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 arguments filed 9-3-25 have been fully considered but they are not persuasive.
Claims 1-9, 11-17, 19, 21-23, 25-28 have been canceled. Claim 30 has been added. Claims 10, 18, 20, 24, 29, 30 are pending and under consideration.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Interpretation
The limitation of “not less than 176 μM” in claim 17 is equivalent to ---at least 176 μM---.
Claim Objections
The preamble can be written more clearly as ---A method of maintaining pluripotency in mammalian pluripotent cells, the method comprising:---
Step a) of claim 10 can be written more clearly as “culturing mammalian pluripotent cells in serum-free medium comprising L-kynurenic acid or kynurenic acid[[,]] such that pluripotency is maintained”.
Step c) can be written more clearly as “culturing the cells obtained in step (b) in [[the] serum-free medium comprising 50-500 μM L-kynurenic acid or kynurenic acid such that
It is unclear why claim 10 is not a dependent claim based on claim 18 because it simply adds a step to claim 18, i.e. ---The method of claim 18, further comprising adding media comprising 50-500 μM KYN to the cultured pluripotent cells---.
These suggestions are not intended to infer allowability because support cannot be found for claim 10 as written (see 112/2nd rejection) and because it was obvious to supplement cells with media (see 103 rejection).
Response to applicants comments
Applicants say they prefer not to change the preamble to include the “method when storing cells”. However, there is no step of storing cells. The claim does not encompass storing cells. There is no suggestion to add a method of storing cells.
Claim Rejections - 35 USC § 103
A) Claims 10, 18, 20, 24, 29 remain and claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Furue (WO 2005063968) in view of Ko (EP2218778), Ince (20140170693), and Cheng (Nature Communications, 2015, Vol. 6, 7209, pg 1-13).
Furue cultured pluripotent cells in serum free medium (para 11) comprising L-tryptophan (TRP) (paragraph 5, Table 11.712 mg/L = 38 μM) (para 5) and passaging the cells more than two times (Example 5).
Furue did not teach replacing TRP with L-kynurenine or kynurenic acid as required in claim 10, 18. However, Chang taught kynurenine (Kyn)6 was a derivative of TRP (pg 2, 1st col. halfway down) and behaved similarly in vitro (pg 4, Fig. 2, and its caption at the bottom of pg 5). Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to replace TRP of Furue with KYN of Chang. Those of ordinary skill in the art at the time of filing would have been motivated to do so as a matter of design choice depending upon cost and availability because Chang taught they were interchangeable.
Furue did not teach the concentration of TRP was at least 50-200 μM as required in claims 10 and 18. However, Ko taught culturing pluripotent cells with 2-100 mg/L TRP (pg 4 in Table 2). 2-100 mg/L TRP described by Ko equals 9.804-490.02 μM/L which encompasses at least 176 μM as required in claims 10 and 18. Thus it would have been obvious to those of ordinary skill in the art at the time of filing to culture pluripotent cells in serum-free media containing TRP or KYN and passaging them as described by Furue wherein the concentration of TRP or KYN was 9.804-490.02 μM/L, as described by Ko. Motivation is also provided by Ince who taught concentrations of a given ingredient in a cell culture medium were routinely optimized for specific cell types (para 70); therefore, those of skill would have increased the concentration of as a matter of routine optimization.
Furue cultured pluripotent cells in serum free medium (para 11) comprising L-tryptophan (paragraph 5, Table 11.712 mg/L = 38 μM) (para 5) and passaging the cells more than two times (Example 5), which is equivalent to the “culturing”, “supplementing [ ] after the culturing”, and “culturing cells obtained by the supplementing” in claim 10.
The limitation of “proliferating” or “promoting proliferation” in the preamble of claim 18 are included because the pluripotent cells proliferated.
Ko converted germ cells into pluripotent cells; therefore, the pluripotent cells are “induced pluripotent cells” as required in claims 20, 24.
Claim 30 has been included because the combined teachings of Furue, Ko, Ince, and Cheng taught proliferating pluripotent cells and maintaining pluripotency. It has also been included because the rejection requires the use of 50-500 μM KYN which inherently MUST promote proliferation of the pluripotent cells as compared to without KYN.
