DETAILED ACTION
Notice of Pre-AIA or AIA Status
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The Examiner for this Application has changed. Please direct all future
correspondence to Juliana Candelaria, AU 1634. Additional contact information can be
found at the end of this paper.
This action is in response to the papers filed on 09/11/2025. Claims 8-10, 13, 15, 19, 20, 22, 23, 28-31, 37 and 38 are currently pending as per claims filed on 09/11/2025. Claim 31 is withdrawn. Claim 24 is cancelled and Claim 8-10, 20, and 22 has been amended by Applicants’ amendment filed on 09/11/2025. Claim 38 has been newly added by Applicants’ amendment filed on 09/11/2025. Claim 8, 22, and 23 are independent claims.
Claim 31 withdrawn from consideration pursuant to 37 CFR 1.142(b), as being drawn to non-elected invention, there being no allowable generic or linking claim.
The examiner acknowledges receiving the Declaration under 37 C.F.R. § 1.132 executed by Dr. Kenji Yoshida (“Yoshida Decl.” ) .
Therefore, claims 8-10, 13-16, 19, 20, 22, 23, 28-30, 37 and 38 are pending and under examination to which the following grounds of rejection are applicable. Claims 1, 22, 23 and 31 are independent claims.
Priority
The instant application is a 371 of PCT/JP2019/005914 filed 02/18/2019.
The instant application claims benefit of foreign filed application JAPAN 2018-027455 filed 02/19/2018. However, a certified untranslated copy has been provided on 8/14/2020.
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 CFR 41.154(b) and
41.202(e). Failure to provide a certified translation may result in no benefit being
Accorded.
Thus, the earliest possible priority for the instant application is 02/19/2018.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/25/2025 was filed after the mailing date of the current office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Withdrawn objections/rejection in response to Applicants’ arguments or
Amendment
Claim Objections
In view of Applicants’ amendment of claim 20, the claim objection has
been withdrawn.
Claim Rejections - 35 USC § 112 (b)
In view of Applicants’ amendment of claim 9 and 10, the claim rejections under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, have
been withdrawn.
Maintained and/or modified rejections in response to Applicants’ arguments or
Amendment
Claim Interpretation
Claim 22 recites the term “artificial”. The specification does not provide a definition for the term “artificial”. The examiner is interpreting “artificial” to mean cell aggregates that are generated ex vivo (i.e. could be through in vitro culture conditions).
Claim Rejections - 35 USC § 101
Claim 22 remains rejected under 35 U.S.C 101 because the claimed invention is directed to a product of nature without significantly more. The claims recite a mixture of artificial cell aggregates derived from in vitro pluripotent stem cells by the production method according to claim 8. This rejection has been modified in consideration of
the applicant's amendment filed on 09/11/2025.
Step 1: Whether the claim is to a statutory category
Under Step 1 of the subject matter eligibility test for products and processes, it must be determined if the claim is to a process, machine, manufacture or a composition of matter. In the instant case, claim 22 is directed to a composition of matter (cells). The claims are therefore directed to a statutory category, a product, and according to the broadest reasonable interpretation, it is also a natural product.
Step 2A: ‘Directed to a judicial exception’ analysis:
Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Markedly different characteristics can be expressed as the product's structure, function, and/or other properties. Non-limiting examples of characteristics that can determine the presence of a marked difference include biological or pharmacological functions or activities; chemical and physical properties; phenotype, including functional and structural characteristics; and structure and form, whether chemical, genetic, or physical.
