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 .
Priority
The instant application is a CON of PCT/JP2021/012327, filed 3/24/2021. Acknowledgement is made of the applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d) to Japanese application 2020-054572, filed 3/25/2020.
Claim Status
In the response filed on July 22, 2025, Applicant cancelled claims 1-21 and filed new claims 22-33.
Applicant’s election without traverse of Group III (claims 10-21) drawn to a method for culturing a cell, comprising culturing in a medium according to 4-(2-hydroxyethyl)- 1-piperazineethanesulfonicacid (HEPES) at a concentration of not less than 30 mM, and having an osmotic pressure of not more than 340 mOsm/kg, classified in C12N 5/0696 was made without traverse in the reply filed on April 10, 2025.
Accordingly, claims 26-29 (i.e. directed to a cell-containing composition) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim
Currently, Claims 22-25, and 30-33 will be examined on the merits herein.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
The rejection of claims 10-13, 16 and 19 under 35 U.S.C. 102(a)(1) as being anticipated by Tsao (US2005/0101011 A1, published 2005, cited IDS 1/11/23) is withdrawn because the prior art is silent regarding stem cells.
The rejection of claims 10-13, and 16 under 35 U.S.C. 102(a)(1) as being anticipated by Keen et al., (US5316938A, published 1994, cited IDS 1/11/2023) is withdrawn because the prior art is silent regarding stem cells.
The rejection of claims 10-13, and 16 under 35 U.S.C. 102(a)(1) as being anticipated by Moore (US5328844, published 1994) is withdrawn because the prior art is silent regarding stem cells.
The rejection of claims 10-21 on the ground of provisional nonstatutory double patenting as being unpatentable over claims 1, 3, 5, and 8-13 of co-pending Application No. 17/863,832 (reference application, hereinafter as the “’832 application”) in view of Muffat et al., (US2018/0179494 A1, published 2018), in view of Michl, et al., (Communications biology 2.1: 144, published 2019; cited IDS 5/15/24) is withdrawn as the Applicant has noted that the application file for the '832 application reveals that a nonfinal Office Action was issued on January 14, 2025 and is now more than six months after the statutory deadline for response and no response has been filed.
Claim Objections
Claim 22 and 30 are objected to because of the following informalities: grammar/typo. Claims 22 and 30 recite “at a concentration of from 30mM to 190mM.” It is suggested that the Applicant delete the “of” since the concentration is being recited as a range. Appropriate correction is required.
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.
Claims 22-25 and 30-33 are rejected under 35 U.S.C. 103 as being unpatentable over Tsao (US2005/0101011 A1, published 2005; cited IDS 01/11/23, prior art of record), in view of Muffat et al., (US2018/0179494 A1, published 2018, prior art of record), and Michl, et al., (Communications biology 2.1: 144, published 2019; cited IDS 5/15/24, prior art of record).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on April 23, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Regarding claim 22, 24-25, 30, and 32-33, Tsao discloses a method for culturing a cell, comprising culturing in a medium comprising 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (i.e. HEPES)(see e.g. abstract, para. 37, 47, 55) at a concentration from 30 mM to 190 mM (i.e. 50mM)(see e.g. claim 11, para. 48; Example 2). Further, Tsao discloses having an osmotic pressure of not more than 340 mOsm/kg (see e.g. para. 55; Example 2).
Tsao is silent regarding where the cell is a pluripotent stem cell that is an induced pluripotent stem cell (iPS).
However, Muffat discloses a method for culturing, preparing, and proliferating an induced pluripotent stem cell (iPS cell) (see e.g. abstract and claims 1, 23, 50; Table 1), comprising 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES)(see e.g. para. 48, 54-55, 162, claim 9, 27, and Table 1) and having an osmolarity of at least 275 mOsm/kg, corresponding to the claim limitation of having an osmotic pressure of not more than 340 mOsm/kg (see e.g. para. 5, 37, 80; claim 1 and 22).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the cell culture methods of Tsao to incorporate a pluripotent stem cell that are iPS cells as taught by Muffat because both Tsao and Muffat (see e.g. para. 186)teach optimizing serum-free cell culture methods and using a medium with HEPES (see e.g. abstracts). As Tsao teaches long-term culture of cells in a medium with HEPES and Muffat teaches methods of pluripotent stem cells in culture using a medium with HEPES and having an osmolarity of at least 275 mOsm/kg, it would have been obvious to incorporate iPS cells with a reasonable expectation of success. Further, Tsao discloses that after the HEPES is added to the medium that the osmolarity should be adjusted to the satisfactory range (see e.g. para. 55). Additionally, the prior art of Michl discloses that when preparing culture media supplemented with HEPES (i.e. non-volatile buffers) a person of ordinary skill in the art should calculate and measure the changes in pH, free calcium, and total osmolarity to avoid non-physiological conditions (see e.g. pages 1-2, 6, 10, Figs.4- 6). Therefore, a person of ordinary skill in the art would have combined similar cell culture medium methods, which would have led to predictable results with a reasonable expectation of success. Furthermore, an artisan of ordinary skill in the art of (i.e. cell culture media) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 23 and 31, Tsao discloses wherein the osmotic pressure of the medium is from 290-325 mOsm/Kg, corresponding to the claimed range of 220 mOsm/kg to 340 mOsm/Kg (see e.g. paras. 14, 55-56)(see e.g. abstract, claim 11, paras. 7, 14, 37, 55-56, 67, 74, and 77; Example 2).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant asserts that although the Tsao reference “includes descriptions that overlap with the osmotic pressure and HEPES concentration specified in the present claims, however Tsao does not indicate that these conditions are simultaneously satisfied”. Applicant argues that “Therefore, Tsao does not disclose, (HEPES) at a concentration of not less than 30 mM, and having an osmotic pressure of not more than 190mM," as presently claimed” (Remarks, page 10).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
Applicant’s response is noted to have recited the presently cancelled claims, where the independent claims 22 and 30 now recite the range of HEPES concentration “from 30mM to 190mM”. Further, the following is noted from the MPEP: MPEP 2144.05: “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).” Accordingly, Tsao discloses the HEPES concentration at 50mM which reads on the claimed range of 30mM to 190mM, as discussed above.