Response to arguments
Applicants argue Cheng is limited to using tryptophan derivative ITE (2-(10H-indole-30-carbonyl)-thiazole-4-carboxylic acid methyl ester) and does not teach using tryptophan derivative kynurenine/kynurenic acid as required in claims 10 and 18. Applicants’ argument is not persuasive. Chang taught kynurenine (Kyn)6 was a derivative of TRP (pg 2, 1st col. halfway down) and behaved similarly in vitro (pg 4, Fig. 2, and its caption at the bottom of pg 5).
Applicants argue ITE used by Cheng is totally different than tryptophan. Applicants’ argument is not persuasive. Cheng taught ITE and KYN are derivatives of TRP (pg 2 cited above).
B) Claims 10, 18, 20, 24, 29 remain and claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Ko (EP2218778) in view of Furue (WO 2005063968) and Cheng (Nature Communications, 2015, Vol. 6, No. 7209).
Ko taught “the ingredients making up a germline cell culture medium that is preferably used in accordance with the method of the invention to culture the GSCs in step (b) are outlined in Tables 1 to 7 as well as in Example 1” (pg 3, para 9, line 28). “The culture media for generating [germline pluripotent stem (gPS)] cells are essentially the same as the culture media established for culture of germline stem cells” (pg 3, para 9, line 19). Table 2 of Ko taught using 2-100 mg/L L-tryptophan (TRP) which is equivalent to culturing with at least 176 μM as encompassed by claim 10 as follows: TRP has a molar mass of 204 g/mol; therefore, 2-100 mg/L TRP described by Ko is 0.000009804-0.0004902 moles/L which is 9.804-490 μM/L which encompasses 50-200 μM as required in claims 10, 18. Example 1 taught “ESCs and gPS cells were grown on MEFs in ESC medium (DMEM supplemented with 15% FBS, MEM nonessential amino acids, 2 mM L-glutamine, penicillin/streptomycin, 50 mM b-mercaptoethanol, and 10<3>U/ml ESGRO”, last lines. Therefore, Ko taught culturing mammalian germline pluripotent stem (gPS) cells in the media of Table 2 which contained 9.8-490 μM TRP.
Ko did not teach the culture was serum-free as required in claim 10, 18. However, Furue cultured pluripotent cells in serum free medium (para 11) comprising L-tryptophan (paragraph 5, Table 11.712 mg/L = 38 μM) (para 5). Thus it would have been obvious to those of ordinary skill in the art at the time of filing to culture pluripotent cells with at least 176 μM TRP as described by Ko using serum free medium containing TRP as described by Furue. Those of ordinary skill in the art at the time of filing would have been motivated to make the culture serum free to avoid contaminants and variables associated with serum.
Ko did not teach replacing TRP with L-kynurenine or kynurenic acid as required in claim 10, 18. However, Chang taught kynurenine (Kyn)6 was a derivative of TRP (pg 2, 1st col. halfway down) and behaved similarly in vitro (pg 4, Fig. 2, and its caption at the bottom of pg 5). Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to replace TRP of Ko with KYN of Chang. Those of ordinary skill in the art at the time of filing would have been motivated to do so as a matter of design choice depending upon cost and availability because Chang taught they were interchangeable.
Ko taught passaging gPS cells (paragraph 14; para 55 description of Fig. 10; para 57) which inherently MUST require removing media and supplementing them with additional media as required in step b), and supplementing the cells obtained in step b) with the media to maintain pluripotency as required in step c) of claim 10.
The limitation of “proliferating” or “promoting proliferation” in the preamble of claim 18 are included because the pluripotent cells proliferated.
Ko converted germ cells into pluripotent cells; therefore, the pluripotent cells are “induced pluripotent cells” as required in claims 20, 24.
The concept of supplementing is performed without replacement of medium in claim 29 has been included because it is indefinite and because it was well-within the purview of the ordinary artisan to do so as a matter of design choice to save money on culture media.
Claim 30 has been included because the combined teachings of Ko, Furue, and Cheng taught proliferating pluripotent cells and maintaining pluripotency. It has also been included because the rejection requires the use of 50-500 μM KYN which inherently MUST promote proliferation of the pluripotent cells as compared to without KYN.
Response to arguments
Applicants argue Cheng is limited to using tryptophan derivative ITE (2-(10H-indole-30-carbonyl)-thiazole-4-carboxylic acid methyl ester) and does not teach using tryptophan derivative kynurenine/kynurenic acid as required in claims 10 and 18. Applicants’ argument is not persuasive. Chang is not limited to ITE. Chang taught kynurenine (Kyn)6 was a derivative of TRP (pg 2, 1st col. halfway down) and behaved similarly in vitro (pg 4, Fig. 2, and its caption at the bottom of pg 5).