The Examiner has interpreted the mixture of artificial cell aggregates of claim 22 as any combination of a plurality of cell clusters that are derived from in vitro pluripotent stem cells and the mixture of cell aggregates comprises dopaminergic neuron progenitor cells, comprise at least 1000 cells and have a circularity of 0.7 or more. Mixtures of cell aggregates such as the ones described above occur in nature. Fiorenzano et al (Nature Communications, 2021, pages 1-19) teaches organoids (i.e. artificial cell aggregates) modeling the development of the human brain from fetal stage, thus including populations of dopaminergic neuron progenitor cells, and found a high similarity between developing (i.e. progenitor) and mature dopamine neuron cell populations in pluripotent stem cell-derived subclusters of organoids and their fetal dopamine neuronal counterparts (Fig. 3k), demonstrating that dopamine neurons in organoids have a similar molecular identity to authentic midbrain dopamine neurons sourced from human fetal brain (page 6, left col, para 2; Figure 3i-k). In essence, Fiorenzano teaches that the organoids are identical to their in vivo counterpart. The characteristics recited in claim 22 do not have a markedly different characteristic between the instantly recited mixture of cell aggregates and their naturally occurring counterparts as, for instance, the organoids (i.e. mixture of cell aggregates) from Fiorenzano can comprise 1000 or more cells, and have a determined circularity and circle diameter as needed. As such, claim 22 recite a judicial exception. Furthermore, Applicant has not provided evidence of a markedly different characteristic between the instantly recited mixture of cell aggregates and cell aggregate and their naturally-occurring counterparts. As such, claim 22 recites a judicial exception.
Under Revised Step 2A, prong 1 of the analysis (determining the Judicial Exceptions), it must be determined if the claim is directed to a law of nature, a natural phenomenon (product of nature) or an abstract idea. In the instant case, the mixture of artificial cell aggregates is a naturally occurring product (mixture of cell aggregates). Because the products are the same as a product of nature, it falls within a judicial exception.
Prong Two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
Under Step 2A, prong 2 of the analysis, it must be determined whether the claim recites additional elements that integrate the judicial exception into a practical application. In the instant case, the claim fails to recite any additional elements that integrate the judicial into a practical application, and therefore the claims remain directed to a judicial exception invoking further analysis under step 2B.
Step 2B: ‘Significantly more’ analysis:
Under Step 2B, it must be determined if the claim recites additional elements that amount to significantly more than the judicial exception. In the instant case, claim 22 fail to recite any additional elements that amount to significantly more than the judicial exception since the claims are recited as product-by-process without reciting any structural features that make the cell aggregates any different than cell aggregates found in vivo. Therefore, the claims as a whole do not amount to significantly more than the exception.
Therefore, claim 22 is directed to subject matter that is not patent-eligible and are, as a result, rejected under 35 U.S.C. 101.
Response to Applicant’s arguments as they apply to rejection of claim 22 under 35 USC § 101
Applicant’s arguments filed 09/11/2025 have been fully considered but not persuasive.
Applicant asserts that the claimed cell aggregates are uniformly aggregated mass comprising dopaminergic neuron progenitor cells and can be distinguished from the cell populations extracted from the human midbrain, such as tissues. Applicants’ arguments have been respectfully considered but have not been found persuasive.
The Examiner notes that the ability to “distinguish” does not imply that the cell aggregates are markedly different than in vivo cells of the human midbrain, as there is no evidence provided to show what exactly makes these cells “distinguishable” from aggregates of cells from in vivo human midbrain cell, other than uniformity. The uniformity of the aggregated cells does not impart structural and thus, functional difference between the claims cell aggregates and in vivo cell aggregates from human midbrain. Therefore, the examiner maintains the 101 rejection as the claimed mixture of cell aggregates are not markedly different of those occurring in nature.
