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 .
Claim status
In the reply on 22 September 2023 Applicant has amended claims 3, 5-6, 9-14, 16-17, 20-21, 30-31. Claims 8, 15, 19, and 22-29 have been. Therefore, claims 1-7, 9-14, 16-18, 20-21, and 30-31 are herein pending.
Priority
This application was filed 09/22/2023 and is a 371 application of PCT/JP2022/014459 filed on 03/25/2022, which claims foreign priority to 2021-051004; 2021-051005 and 2021-051006 filed on 03/25/2021. Thus, the earliest possible priority for the instant application is 03/25/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/22/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner and the signed and initialed PTO Forms 1449 are mailed with this action.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-7, 9-14, 16-18, 20-21, and 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over Davis et al., (US20160215257A1; published on Jul. 28, 2016; cited in IDS filed 09/22/2023; hereinafter “Davis’257”), in view of Fryer et al., (US20140295552A1; Pub. Date: Oct. 2, 2014; cited in IDS filed 09/22/2023; hereinafter “Fryer”) and supporting evidentiary reference Takashima et al., (WO2019093340; published on 05/19/2019; cited in PTO892; hereinafter “Takashima”).
Regarding claims 1, and 11-12, Davis’257 describes a method of expanding cell aggregates of pluripotent stem cells and/or the progeny thereof by continuous passaging in a closed system using a stirred tank bioreactor [0033], said method comprising the steps of: the automated perfusion of cell aggregates in the vessel; gravity settling of the cell aggregates during perfusion, aggregate harvest, and passaging in the closed system; and additional expansion of the cell aggregates or progeny thereof by conducting serial passaging (abstract; claims 1, 19-20, [0102] ¶ of Davis’257). The pluripotent stem cell population comprises a cell aggregate, and the cell aggregate is collected during the suspension culture step ([0101] of Davis’257).
In addition, Davis’257 states that culturing in the closed system [0083] for PSC expansion is carried out in the presence of a Rho-associated protein kinase (ROCK) inhibitor [0071]; temperature 37[Symbol font/0xB0]C, CO2 level 5%, ambient O2 (-21%) or a reduced Oxygen level, continuous or discontinuous stir speed of 40 rpm [0096]; and that in the culturing of embryonic stem cells in a 250 mL bioreactor, approximately 150 mL/day of medium was exchanged (claims; [0097]-[0103] of Davis’257).
Nevertheless, it would have been obvious to one having ordinary skill in the art at the time the invention was filed to prepare said nucleic acid because each of the individual elements of the instant claims are independently presented by Davis’257 as embodiments and are taught that they can be combined in various embodiments; therefore a combination of all the elements into a single embodiment would be apparent to an artisan skilled in cell therapy in light of the Supreme Court’s KSR decision (see MPEP 2143 Exemplary Rationale (A)). Regarding the rationale for combining prior art elements according to known methods to yield predictable results, all of the claimed elements were known in the prior art and one skilled in the art could have combined the element as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Each of the elements for the method of producing a pluripotent stem cell population, the suspension culture step comprises controlling the amount of medium perfused per unit time in a variable culture volume as taught by Davis’257 and further taught in various combinations of culture method. It would be therefore predictably obvious to use a combination of these elements in said expression.
Regarding claim 2, Davis’257 discloses that the amount of medium perfused per unit time is determined based on a value obtained by multiplying the culture volume by a proportion of a length of the unit time to 24 hours ([0098]-[0099] of Davis’257).
Regarding claims 3-5, Davis’257 discloses that the suspension culture step is based on one or more culture variables (e.g., ROCK, pH), wherein the control allows the amount of medium perfused per unit time to be proportional to each of the one or more culture variables and the cell density increasing rate represents a proportion of a cell density to a cell density of the pluripotent stem cells at the start of the control ([0066], FIGS.5-7, [0086] of Davis’257).
Regarding claims 6-7, Davis’257 discloses that the culture variables is a pH of a culture solution. The continuous or discontinuous stirring of the culture fluid provides mixing and aeration, resulting in a robust environment for pluripotent stem cells growth. The method employs culture vessels of varying sizes, providing ease of operation and protection against cross-contamination. Sensors are available for continuous monitoring of dissolved oxygen, pH and medium components such as lactate and glucose, with real time controls and data storage. The platform software provides the ability to perform continuous or discontinuous perfusion/medium exchange in a closed system ([0043] of Davis’257). Therefore, POSITA at the time of filling would recognize that oxygen or pH may modify the threshold concentration that provides relatively higher viability and recovery pluripotent stem cells. MPEP 2144.05 states that Generally, 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).
With respect to claim 9, Davis’257 is silent to the culture variables is a lactic acid production rate of the pluripotent stem cells, however, such was known in the prior art.
Regarding claims 9-10, 16-18 and 20, Fryer states that in the culturing of pluripotent stem cells using a stirred-tank bioreactor, and optimized the PSCs production rate using several variables such as lactic acid ([0235], Fig. 48) dissolved oxygen is regulated with CO2, air, O2, and N2, and the pH is adjusted with CO2 ([0155]- [0157], [0200], Fig. 46 of Fryer).
