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 .
Status of the Claims
Claims 1-5, 7-9, 11, 13-15, 17, 19-20, 22, 26-28, and 29 are currently pending.
Claims 3-5, 7, 11, 13, 17, 19-20, 22, and 26-29 are amended.
Claims 1-5, 7, 14-15, 17, 19-20, 22, 27, and 29 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 6, 10, 12, 16, 18, 21, and 23-25 are cancelled.
Claims 8-9, 11, 13, 26, and 28 have been considered on the merits.
Withdrawn Rejections
The objections made onto claims 9, 11, and 13 are withdrawn in light of the amendments made in the reply filled on 06/23/2026.
The objections made onto the specification and drawings have been withdrawn in light of the amendments made onto the specification in the reply filled on 06/23/2026.
The 112(b) rejections made onto claims 26 and 28 are withdrawn in light of the amendments made onto the claims in the reply filled on 06/23/2026.
The 112(d) rejections made onto claims 26 and 28 are withdrawn in light of the amendments made onto the claims in the reply filled on 06/23/2026
New and Maintained Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 8-9, 11, 13, 26, and 28 are newly 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.
Claim 8 has been amended to include the following phrase/limitation regarding the specific steps involved in the claimed “step (c)”:
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However, this amendment renders the claim indefinite. It is unclear how the newly added steps 1-4 relate and or fit within step c. There does not appear to be a nexus between step c and the sub-steps 1-4. Further, it appears that sub-step 4 is the claimed step c, which further confuses the claimed order of steps. The claim is being interpreted to include that step c and step 4 are identical steps and that sub-steps 1-3 should be performed before the claimed step c. Appropriate clarification is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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 8-9, 11, 13, 26, and 28 remain rejected under 35 U.S.C. 103 as being unpatentable over Nogueira et al (Journal of Biological Engineering, 2019), in view of Knoblich et al (US20150330970A1) and Kato et al (Unofficial Translation from Information Disclosure Statement and NPL reference provided by Applicant on 09/12/2023, “Development of 3D floating iPS cell differentiation induction culture device for industrial use”, 2018; also cited in WIPO Written Opinion mailed on 03/22/2022).
Claim interpretation: The specification defines “the term ‘unsteady’ means not unidirectional drive (operation)/motion (movement) of the stirring blade, but drive/motion with a variable speed/reciprocating motion/reverse motion”, therefore the claimed phrase “unsteadily operating the stirring blade” is interpreted to mean operating the stirring blade with variable speed, reciprocating motion, or reverse motion.
Claim 26 recites “the method of claim 8, wherein the cultured spherical body comprises a spinal cord motor neuron”. Additionally, claim 28 recites “the method of claim 8, wherein the cultured spherical body comprises a GABAergic neuron or its progenitor cell”. These claims appear to be reciting an intended result of practicing the method rather than requiring an additional step to be performed. Therefore, Claims 26 and 28 are being interpreted to be met by the completion of the method of claim 8.
Regarding claim 8, Nogueira teaches a method of producing a spherical body (spheroid), comprising the steps of (a) placing pluripotent stem cells in a culture tank with a stirring blade (See Fig. 1 and description). Nogueira teaches the step (b) of operating the stirring blade to perform stirring culture of the pluripotent stem cells in the presence of a pluripotent stem cell maintenance medium within a culture apparatus which comprises an unconventional vertical wheel stirring apparatus (See Fig. 1 and description; pg. 2, col. 2, last para). Nogueira teaches that the pluripotent stem cells which have been cultured in the unconventional vertical wheel stirring apparatus are capable of differentiating into neural progenitor cells (pg. 7, Col. 1, last para).
Nogueria does not teach step (c) of claim 8 which requires performing stirring of the pluripotent stem cells in the presence of a neuronal differentiation medium. Nogueria does not teach the newly amended limitations of claim 8 step (c) which require that the step comprises (1) culturing in an embryoid formation medium, (2) culturing in a neural stem cell induction medium, (3) culturing in a neural stem cell proliferation medium; and (4) culturing in a neuron differentiation/maturation medium that is free from a basement membrane matrix. Nogueria does not teach that the neuronal differentiation medium contains retinoic acid as required by claim 13.
However, Knoblich teaches methods of performing 3D culture of organoids/spheroids which contain multiple cell types (abstract).
Regarding claims 8 and 13, Knoblich teaches the directed differentiation of human pluripotent stem cells in culture in a spinning bioreactor in differentiation media containing retinoic acid ([0070]). Additionally, Knoblich teaches at the stage where the spheroid culture is stirred or shaken in a bioreactor, the culture reaches an enlarged size which is dependent on constant nutrient supply, best achieved by flushing the cells through stirring or shaking ([0039]).
