anticipates claims 1-4 and renders obvious claims 5, 10-12, and 19 obvious.
La Puente et al and CINJ render claim 6 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 1-5, 8-12, 15, 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 Jackson et al (PMC, 2011).
The teachings of La Puente et al are set forth above.
La Puente et al anticipates claims 1-4 and renders obvious claims 5, 10-12, 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.
Claims 1-5, 10-12, 16, 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).
The teachings of La Puente et al are set forth above.
La Puente et al anticipates claims 1-4 and renders obvious claims 5, 10-12, and 19 obvious.
Regarding claim 16: Following the discussion of claims 5, 11, and 12 above, La Puente et al teach a method of culturing stem cells in a plasma matrix produced by cross linking fibrinogen. La Puente et al further teach collagenase can be used to digest the plasma matrix (reads on resolubilizing ) in order to retrieve the cells for analysis by flow cytometry.
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 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. 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
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 MARISOL A O'NEILL whose telephone number is (571)272-2490. The examiner can normally be reached Monday - Friday 7:30 - 5:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at (571) 272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARISOL ANN O'NEILL/ Examiner, Art Unit 1633
/ALLISON M FOX/ Primary Examiner, Art Unit 1633