Claim Rejections - 35 USC § 103
Claims 8-10, 13, 15, 16, 19, 20, 22-23, 28-30, 37, remain rejected and claim 38 is newly rejected under 35 U.S.C. 103 as being unpatentable over Takahashi et al. (US 2016/0215260 A1) (same as WO 2015/034012 A1 cited in IDS filed in 11/09/2020) in view of Rodrigues et al. (Biotechnology Journal, 2015, 10:1103-1114) (cited in Office Action mailed on 04/10/2024) as evidenced by Cytonome® (Cytonome Gigasort® Product Sheet, 2017) (cited in Office Action mailed on 04/10/2024) in further view of Honegger et al. (Chapter Fifteen: Aggregating Neural Cell Cultures, Protocols for Neural Cell Culture, Springer Protocols Handbooks. Humana Press. https://doi.org/10.1385/1-59259-207-4:199; as cited in Office Action mailed 04/11/2025) and Loewke et al. (US 2015/0087240 A1, 2015; as cited in Office Action mailed 04/11/2025) as evidenced by Lugand et al. (Frontiers in Oncology, 12, 898732, 2022; as cited in Office Action mailed 04/11/2025). This rejection has been modified in consideration of the applicant's amendment filed on 09/11/2025.
Regarding independent claim 8, steps (1) and (2), independent claims 22 and 23, and dependent claims 37and 38, Takahashi discloses a method for producing dopaminergic neuron progenitor cells by (i) differentiating pluripotent stem cells in a medium containing reagent(s) selected from the group consisting of BMP inhibitor, TGFβ inhibitor, SHH signal-stimulating agent, FGF8 and a GSK-3β inhibitor; (ii) collecting Corin- and/or Lrtm1-positive cells from the cells obtained in step (i) using a substance which binds to Corin and/or a substance which binds to Lrtm1 (selectively separating the neuronal precursor cells in a first differentiation stage from the plurality of cells obtained in step (1)); and (iii) performing suspension culture of the cells obtained in step (ii) in a medium containing a neurotrophic factor, wherein the neurotrophic factor is BDNF and GDNF (see abstract; [0013-0017]; [0029]; [0120]). Corin and Lrtm1 are marker genes for dopaminergic neuron progenitor cells and floor plate ([0012]; [0154] right col.). The obtained cells show expression of Corin, Lmx1a and En1 (midbrain markers) and Foxa2 (floor plate marker) ([0158]). Cell clusters or spheres (artificial cell aggregates as they are ex vivo/in vitro) are obtained after the differentiation induction ([0060]; Fig. 1; Fig. 10). The obtained cell aggregates after sorting comprise Corin-positive cells (dopaminergic neuron progenitor cells) (claimed characteristic (b1)) ([0154]). Takahashi’s method intends to generate safe cells that can be selected using marker genes and that are safe for transplantation [0003] and suggests that the method may still need to be improved from the viewpoint of reducing the influence of lot-to-lot variability due to biological components contained therein [0005].
Regarding the limitation “wherein the mixture of cell aggregates comprises 50% or more of cell aggregates having characteristics (b1), (b2), (b3) and (b4)” of claim 8 and claim 22, Takahashi teaches that cells positive for Corin (marker for dopaminergic progenitor cells) appeared on Day 10 and reached the peak between days 21 and 28 (50% or more positive cells as shown in Fig. 4), thus concluding that in cases where Corin-positive cells are obtained by sorting, the sorting is preferably carried out on Day 10 or later (reads on characteristic (b1) requiring 50% or more of cell aggregates comprising dopaminergic neuron progenitor cells in a second differentiation stage) (Fig. 4; [0154]).
Regarding the characteristic (b2) of claim 8 and claim 22, Takahashi does not explicitly disclose the number of cells in the cell aggregates. Regarding the characteristic (b3), Takahashi teaches the diameter of the Corin+ cell aggregates, which is close to 600 µm at day 28 (Fig. 10B), but does not disclose the equivalent circle diameter is 300 µm to 600 µm. Regarding the characteristic (b4), Takahashi does not disclose the circularity of the cell aggregates and neither discloses the coefficient variation of any of the indexes recited in claim 8, 22, and 38.
Honegger, Loewke, and Lugand remedies Takahashi’s deficiencies in relation to the characteristics (b2)-(b4) of claims 8 and 22.
