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 amendments and arguments filed on 06-30-2025 have been received and entered. Claims 1, 5, 10, 11, 14 have been amended. Claims 2-4, 6-9, 12, 15-19 have been canceled. Claims 1, 5, 10-11, 13-14 are pending and under consideration.
Priority
This application is a continuation of application PCT/JP2021/000746 filed on 01/13/2021that claims priority from foreign application JP 2020-003959 filed on 01/14/2020.
Receipt is acknowledged of certified copies of papers required by 37 CPR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)- (d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CPR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Claim Objections
Claims 10 is objected to because of the following informalities:
In the instant case, the phrase “induced pluripotent ste” in claim 10 should read “induced pluripotent stem”.
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Withdrawn-Claim Rejections - 35 USC § 112
Claims 1-18 were 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. In view of Applicants' amendment of base claim 1 and claims’ cancelation, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn-Claim Rejections - 35 USC § 102
Claims 1-4, 19 were rejected under 35 U.S.C. 102 (a)(1) and(a)(2) as being anticipated by Budach et al (Pub. No.: US 2013/0102032 A1, Pub. Date: Apr. 25, 2013). In view of Applicants' amendment of base claim 1 and claims’ cancelation the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below.
New- Claim Rejections - 35 USC § 112- necessitated by amendments
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 13-14 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
In the instant case, claims 13-14 do not satisfy the requirements of 112(d) because claim 1 is directed to “pluripotent stem cells, adult stem cells or progenitor cells”; however, claims 13-14 are directed to “the cell is derived from an iPS cell” which encompass not only stem cells or progenitor cells but also various differentiated cell types or terminally differentiated cells. Thus, the scopes of claims 13-14 do not further limits the subject matter of the claim 1 (and claim 5 which depends from claim 1).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Maintained in modified form and New- Claim Rejections - 35 USC § 103- necessitated by amendments
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, 5, are rejected under 35 U.S.C. 103 as being unpatentable over Budach et al (Pub. No.: US 2013/0102032 A1, Pub. Date: Apr. 25, 2013) in view of Clemens et al (Pub .No.: US 2018 /0346881 A1, Pub. Date: Dec. 6, 2018)
Claim Interpretation
The specification of the claimed invention teaches that the choline to be used in the method of the present invention is not particularly limited as long as it is of the grade used for cell culture, and a commercially available product may be used. Preferred choline includes choline chloride, choline bitartrate, choline bicarbonate, choline phosphate, choline dihydrogen citrate and the like, with preference given to choline chloride (Last para. on page 4 to first para. on page 5). Thus, choline salts such as choline chloride are interpreted as the choline that can be used.
The specification of the claimed invention teaches that in the case of suspension culture of iPS cells, culture at a density of not less than 6x10 5 cells/mL is defined as the high-density culture in the present specification. Thus, culture at a density of not less than 6x105 cells/mL is interpreted as the high-density culture.
Regarding to claim 1, the preamble, Budach et al teach that a cell culture medium with high content of choline chloride and the cell culture media with high content of choline chloride are particularly suitable for fed-batch cell culture whereby cell viabilities stay at a higher level for a longer time (Abstract).
Regarding to claim 1, step (1), Budach et al teach that the cell culture medium according to the present invention can be used in various cell culture processes. Cultivation of cells can be carried out in suspension culture ([0091], page 6)
Regarding to claim 1, step (2), Budach et al teach that a cell culture medium is provided with a content of choline chloride in the range of 60 mg/L to 2500 mg/L ([0031], page 2). Budach et al teach feeding rate of 2 and 0.4% of the initial culture volume per day ([0130], page 8). Since 2 and 0.4% of the culture medium is added per day, it is considered that the choline can be added to the culture medium at a rate of 60 mg/L/day (2.4 %*2500 mg/L).
It is noted that Budach et al teach commonly used cell culture media like D-MEM (Dulbecco's Modified Eagle Medium) and D-MEM/F-12 have been widely used for the growth of a wide range of mammalian cell lines. These media include amounts of choline chloride of 4 mg/L and 8.98 mg/L, respectively (see [0015], page 1). However, Budach et al do not specifically teach “the cells are pluripotent stem cells, adult stem cells or progenitor cells” and “high density culturing the cells”. Clemens et al cure the deficiency.
Clemens et al teach a basal cell culture medium and a feed medium with novel amino acid ratios and/or iron choline citrate as iron carrier that result in improved performance of mammalian cell culture processes (Abstract). Clemens et al also teach RPMI Feed premix (1x) with 3 mg/L Choline Chloride (TABLE 5a, page 28), and the cell line was seeded at 0.7x106 cells/ml (7x105 cells/ml) ([0295], page 34) (For the claimed: “high density culturing the cells”) .
Clemens et al teach that “the basal cell culture medium and /or the feed medium or the medium platform of the present invention can be applied to all mammalian cell lines …. the mammalian cell according to the invention may be oocytes, embryonic stem cells , hematopoietic stem cells…” ([0125], page 15). Thus, a person of ordinary skill in the art would be able to use Choline such as 3 mg/L Choline Chloride for culturing all mammalian cell lines such as embryonic stem cells (For the claimed: wherein the cells are pluripotent stem cells, adult stem cells or progenitor cells.).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Budach et al by culturing all mammalian cell lines such as embryonic stem cells and seeding cell concentration at 0.7x106 cells/ml as taught by Clemens et al, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Clemens et al teaches a basal cell culture medium and a feed medium that result in improved performance of mammalian cell culture processes (Abstract). Clemens et al also teach that maximal viable cell count, final product titer, metabolic waste accumulation is significantly improved in a fed-batch process due to the replenishment of nutrients, vitamins, salts and other components ([0121], page 15). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Clemens et al were successful in improved performance of mammalian cell culture processes (abstract) and successful in manufacturing scale-up by applying a platform process with the 2L bioreactor system ([0217], page 26) with detailed instructions and working examples.
