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 .
Applicant’s amendment and response filed on 10/24/2025 has been received and entered into the case.
Claims 2, 9 and 17-18 have been canceled, and claims 1, 3-8, 10-16 have been considered on the merits. All arguments have been considered.
Response to Amendment
The claim rejection under 35 USC 35 U.S.C. 112(a) has been withdrawn due to the instant amendment.
The claim rejection under 35 USC 35 U.S.C. 112(b) has been withdrawn due to the instant amendment.
The claim rejection under 35 USC 35 U.S.C. 101 has been withdrawn due to the instant amendment.
The claim rejection under 35 USC 35 U.S.C. 102 has been withdrawn due to the instant amendment.
The claim rejection under 35 USC 35 U.S.C. 103 has been withdrawn due to the instant amendment. As shown below, a new 103 rejection has presented in order to address the newly added limitations.
The double patenting rejection has been modified to address the newly added limitations.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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 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.
Claim(s) 1, 3-7, 10-11 and 13-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sekiya2019 (2019, Cell Transplantation; IDS ref.) in view of Waise et al. (2019, Scientific Reports), Sugita et al. (2016, Regenerative Therapy; of record), Helweg (2019, VitaCyte; of record) and Rahimian (US2016/0228607; of record) as evidenced by Roche2020 (2020, Collagenases from Clostridium histolyticum; of record).
Regarding claims 1 and 3-5, Sekiya2019 teach a method of isolating synovium-derived MSCs from a human synovium tissue by digesting in a solution of 5 mg Liberase MNP-S GMP in 5 ml HBSS for 3 hr, and then the digested cells were cultured in a-MEM containing 10% autologous human serum (p.1147, 1st col.). The Liberase MNP-S GMP of Sekiya2019 and its concentration (i.e. 5 mg/ml) would meet the enzyme of claims 1 and 3-5.
Sekiya2019 do not teach that the aqueous solution for the step of treating a synovial tissue comprising an enzyme and human serum.
However, it is known in the art that the tissue digestion with collagenase and protease can be carried out in a culture medium containing serum.
Sugita et al. teach that the tissue dissociation of synovial membrane can be carried out in a growth medium containing DMEM supplemented with FBS and collagenase (p.80, 1st col. Materials and methods).
Waise et al. teach the use of different protease cocktails including Collagenase P, Liberase DL, TL and TM on fibroblast isolation from lung tissue in the ‘complete’ DMEM containing fetal calf serum (p.7, Tissue disaggregation). Waise et al. teach that the ‘complete’ DMEM is utilized for the culturing of the cells (p.8, Cell Culture).
It would have been obvious to a person skilled in the art to use the culture medium utilized for culturing the synovial derived MSCs, i.e. a-MEM containing 10% autologous human serum, for tissue digestion. A person of ordinary skilled in the art would have been motivated to do so because it is known in the art that Liberases can be utilized for tissue digestion/disaggregation in the culture medium containing serum as taught by Waise et al. and Sugita et al. Furthermore, it is known in the art that collagenases, present in Liberase, cannot be effectively inhibited or inactivated by serum-containing media/buffers according to Helweg (p.1). It is also evident that collagenases are inherently not inhibited by serum according to Roche2020 (p.6, Inhibition). Therefore, one skilled in the art would use the a-DMEM containing human serum for the treating the synovial tissue with Liberase MNP-S GMP with a reasonable expectation of success as the complete culture medium including serum would be recognized as the most suitable solution to maintain the viability of the desired cells, i.e. synovial-derived MSCs.
Sekiya2019 in view of Sugita et al., Waise et al., Helweg and Roche2020 do not particularly teach the step of washing the enzyme until a residual enzyme concentration in a supernatant is 0.5 ng/ml or less, and the washing includes a plurality of washing times using a culture medium.
As Helweg and Roche2020 indicated, collagenases in Liberase MNP-S would not be inhibited by the presence of serum, thus, one skilled in the art would recognize that in order to inactivate or stop the reaction of collagenase, the enzyme has to be physically removed from the cell preparation.
It is also known in the art that residual collagenase would be removed by a repeated washing step according to Rahimian. Rahimian teaches a method of isolating adipose-derived stem cells from a adipose tissue using collagenase (paras. 25-28), and the residual collagenase is removed by repeated washing steps involving centrifugation (para. 30).
Therefore, it would have been obvious to a person skilled in the art to wash repeatedly (i.e. plurality of washing times) to remove the residual enzyme until there is no detectable enzyme present or detectable in the cell preparation with a reasonable expectation of success.
Regarding the washing step using a culture medium, the cited references do not particularly teach the use of culture medium for washing after tissue digestion. However, as the digestion can be carried out using the culture medium as discussed above, and the resulting synovial MSCs after digestion are cultured in the same culture medium, it would have been obvious to a person skilled in the art to use the culture medium to wash the digested tissue/cells prior to the culturing steps with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so because one skilled in the art would recognize that a culture medium would be the most suitable solution for maintaining viability of the cells during the handling of the cells including digestion, washing and culturing.