Regarding sub-steps 1-4 of claim 8, Knoblich teaches (1) culturing in an embryoid formation medium ([0033]), (2) culturing in a neural stem cell induction medium ([0034]), (3) culturing in a neural stem cell proliferation medium ([0035]), and (4) culturing in a neuron differentiation/maturation medium that is free from a basement membrane matrix ([0036]).
Knoblich teaches that the 3D spheroids comprise a heterogenous population of neuronal tissue cells ([0041]).
Regarding claim 11, Knoblich teaches the spheroids are introduced to the bioreactor on day 11 ([0070]) and allowed to differentiate until 20 days of differentiation ([0071]), which meets the alternative limitation of claim 11 requiring that step (c) of claim 8 be performed for at least 10 days.
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of pluripotent stem cell spheroid culture of Nogueria with the method of differentiating neural spheroids of Knoblich to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Nogueria teaches that the cultured pluripotent stem cell spheroids are able to differentiate into neural cells and Knoblich teaches the directed differentiation of human pluripotent stem cells into neural spheroids. Additionally, one of ordinary skill in the art would be motivated to make the specific combination where the cells are differentiated within a stirred/shaken bioreactor environment because Knoblich teaches at the stage where the spheroid culture is stirred or shaken in a bioreactor, the culture reaches an enlarged size which is dependent on constant nutrient supply, best achieved by flushing the cells through stirring or shaking ([0039]). One of ordinary skill in the art would have a reasonable expectation of success when combining Nogueria with Knoblich because both teach similar embodiments of spheroid culture within bioreactors and therefore all the necessary information to make the combination successfully is taught.
Nogueria and Knoblich do not teach that the stirring of the bioreactor is “unsteadily” performed as required by steps (b) and (c) of claim 8. Nogueria and Knoblich do not teach that the unsteady operation step comprises an up-and-down reciprocating motion, a left-and-right reciprocating motion, a rotational motion with a variable speed, or a rotational reciprocating motion of the stirring blade, in the steps (b) and (c) as required by claim 9.
However, Kato discloses a bioreactor termed the “VMF reactor”.
Regarding claim 8, Kato discloses the VMF reactor with unsteady stirring using a vertical agitation device (described in translation on pg. 7, lines 27-28). Kato describes human iPS cell differentiation using the VFM reactor and further states that “Figure 16c shows neurons induced to differentiate from human iPS cells by the VMF reactor. Although an unprecedented differentiation efficiency was obtained, the details are omitted in this paper because the results should be introduced by researches on another occasion” (stated in translation, pg. 9, last para spanning pg. 10).
Regarding claim 9, the VMF reactor is described to employ vertical or up-down reciprocating motion of an elliptical blade (described in translation on pg. 7, paras 1-2).
Regarding claims 26 and 28, the claims require the method of claim 8 be completed which is taught by the combination of Nogueria, Knoblich, and Kato (see claim interpretation at beginning of rejection).
Together the combination of Nogueria, Knoblich, and Kato teach that the unsteady stirring culture is performed from the start to the end of all of the steps as required by claim 8.
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of pluripotent stem cell differentiation into neural lineage cells employing a bioreactor taught by Nogueria and Knoblich with the VMF bioreactor taught by Kato to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Nogueria teaches that the cultured pluripotent stem cell spheroids from the vertical wheel bioreactor are able to differentiate into neural cells and Knoblich teaches the directed differentiation of human pluripotent stem cells into neural spheroids employing stirring/shaking within a bioreactor. Additionally, one of ordinary skill in the art would be motivated to make the specific combination where the VMF reactor with unsteady stirring using a vertical agitation device is employed to culture pluripotent stem cells because Kato teaches that the bioreactor is able to differentiate iPS cells into neurons and states “an unprecedented differentiation efficiency was obtained” (stated in translation, pg. 9, last para spanning pg. 10). One of ordinary skill in the art would have a reasonable expectation of success when combining Nogueria and Knoblich with Kato because both teach similar embodiments of spheroid culture within bioreactors and therefore all the necessary information to make the combination successfully is taught. Additionally, Kato teaches that they were able to successfully culture and differentiate pluripotent stem cells into neurons using the bioreactor apparatus which is a demonstration of success.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 06/23/2026 have been fully considered but they are not persuasive.
Applicant argues (pg. 11) that the amendments made onto claim 8 are not taught by the cited art, Nogueria, Knoblich, and Kato.
In response, the argument is not found persuasive. Regarding sub-steps 1-4 of claim 8, Knoblich teaches (1) culturing in an embryoid formation medium ([0033]), (2) culturing in a neural stem cell induction medium ([0034]), (3) culturing in a neural stem cell proliferation medium ([0035]), and (4) culturing in a neuron differentiation/maturation medium that is free from a basement membrane matrix ([0036]). Therefore, the argument is not found persuasive.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632
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