Honegger teaches a protocol for preparing aggregating neural cell cultures (Introduction). Honegger teaches that neuronal cell aggregates consist of even-sized spherical structures that form spontaneously and rapidly under appropriate culture conditions. Honegger further teaches that tissue-specific environment enables aggregating neural cells to differentiate and to develop specialized structures (Introduction). Honegger underscores the importance of obtaining even-sized aggregates with a final diameter of 300-400 µm (pg. 213, section 10).
Loewke discloses a method for characterizing a cell population including a set of cell subpopulations and individual or clustered cells (cell aggregates) by determining shape, geometry and spatial parameters to determine the quality of said cell population (see whole document). Analyzed features include: geometric features such as area and perimeter, shape features such as circularity and convexity, texture features, degree of cell compaction, colony border spikiness, and prevalence of dead cells [0034] [0037].. Loweke also compares at least one parameter with a set of reference values to generate an indication of quality of the cell population [0046]. The relationship between cell aggregates and the parameters taught by Loewke and which are instantly claimed, as well as the importance of analyzing them when obtaining cell aggregates is further evidenced by Lugand.
Lugand discloses the need to optimize the production and analysis of spheroids to reach high-throughput and more relevant results, and that for functional experiments, area, circularity and roundness are relevant quality criteria (pg. 6, left col., par. 2; pg. 9, left col., par. 1). Lugand defines circularity as the degree of similarity to a perfect circle, where a value of 1 indicates a perfect circle. Solidity describes the extent to which a shape is convex or concave, where a value of 1 indicates a completely convex shape (pg. 6, right col.). Lugand also evaluates area and perimeter as part of the spheroid characterization and teaches that abnormal spheroids (irregular shape) present poor scores in each shape descriptor (pg. 7, right col.). In addition, Lugand demonstrates the relationship between circularity values and the shape of cell aggregates. Fig. 3E (below) shows illustrative spheroids 1-7 having different morphological characteristics and different circularity, as seen in Fig. 3B (below), where spheroid 7, appearing round and uniform, has a circularity of more than 0.8 (regarding characteristic (b4)), while spheroid 1, having poor roundness, has a circularity of less than 0.6.
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It would have been obvious to one of ordinary skill in the art at the effective filing date to combine the teachings of Takahashi regarding a method for producing dopaminergic neuron progenitor cell aggregates with the teachings of Honegger regarding the production of even-sized neural cell aggregates and the teachings of Loewke regarding the analysis of morphological parameters to determine quality and health of individual cells or cell aggregates as evidenced by Lugand’s teachings regarding such parameters, to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to make the combination and develop a method for producing a mixture of cell aggregates wherein the mixture comprises 50% or more of cell aggregates having characteristics (b1)-(b4) since the prior art provided the following teachings:
Neural cell aggregates form spontaneously under appropriate culture conditions, as taught by Honegger
Neural cell aggregates have a diameter of at least between 300-400 and 600 µm, as taught by Takahashi and Honegger
Neural cell aggregates consist of even-sized spherical structures and cell aggregate morphology is analyzed in the prior art in terms of parameters such as circularity, convexity, area or solidity to determine quality and health of the cell aggregates, as taught by Honegger and Loewke, as evidenced by Lugand.
Therefore, a person of skill would have been motivated to do so with the purpose of obtaining even-sized or highly uniform cell aggregates that are characterized by having, for example, a value of circularity close to 1, e.g., 0.7 or more, and a low coefficient of variation, as claimed, as evidenced by Lugand, and that are useful and safe for transplantation. Furthermore, it would be obvious to optimize a protocol for forming and selecting highly uniform cell aggregates, as evidenced by Lugand, in order to reduce the influence of lot-to-lot variability for transplantation purposes, as taught by Takahashi. Furthermore, a skilled artisan would have had a reasonable expectation of success since protocols for producing neuronal cell aggregates from pluripotent stem cells, the occurrence of even-sized spherical neural cell aggregates and the characterization of cell aggregate morphology were successfully performed and described in the prior art, as disclosed by the combined teachings of Takahashi, Honegger and Loewke as evidenced by Lugand.