Applicants argue ITE used by Cheng is totally different than tryptophan. Applicants’ argument is not persuasive. Cheng taught ITE and KYN are derivatives of TRP (pg 2 cited above).
Claim Rejections - 35 USC § 112
Written Description
Claims 10, 29 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
A) The specification lacks written description for “supplementing” the cells obtained in step a) with KYN “such that a concentration of 50-500 μM [KYN] in the medium is obtained” as required in step b) of claim 10. Pg 22, lines 6-16, discusses culturing pluripotent cells in medium comprising TRP or a derivative thereof and “successively culturing the pluripotent stem cells culture added with” TRP or a derivative thereof. Pg 25, line 21-25, contemplates not having to replace the whole medium and adding TRP or a derivative thereof alone. The specification does not teach supplementing pluripotent cells in step a) with serum-free medium containing KYN “such that 50-500 μM [KYN] is obtained” as required in step b) of claim 10. Applicants do not teach how to test the concentration of KYN following a number of days in culture before “supplementing”. Applicants do not teach contemplate adjusting the amount of KYN in the “supplementing” media so that a concentration of 50-500 μM KYN is maintained as broadly encompassed by step b). The specification does not teach how long KYN is maintained in culture or how quickly it is “used up” by the pluripotent cells in culture so that the amount of KYN in the supplementing step can be adjusted “such that 50-500 μM [KYN] is obtained”. Without these concepts, applicants’ disclosure is limited to adding media containing 50-500 μM KYN which is much narrower than what is claimed.
Response to arguments
Applicants argue original claim 10 and pg 22, lines 6-16, supports the concept. Applicants’ argument is not persuasive. Pg 22 taken with pg 25, line 21-25 (which contemplates not having to replace the whole medium and adding TRP or a derivative thereof alone) are inadequate. There is nothing in the citations that teach how to add serum-free medium to cells in step a) that already have medium containing KYN at a concentration of 50-500 μM (some of it spent) “such that 50-500 μM [KYN] is obtained” as required in step b). If applicants believe the specification supports adding medium containing 50-500 μM KYN regardless of the amount of KYN remaining in the cells of step a) (i.e. without removing the spent medium) as contemplated on pg 25, please provide a more reasoned explanation of how to determine when 50-500 μM KYN has been achieved, and limit claim 10 accordingly. If applicants believe the specification supports removing medium from the cells in step a) followed by adding medium containing 50-500 μM KYN, please point specifically to such support, and limit claim 10 accordingly.
B) The specification lacks written description for the concept of supplementing cells with media containing KYN “without replacement of the medium” in claim 29. The claim encompasses adding media containing 50-500 μM KYN or maintaining a concentration of 50-500 μM KYN after addition of the media without replacing the medium. Support cannot be found anywhere in the specification or the art at the time for this. The specification is limited to culturing pluripotent cells in serum-free medium containing 50-500 μM KYN such that pluripotency is maintained (Examples 1, 2, 4, 5; Fig. 1-5, 7, 8). The specification does not teach adding media containing KYN on top of cells in spent media as required in claim 29. Accordingly, the concept lacks written description.
Response to argument
Applicants point to pg 25, line 21-25. Applicants’ argument is not persuasive. Pg 22 taken with pg 25, line 21-25 (which contemplates not having to replace the whole medium and adding TRP or a derivative thereof alone) are inadequate. There is nothing in the citations that teach how to add serum-free medium to cells in step a) that already have medium containing KYN at a concentration of 50-500 μM (some of it spent) “such that 50-500 μM [KYN] is obtained” as required in step b). If applicants believe the specification supports adding medium containing 50-500 μM KYN regardless of the amount of KYN remaining in the cells of step a) (i.e. without removing the spent medium) as contemplated on pg 25, please provide a more reasoned explanation of how to determine when 50-500 μM KYN has been achieved, and limit claim 10 accordingly. If applicants believe the specification supports removing medium from the cells in step a) followed by adding medium containing 50-500 μM KYN, please point specifically to such support, and limit claim 10 accordingly.
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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Michael C. Wilson
/MICHAEL C WILSON/Primary Examiner, Art Unit 1638