While the cited references do not particularly teach that the washing step until the supernatant comprises a residual enzyme concentration being 0.5 ng/ml or less, however, it would have been obvious to a person skilled in the art to determine the concentration of collagenase from the supernatant obtained after centrifugation taught by Rahimian whether the enzyme is effectively removed. As the concentration of “0.5 ng/ml or less” is interpreted as an undetectable amount of the enzyme, and thus, one skilled in the art would determine the concentration of collagenase of Sekiya2019 after each washing step until there is no residual enzyme in the cell preparation.
Regarding claim 6 directed to the synovial tissue being derived from a single donor, Sugita et al. teach the method of isolating human mesenchymal stem cells from synovial membrane by using a synovial tissue and synovial tissues from each donor were divided into three aliquots (0.5 g each) and meticulously minced using surgical scissors and then digested with a collagenase solution (p.80, 1st col., 2.1).
It would have been obvious to a person skilled in the art to use the synovial tissue from a single donor to prepare synovium derived MSCs of Sekiya2019 as Sugita et al. teach the use of the synovial tissue from each individual donor for preparing the MSCs with a reasonable expectation of success.
Regarding claim 7, the wherein clause is considered optional as the step of transplanting is not required by the claimed method of producing the synovium-derived mesenchymal stem cells. Thus, the wherein clause of claim 7 does not provide patentable weight in determining patentability of the claimed method of producing the synovium-derived MSCs. Regardless, Sekiya2019 teach the step of transplanting autologous synovium-derived MSCs to the patient (Abstract; p.1447).
Regarding claim 10 directed to the culture medium being a-MEM, Sekiya2019 teach the use of a-MEM for culturing the synovium-derived MSCs (p.1447, 1st col.).
Regarding claim 11 directed to the culturing step for 10-21 days, Sekiya2019 teach the step of culturing autologous synovial MSCs for 14 days after harvest (p. 1447, 1st col.).
Regarding claim 13 directed to the culturing in a culture medium containing an autologous serum, Sekiya2019 teach the limitation (p.1447, 1st col.).
Regarding claim 14 directed to the culturing the synovium-derived MSCs without any other cell, the culturing step taught by Sekiya2019 does not include any other cells, and thus meet the limitation of claim 14.
Regarding claims 15-16, the limitation directed to the production method comprising the step of producing a synovium-derived MSCs by the method of claim 1 is met by the teachings of Sekiya2019 in view of Sugita et al., Waise et al., Helweg and Rahimian as discussed above. The second producing step for a cell preparation or the intended purpose of a joint medical treatment which is a meniscus injury does not provide any active step. Regardless, Sekiya2019 teach treating a medial meniscus tear in the knee using synovial MSCs (abstract), and this would meet the second production step of claims 15-16.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sekiya2019 in view of Sugita et al., Waise et al., Helweg and Rahimian as applied to claim 1 above, and further in view of Novagen (2008, ProteoExtract Collagenase Set; of record).
Regarding claim 8 directed to the mass ratio between the synovial tissue to the enzyme being 1,000:1 to 10:1, Sekiya2019 in view of Waise et al., Helweg and Rahimian do not particularly teach the limitation.
However, the mass ratio between the substrate (synovial tissue) and enzyme (collagenase; Liberase) would have been readily modified in order to obtain desired dissociation of the tissue to release synovium-derived cells including MSCs by routine experimentations. Furthermore, according to Novagen, the starting point for the concentration of collagenase is about 10,000 units per g of tissue (p.3), and considering the activity of collagenase per mg of dry weight being more than 100, 125 or 160 (see Table at p. 2), 10,000 units would be about 60-100 mg (or 0.06-0.1 g). From this calculation, the mass ratio of the tissue to enzyme would be 1 g of tissue to 0.06-0.1 g of collagenase, which is 17:1 to 10:1.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sekiya2019 in view of Waise et al., Helweg and Rahimian as applied to claims 1 and 11 above, and further in view of Khong et al. (2017, Exp. Cell Res.; of record)
Regarding claim 12 directed to the culturing step for 10 days or more without culture medium change, the cited references do not particularly teach the limitation.
Khong et al. teach that MSCs can be cultured for 10 days before media change (p.103, 1st col., 2.1 Isolation of MSCs and whole BMCs).