In response to Applicants argument that Tsao does not indicate that these conditions are “simultaneously satisfied,” although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Furthermore, 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). The claim does not read that the HEPES concentration and osmolarity are simultaneously satisfied. However, Tsao discloses that after the appropriate concentration of HEPES is added to the medium that the osmolarity should be adjusted to the satisfactory range (see e.g. para. 55). Accordingly, it would have been obvious for a person of ordinary skill in the art to adjust the concentration and osmolarity as taught by Tsao because Tsao discloses that it would have been obvious to optimize to the appropriate concentration and osmolarity. Further, it is noted that the independent claims 22 and 30 recite the claim language of “comprising” which does not exclude other embodiments (see MPEP 2111.03).
Applicant asserts that the inventors found that “even with a high concentration of HEPES, damage to cells can be reduced by lowering the osmotic pressure, and that this finding allowed the inventors to be the first to identify the utility of appropriately defining the numerical ranges for both HEPES concentration and osmotic pressure in the context of the claimed methods” (Remarks, page 11).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicants’ argument, the following is noted from the MPEP: MPEP § 2144.05 (II) states, “Generally, differences in time, concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical”. Per M.P.E.P. § 2144.05(II)(A), “[g]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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 the instant case, neither the specification nor Applicant have provided evidence of that the claimed concentration range of HEPES is critical. Thus, the general conditions of claims 22 and 30 are disclosed in the prior art, as discussed above, and the limitation of concentration and osmolarity is considered a variable that is also able to be optimized under routine conditions. Furthermore, it is noted that the claims do not recite a method with “a high concentration of HEPES, and a step of lowering the osmotic pressure”. Regardless, Tsao discloses a range of HEPES concentrations and osmolarity and renders the claimed concentration obvious, as discussed above.
In response to applicant's argument that damage to cells can be reduced by lowering the osmotic pressure, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Applicant acknowledges that “Tsao discloses an upper limit of the HEPES concentration of 50 mM” (Remarks, page 11). Applicant argues that “although the Michl reference is cited to assert that optimizing cell culture conditions is obvious to a person skilled in the art, in the ordinary course of reasoning (i.e., considering that high concentrations of buffering agents would be expected to cause cellular damage), Michl would not have led a skilled artisan to arrive at the appropriate ranges of HEPES concentrations and osmotic pressure as defined in the present claims” (Remarks, page 12).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive. As discussed above, the HEPEs concentration is a range, as discussed above.
In submitting evidence asserted to establish unobvious results, there is a burden on an applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. See In re Borkowski, 595 F.2d 713, 184 USPQ 29 (CCPA 1974); In re Goodman, 339 F.2d 228, 144 USPQ 30 (CCPA 1964). It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. In re Merck, 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986); In re Longi, 759 F. 2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Klosak, 455 F2d 1077, 173 UAPQ 14 (CCPA 1972); In re D’Ancicco, 429 F.2d 1244, 169 USPQ 303 (CCPA 1971 ). Ex parte Gelles, 22 USPQ2d 1318 (BPAI 1992).
In response to Applicant argument that Michl would not have led a skilled artisan to arrive at the appropriate ranges of HEPES concentrations and osmotic pressure as defined in the present claims, it is noted that Applicant has not cited where Michl teaches away from the claimed invention. As discussed above, Michl is cited for optimizing cell culture conditions, which would be obvious to a person skilled in the art, because Michl teaches controlling pH in mammalian live-cell culture systems and methods for enhancing buffer capacity with HEPEs and the effect of its relationship with osmolarity (see e.g. fig. 4). Furthermore, Michl is not cited for teaching the HEPES concentration and osmolarity, the prior art of Tsao and Muffat are cited for disclosing the HEPES concentration and osmolarity, as discussed above.
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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JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631