Regarding to claim 5, Clemens et al teach cell line was seeded at 0.7x106 cells/ml (7x105 cells/ml) ([0295], page 34)
Claims 10-11, 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Budach et al (Pub. No.: US 2013/0102032 A1, Pub. Date: Apr. 25, 2013) in view of Clemens et al (Pub .No.: US 2018 /0346881 A1, Pub. Date: Dec. 6, 2018) as applied to claims 1, 5 above, and further in view of Tomizawa (Pub. No.: US 2016/0053230 A1, Pub. Date: Feb. 25, 2016).
The teachings of Budach et al and Clemens et al above are incorporated herein in their entirety.
Although Budach et al and Clemens et al teach culture medium with choline for mammalian cell such as embryonic stem cells, they don’t specifically teach iPS cell and the cell is derived from an iPS cell. Tomizawa cures the deficiency.
Regarding to claims 10-11, 13-14, Tomizawa teaches “ medium having a composition shown in Table 1, the concentrations of constituents of MEM vitamin solution in terms of final concentration are as follows: … 0.001 g of choline chloride” (0.001 g of choline chloride = 1mg of choline chloride) ([0061], page 5). Tomizawa teaches a method of inducing differentiation of pluripotent stem cells, such as induced pluripotent stem cells (here in after abbreviated as iPS cells), to hepatocytes in a short period of time, and a substance to be used in the method …… culturing pluripotent stem cells, such as iPS cells, in a culture medium having a composition shown in Table 1 , and a culture medium for inducing differentiation of pluripotent stem cells into hepatoblasts, which has a composition shown in Table 1 (Abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claims to combine the teachings of prior art to modify the method of culturing mammalian cell of Budach et al and Clemens et al by culturing iPS cells or cell derived from an iPS cell such as hepatocytes as taught by Tomizawa, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Tomizawa teaches advantages of using media containing choline chloride such as HDI medium for differentiation of iPS cells into hepatoblasts in short period of time by culturing the iPS cells for 2 days in the culture medium ([0041], page 3), and a cell survival rate is increased in the case where the pluripotent stem cells are precultured ([0069], page 6) in a choline chloride containing culture medium such as DF12 (see DF12-HDI in [0056], page 5). One of skill in the art would have been expected to have a reasonable expectation of success because Tomizawa was successfully generated hepatoblasts by culturing the iPS cells for 2 days in the culture medium, and Tomizawa also provided detailed instructions for medium composition and culturing steps.
Response to Arguments
Applicant's arguments filed on 06-30-2025 have been fully considered but they are not persuasive.
Applicant argues that the claims have been amended to limit the cell to a pluripotent stem cell, an adult stem cell or a progenitor cell. In contrast, Budach et al. and Clemens et al. merely disclose a method for high density suspension culturing Chinese hamster ovary (CHO) cells, which are terminally differentiated cells. Thus, these references fail to teach or suggest that daily addition of choline to a medium for improved expansion of stem/progenitor cells such as iPS cells in high density suspension culture.
Although Tomizawa discloses the use of l mg/L choline in a medium for inducing differentiation ofpluripotent stem cells into hepatocytes, it fails to teach or suggest daily addition of choline. Furthermore, Tomizawa fails to teach or suggest daily addition of choline for high density and suspension culture of stem/progenitor cells. Namely, Tomizawa discloses method of adhesion culture on a Matrigel-coated culture plate.
Thus, the culture methods disclosed in Budach et al. (and Clemens et al.) and Tomizawa are quite different in the cell type to be cultured and the manner of culture (high density suspension culture vs adhesion culture). As such, one of ordinary skill in the art would not have been motivated to combine the disclosures of Budach et al. and Tomizawa to replace CHO cells with pluripotent stem cells (Remarks, page 5).
Response to Arguments:
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In the instant case, Budach et al teach commonly used cell culture media like D-MEM (Dulbecco's Modified Eagle Medium) and D-MEM/F-12 have been widely used for the growth of a wide range of mammalian cell lines. These media include amounts of choline chloride of 4 mg/L and 8.98 mg/L, respectively (see [0015], page 1). Additionally, Clemens et al teach RPMI Feed premix (1x) with 3 mg/L Choline Chloride (TABLE 5a, page 28), and the cell line was seeded at 0.7x106 cells/ml (7x105 cells/ml) ([0295], page 34). Clemens et al also teach that “the basal cell culture medium and /or the feed medium or the medium platform of the present invention can be applied to all mammalian cell lines …. the mammalian cell according to the invention may be oocytes, embryonic stem cells , hematopoietic stem cells…” ([0125], page 15). Finally, Tomizawa teaches medium having 0.001 g of choline chloride (0.001 g of choline chloride = 1mg of choline chloride) ([0061], page 5) for inducing differentiation of pluripotent stem cells, such as induced pluripotent stem cells to hepatocytes in a short period of time (Abstract), and Tomizawa teaches that it is appropriate that medium exchange be performed once every preferably from 1 day to 2 days ([0068], page 6). Thus, a person of ordinary skill in the art would recognize that culturing cells such as iPS can be performed in a medium containing choline chloride as claimed invention with high density of cells.
Conclusion
No Claim is 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.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632