It would have been obvious to a person skilled in the art to culture the synovium-derived MSCs isolated by the method of Sekiya2019 for 10 days before media change taught by Khong et al. with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so because frequent media change can be expensive and as MSCs can culture without media change for 10 days, one skilled in the art would try to culture the synovium-derived MSCs without media change for 10 days.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-8, 10-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application No. 18145922 (reference application) in view of Sugita et al. (supra), Waise et al. (supra), Helweg (supra) and Rahimian (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘922 application disclose the production method for a synovium-derived mesenchymal stem cells by using a mixed enzyme comprising collagenases and neutral proteases for 2 hours or more and culturing for 10 days or more, which is identical to the condition including concentration, duration, source, etc. disclosed in the instant application.
The claims of the ’922 application do not disclose the limitation with regard to the presence of human serum along with an enzyme in the aqueous solution to treat the synovial tissue. However, it is known in the art that the tissue digestion with collagenase and protease can be carried out in a culture medium containing serum.
Sugita et al. teach that the tissue dissociation of synovial membrane can be carried out in a growth medium containing DMEM supplemented with FBS and collagenase (p.80, 1st col. Materials and methods).
Waise et al. teach the use of different protease cocktails including Collagenase P, Liberase DL, TL and TM on fibroblast isolation from lung tissue in the complete DMEM containing fetal calf serum (p.7, Tissue disaggregation).
It would have been obvious to a person skilled in the art to use the culture medium utilized for culturing the synovial derived MSCs, i.e. a-MEM containing 10% autologous human serum, for tissue digestion. A person of ordinary skilled in the art would have been motivated to do so because it is known in the art that Liberases can be utilized for tissue digestion/disaggregation in the culture medium containing serum as taught by Sugita et al. and Waise et al. Furthermore, it is known in the art that collagenase, present in Liberase, cannot be effectively inhibited or inactivated by serum-containing media/buffers according to Helweg (p.1). It is also evident that collagenases are inherently not inhibited by serum according to Roche2020 (p.6, Inhibition). Therefore, one skilled in the art would use the a-DMEM containing human serum for the treating the synovial tissue with Liberase MNP-S GMP with a reasonable expectation of success.
Regarding the washing step using a culture medium, the cited references do not particularly teach the use of culture medium for washing after tissue digestion. However, as the digestion can be carried out using the culture medium as discussed above, and the resulting synovial MSCs after digestion are cultured in the same culture medium, it would have been obvious to a person skilled in the art to use the culture medium to wash the digested tissue/cells prior to the culturing steps with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so because one skilled in the art would recognize that a culture medium would be the most suitable solution for maintaining viability of the cells during the handling of the cells including digestion, washing and culturing.
The claims of the ’922 application do not disclose the limitation with regard to the plurality of the washing step.
However, it is known in the art that collagenase cannot be effectively inhibited or inactivated by serum-containing media/buffers according to Helweg (p.1). It is also evident that collagenases are inherently not inhibited by serum according to Roche2020 (p.6, Inhibition). Thus, one skilled in the art would recognize that in order to inactivate or stop the reaction of collagenase, the enzyme has to be physically removed from the cell preparation.
It is also known in the art that residual collagenase would be removed by a repeated washing step according to Rahimian. Rahimian teaches a method of isolating adipose-derived stem cells from a adipose tissue using collagenase (paras. 25-28), and the residual collagenase is removed by repeated washing steps involving centrifugation (para. 30).
Therefore, it would have been obvious to a person skilled in the art to wash repeatedly to remove the residual enzyme until there is no detectable enzyme present or detectable in the cell preparation with a reasonable expectation of success.
While the cited references do not particularly teach that the washing step until the supernatant comprises a residual enzyme concentration being 0.5 ng/ml or less, however, it would have been obvious to a person skilled in the art to determine the concentration of collagenase from the supernatant obtained after centrifugation taught by Rahimian whether the enzyme is effectively removed. As the concentration of “0.5 ng/ml or less” is interpreted as an undetectable amount of the enzyme, and thus, one skilled in the art would determine the concentration of collagenase of Sekiya2019 after each washing step until there is no residual enzyme in the cell preparation.
Thus, the claims of the ‘922 application in view of Waise et al., Helweg and Rahimian render the claims of the instant application obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant’s arguments with respect to the rejection(s) have been fully considered and are persuasive. Therefore, the rejections have been withdrawn as indicated above. However, a new ground(s) of rejection is necessitated based on the instant amendment that requires limitations not examined previously.
It is noted that applicant alleged that there is a significant increase in cell yield referring paragraph [0060] of the instant specification. Applicant further stated that the claimed invention demonstrates a more advanced technical effect in that the necessary cell yield is reliably obtained and efficacy can be reliably achieved. Applicant’s statement is not particularly supported by factual evidence, and applicant is advised to provide factual evidence, preferentially via a declaration, supporting the allegation, and address how the cell yield as alleged from the claimed method would be unexpected and/or surprising in comparison to the prior art teachings.
Conclusion
No claims are allowed.
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 TAEYOON KIM whose telephone number is (571)272-9041. The examiner can normally be reached 9-5 EST Monday-Friday.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631