While Takahashi discloses sorting (separating) the cells using FACS to collect Corin-positive cells ([0151]), Takahashi fails to disclose suspending the plurality of cells obtained in step (1) in a continuous flow of a liquid vehicle and separating the neuronal precursor cells and other cells so as to let the cell mixture flow into different continuous flows of the liquid vehicle, as recited in claim 8.
Rodrigues remedies Takahashi’s deficiencies in relation to suspending the plurality of cells obtained in step (1) in a continuous flow of a liquid vehicle before the detecting step.
Rodrigues reviews separation methods that have facilitated the safe and controlled application of hPSC-derived cells in laboratory settings and pre-clinical research (see abstract). Rodrigues discusses FACS with respect to hPSC-derived neuronal cells and discloses that the throughput of FACS might limit its utility in the large-scale production of hPSC-derived cells (pg. 1110, right col., par. 1) and further discloses that the use of FACS may cause some negative outcomes, such as decreased cell viability after sorting as a result of the shear stress imposed to the cells. Rodrigues highlights the Cytonome GigaSort® as a device having increased capabilities, separating up to 7.2 x 108 cells in one hour by parallelizing 72 microfluidic channels (pg. 1110, right col., par. 1). The GigaSort® platform is a high-throughput microfluidic multi-sorter system where the cells are separated into different continuous flows of the liquid vehicle, as evidenced by Cytonome® (see whole document, and specifically pg. 3, diagram “Individual Multifluidic Channel”). In addition, Cytonome® discloses that the GigaSort® platform doesn’t require electrostatic charging of droplets, which makes for a much gentle, cell-friendly environment (pg. 3).
Accordingly, it would have been obvious to one of ordinary skill in the art at the effective filing date to combine the teachings of Takahashi regarding a method for producing dopaminergic neuron progenitor cells comprising a step of sorting neuronal precursor cells using FACS, with the teachings of Rodrigues regarding the advantages and disadvantages of FACS and its comparison with other devices, such as a high-throughput microfluidic multi-sorter system (e.g., GigaSort®), to arrive at the invention as claimed. A person of ordinary skill in the art would have been motivated to make the combination since Rodrigues taught several disadvantages of sorting cells with FACS, including limited utility in large-scale production of hPSC-derived cells and decreased cell viability after sorting, and Takahashi discloses that a purpose of the method is obtaining cells for transplantation and reducing lot-to-lot variation. Therefore, a skilled artisan would have been motivated to separate the neuronal precursor cells using a safer and gentler technique, for instance, with a continuous flow microfluidic device, as taught by Rodrigues as evidenced by Cytonome, to reduce shear stress and thus, increase cell survival after sorting with the purpose of obtaining safe and sufficient cells for large-scale applications or transplantation.
With regard to the recitation of the “wherein” clause in claim 8 and 22 (e.g. “wherein the mixture of cell aggregates comprises 50% or more of cell aggregates having characteristics (b1), (b2), (b3) and (b4)”), it is noted that the claim is directed to an inherent result based on the methodology of producing a mixture of cell aggregates. Because Takahashi and Rodrigues combine to disclose the methodology as claimed a method of producing a mixture of cell aggregates) the effect of the methodology is rendered obvious by the combination of references, absent evidence to the contrary.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, especially in the absence of evidence to the contrary.
Regarding claim 9, the teachings of Takahashi, Honegger, Loewke, Lugand, and Rodrigues render obvious claim 8. Moreover, Takahashi teaches that the obtained dopaminergic neuron progenitor cells have a high survival rate [0050] [0167]. Moreover, with regard to the recitation, “wherein cell death of the cell aggregates having characteristics (b1), (b2), (b3), and (b4) in the mixture of cell aggregates is suppressed”, the “wherein” clause does not provide an active step, and appears to be an inherent effect of the methodology of claim 8. The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966). See M.P.E.P. § 2112.02.