Optimizing cell culturing conditions is a widely known problem, and Davis’257 disclose the technical concept of adjusting the medium perfusion rate by monitoring various culture variables in the perfusion culturing of pluripotent stem cell. Generally, 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) (MPEP 2144(II)(A). In the methods of perfusion culturing of pluripotent stem cells described in Davis’257, a POSITA could have easily conceived of adjusting the medium perfusion rate based on culture variables such as pH, dissolved oxygen, temperature, cell density, metabolites, etc. In addition, when adjusting the culturing conditions, a person skilled in the art as taught by Fryer would not find it particularly difficult to focus on the amount of CO2 supplied in addition to the medium perfusion rate based on the abovementioned content of Davis’257, and to optimize the culture medium using the known culturing ingredients described in Fryer. Furthermore, it is common technical knowledge that in a perfusion culturing method with controlled medium perfusion, etc., the effect set forth in the present application, namely, an increase in the productivity of pluripotent stem cells and an increase in positivity rate of undifferentiated markers, can vary greatly depending on the culturing conditions, and therefore said effect cannot be considered a particularly prominent advantageous effect that could not be predicted by a person skilled in the art.
Accordingly, it would have been obvious to practice the suspension culture method of Davis’257 and optimize the lactic acid, CO2, air, O2, and N2, and the pH as taught by Fryer with a reasonable expectation of success. The POSITA would have been motivated at the time of filing to do so as taught by Fryer because it will drastically increase the cell density (Fig. 45 of Fryer). The POSITA would have had a reasonable expectation of success in combining the teachings of Davis’257 and Fryer because each of these teachings both successfully culture the pluripotent stem cell population. Therefore, the products and method as taught by Davis’257 et al. in view of Fryer et al. would have been prima facie obvious over the products and method of the instant application. In regard to the reasonable expectation of success in doing so, optimize the lactic acid, CO2, air, O2, and N2, and the pH in cell culture method of Fryer had a reasonable expectation of success since the steps thereof required no more than pipetting buffer (e.g., lactic acid, pH) with controlled air flow (e.g., CO2, air, O2, and N2) and cell culture technology.
Regarding claims 12-13, Davis’257 discloses that the pluripotent stem cell population comprises a cell aggregate, and the aggregates formed 2-12 hours after addition of single cells/small clumps to the vessel. The cells formed aggregates between about 50 and 200 µm diameter [0094]. Therefore, POSITA at the time of filling will recognize that one of the culture variables is a cell aggregate volume increasing rate, and the cell aggregate volume increasing rate represents a proportion of a cell aggregate volume to a cell aggregate volume at the start of the control.
Regarding claim 14, Davis’257 discloses that the aggregates remain in the optimal cell culture conditions in the vessel (e.g., a stirred tank bioreactor) during the medium removal step. Medium removal can be continuous e.g., for up to 8 hours, up to 4 hours, and the like, but medium removal can be performed for much shorter or longer lengths of time [0049]. The cell aggregate concentrations below about 3x106 cells per mL produced higher viability samples with higher recovery than cell concentrations greater than about 3x106 cells/mL using a slicer geometry ([0066] of Davis’257). Therefore, POSITA at the time of filling will recognize the cell density of the pluripotent stem cells reached desire cells/mL by increasing an amount of medium perfusion. MPEP 2144.05 states that Generally, 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).
Regarding claim 21, Davis’257 discloses that the methods described above, during the expansions and/or passages, the average diameter of each expanded cell aggregate is no more than about 300-800 micron in size [0069], wherein the aggregates formed 2-12 hours after addition of single cells/small clumps to the vessel [0094].
Regarding claim 30, MPEP 2112.01 states that “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established,” In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). it is noted that the claimed wherein clauses do not recite any additional active method steps, but simply state a function, characterization or measurement of the results of product pluripotent stem cell marker positively recited (e.g., OCT4, SOX2 and NANOG). In here, Davis’257, suggest producing the instant claim pluripotent stem cell specifically, using same cell culture method, so the process of making the product would have been obvious. Furthermore, Davis’257 discloses that the purity and/or homogeneity of the expanded cells obtained from the methods described herein is about 100%. In a supporting document Takashima teaches that the iPS cells expressing OCT4, SOX2 and NANOG, thus the pluripotent stem cells would all have an expression of 90% or higher (see [0011] ¶ of attached STIC MT of Takashima). Accordingly, at the time of the invention POSITA would have obvious expectation that the product pluripotent stem cell will have an expression of 90% or higher OCT4, SOX2 and NANOG marker, and this limitations are not unexpected.
Regarding claim 31, Davis’257 discloses that the Pluripotent stem cells include induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) ([0031] of Davis’257).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MASUDUR RAHMAN whose telephone number is (571)272-0196. The examiner can normally be reached M-F 8-5 (EST).
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/MASUDUR RAHMAN/ Patent Examiner, Art Unit 1633
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684