Regarding claim 10, the teachings of Takahashi, Honegger, Loewke, Lugand, and Rodrigues render obvious claim 8 and 9. Moreover, Takahashi discloses that step (iii) (culture of the cells obtained in Step (ii) in a medium containing BDNF and GDNF) is carried out for at least 7 days, for 14-20 days, and 14-16 days [0036-0038].
While the combined teachings of Takahashi, Honegger, Loewke, Lugand, and Rodrigues do not explicitly disclose the mixture of cell aggregates have a number of cells at the completion of culture that is 5% or more of a number of cells at the beginning of culture, as recited in claim 10, it is noted that the claim is directed to an inherent result based on the methodology of the culture of the cell aggregates. Because Takahashi and Rodrigues combine to disclose the methodology as claimed (a method of producing a micture of cell aggregates), the effect of the methodology is rendered obvious by the combination of references, absent evidence to the contrary.
Regarding claim 13, the teachings of Takahashi, Honegger, Loewke, Lugand, and Rodrigues render obvious claim 8.
The combined teachings of Takahashi, Honegger, Loewke, Lugand, and Rodrigues do not explicitly disclose the wherein the cell aggregates further have the characteristics: convexity or solidity is 0.5 or more; and Feret diameter ratio is 0.5 or more. However, the “wherein” clause does not provide an active step, and appears to be an inherent effect of the methodology of claim 8. The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966). See M.P.E.P. § 2112.02.
Regarding claim 15 and 16, the teachings of Takahashi, Honegger, Loewke, Lugand, and Rodrigues render obvious claim 8. Moreover, Rodrigues teaches the Cytonome GigaSort® (i.e. a closed system) as a device having increased capabilities, separating up to 7.2 x 108 cells in one hour by parallelizing 72 microfluidic channels (pg. 1110, right col., par. 1).
Regarding claim 19, the teachings of Takahashi, Honegger, Loewke, Lugand, and Rodrigues render obvious claim 8. Moreover, Takahashi teaches the neuronal precursor cells obtained in Step (i) (first differentiation stage) are Corin-positive and/or Lrtm1-positive cells ([0016]).
Regarding claim 20, the teachings of Takahashi, Honegger, Loewke, Lugand, and Rodrigues render obvious claim 8. Moreover, Takahashi teaches the dopaminergic neuron progenitor cells in a second differentiation stage (on Day 28 and Day 42 of Takahashi’s disclosure) are dopaminergic neuron progenitor cells positive for FoxA2, LMX1A, EN1, Nurr1 and TH ([0055]; Fig. 5B).
Regarding claims 28, the teachings of Takahashi, Honegger, Loewke, Lugand, and Rodrigues render obvious claim 8. Moreover, Takahashi studied the dopaminergic neural cells on Day 28 and Day 42 (after differentiation induction) and observed that the proportion of Foxa2-positive cells was 70% to 75% (0161).
Regarding claim 29, the teachings of Takahashi, Honegger, Loewke, Lugand, and Rodrigues render obvious claim 8 and 28. Moreover, Takahashi teaches Takahashi studied the dopaminergic neural cells on Day 28 and Day 42 (after differentiation induction) and observed that the proportion of Foxa2-positive cells was 70% to 75% (0161).
Regarding claim 30, the teachings of Takahashi, Honegger, Loewke, Lugand, and Rodrigues do not disclose if the cell aggregates comprise no debris layer on a surface thereof, and a borderline of the cell aggregate is clear under a microscope. Loewke does teach that low prevalence of dead cells and/or debris can be used as an indication of healthy cell colonies [0043]. However, the “wherein” clause does not provide an active step, and appears to be an inherent effect of the methodology of claim 8. The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966). See M.P.E.P. § 2112.02.
Response to Applicant’s arguments as they apply to rejection of claims 8-10, 13, 15, 16, 19, 20, 22, 23, 28-30 and 37 under 35 USC § 103
Applicant’s arguments filed 09/11/2025 have been fully considered but not persuasive.
Applicant asserts that 1) the combination of Takahashi and Rodrigues,
and to use Gigasort for sorting lacks motivation as claim 8 of the present invention is not a method for producing dispersed cells, but a method for producing cell aggregates and that it would not have been obvious that there would be a difference in cell aggregates after the second differentiation step such that the morphology of the mixture of cell aggregates would differ; 2) Takahashi does not teach or suggest how to improve the process in order to obtain the cell population produced by the method of claim 8; 3) Loewke with other cited references would not have expected success from such a combination and Loewke only discloses a method and system for characterizing cell population; 4) Lugand merely teaches measuring physical attributes of spheroids and manually selecting preferred spheroids without teaching any level of uniformity that is desirable; and 5) the office action incorrectly alleges that the previous response to the office action dated July 11, 2024 inappropriately relies on arguments of counsel and has included a declaration by an inventor of the claimed invention to demonstrate the method is superior gave unexpected results compared to the prior art.
In regards to argument 1, based on the recitation of claim 8, the claim simply recites that the separation of the neuronal precursor cells in a first differentiation stage from other cells such that the neuronal precursor cells in a first differentiation stage flow into a different continuous flow of a liquid vehicle, hence the Rodrigues art, as evidenced by Cytonome, teaches the limitation technique of cell separation and that it is a gentler than approach FACS, therefore one would be motivated to use the technique for generating the mixture of cell aggregates with the claimed features. The resulting difference, as it appears to be due to the cell separation step of claim 8, would inherently occur due to the employed methodology of the combined teaches of Takahashi and Rodrigues. Therefore, the combined art of Takahashi and Rodrigues indeed is obvious over claim 8.
In regards to argument 2-4, while Takahashi does not teach or suggest how to improve the process to obtain the cell population produced by the method of claim 8, the combination with prior art from Lugand, as stated in page 13 of Office Action 4/11/2025, provides the motivation to need to optimize production and analysis of spheroids (i.e. cell aggregates), specifically their structure including circularity, for high throughput production which would be important for transplantation purposes as taught by Takahashi. Indeed, Lugand teaches the selection of spheroids with high scores of circularity and roundness and these are relevant criteria for functional experiments (i.e. transplantation) and teaches a need for selecting a homogenous population of spheroids (i.e. low variation; see page 6, “Selection of a Homogeneous Spheroid Population, Based on Automatic Analysis of Morphological Criteria”). Similarly, Loewke, teaches cell characterization methods including the assessment of many geometric features and discloses that the cells analyzed can indeed be “clustered cells” i.e cell aggregates (para 0045), further emphasizing it was known that characterizing of cell aggregates is important. Likewise, Lugand does is in fact analogous art despite relating to tumor model as the tumor model is still a three-dimensional cell aggregate, just made of different cell types and would likewise require assessment of geometric characteristics for further use. Therefore, the combined teachings provide motivation to improve the process of generating cell aggregates that are uniform by using criteria such as circularity.
Regarding claim 5, the inventor asserts that the presently claimed method achieves highly uniform cell aggregates which are superior to and unexpected from the cited references. While the examiner acknowledges that the specification provides data demonstrating the difference in indexes such as circle diameter and circularity and shows reduced variation in those indexes when comparing two sorting techniques, the claims fail to recite any specifics about the separation of the cells, protocol of differentiations of aggregates at second differentiation stage from the 12th day after initiation of differentiation induction to the 28th days, e.g., day 16, 20, 24, 28 after sorting (see para. 5 of the Yoshida Decl.),other than the separation causes cells to flow into different continuous flows of a liquid vehicle, such that the proceeding steps of aggregation lead to superior results with coefficient of variations for each of the physical metrics significant lower relative physical metrics when FACS is used (see para. 5 of the Yoshida Decl). Indeed, the lack of detail pertaining to the separation step in claim 8 permits the claim to be taught by any method of separation of cells that uses a different continuous flow of a liquid vehicle, i.e. FACS. In essence, the evidence provided by the specification, and reiterated in the declaration provided 4/11/2025, is not commensurate with the claims as written. It is suggested that the applicant include details relating to the separation step in claim 8 to provide needed support for the alleged unexpected results of more uniform mixtures of cell aggregates as claimed.
New rejections in response to Applicants’ arguments or
Amendment
Claim Rejections - 35 USC § 112 (b)
Claim 22 is 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 recites “detecting” in line 10. It is not clear how the neuronal precursor cells are detected. This rejection has been modified in consideration of
the applicant's amendment filed on 09/11/2025.
Claim 22 recites “artificial” in line 24. There is no definition provided in the specification as to what “artificial” denotes in the context of cell aggregates. Therefore, the metes and bounds of the claim are indefinite.
Claim Rejections - 35 USC § 112 (a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 22 is 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. This is a new rejection necessitated by amendment of the claims in the response filed 09/11/2025.
MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112, para. 1, as lacking adequate written description”. According to MPEP § 2163.I.B, “While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure” and “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117”.
Amended claim 22 recites “a mixture of artificial cell aggregates”. There is no basis in the as-filed disclosure for the cell aggregates to be artificial. Original claim 22 recited a mixture of cell aggregates, i.e. the cell aggregates are generic.
Jiang et al (ACS Nano, 2022, pages 15705-15733) teaches that “Artificial cells are derived from lipids, polymers, lipid/polymer hybrids, natural cell membranes, colloidosome, metal−organic frameworks and coacervates.” (abstract) and that “Artificial cells are also classified depending on the construction method as top-down and bottom-up artificial cells. The top-down method uses biological methods to remove unnecessary genes and organelles of living cells or completely replace the genome with a synthetic genome until the smallest unit that can survive is obtained. The bottom-up approach develops cells from scratch, that is, through chemical methods to assemble organic biomolecules or inorganic materials to construct microvesicles that simulate cells with certain functions.” The original disclosure does not contemplate that the cell aggregates are generated by any of the methods described by Jiang.
Original claim 22 claimed “a mixture of cell aggregates” and the specification discloses “The three-dimensional adherent cell population, which is also referred to as a cell aggregate, is not particularly limited as long as it is an aggregate of cells forming a three-dimensional structure and may be spherical or non-spherical. In the present specification, a cell aggregate is a cell aggregate preferably having a three-dimensional shape close to a sphere. The three-dimensional shape close to a sphere is a shape having a three-dimensional structure, whose figure projected:” (para 0012). There is no indication in the specification that the cells are “artificial”. In fact, the specification discloses that “cells (including cells of a cell aggregate) refer to mammalian cells” (para 0015).
Insertion of the limitation “artificial” is a new concept because it neither has literal support in the as-filed specification by way of generic disclosure, nor are there specific examples of the newly limited genus which would show possession of the concept of cells. The specification only contemplates use of naturally-occurring cells. (Paragraphs 0147, for example disclose obtaining pluripotent stem cells from human bone marrow cells.)
This is a matter of written description, not a question of what one of skill in the art would or would not have known. “The trouble is that there is no disclosure, easy though it is to imagine it.” In re Ruschig, 379 F.2d 990, 995, 154 USPQ 118, 123 (CCPA 1967); M.P.E.P. § 2163.05, part II. The material within the four corners of the as-filed specification must lead to the generic concept. If it does not, the material is new matter. Declarations and new references cannot demonstrate possession of a concept after the fact. Thus, the insertion of “artificial” is an insertion of new matter.
Applicants allege that amended claim 22 find support throughout the original specification. The examiner disagrees. All of the original claims were limited to “a mixture of cell aggregates” and there is inadequate support to claim that the cell aggregates are “artificial” generally.
Claims 22 will remain rejected until Applicant cancels all new matter.
Conclusion
No claims are allowed.
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/JULIANA IRENE CANDELARIA/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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