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
This application was filed on June 14, 2022, and is a 371 application of PCT/JP2020/001488 filed on January 17, 2020.
Election/Restrictions
In the response filed on September 10, 2025, Applicant has elected Group I (i.e. claims 12-18) drawn to a method for evaluating differentiation state of cells, and elected Species III (i.e. an evaluation that involves neuronal cells) without traverse is acknowledged.
Claims 13-14, 16-17, and 19-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 10, 2025.
Claims 12, 15, and 18 read on the elected invention (i.e. method for evaluating differentiation state of neuronal cells).
Claim Status
Currently, claims 12, 15, and 18 are under examination in this application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on June 14, 2022, and August 29, 2023, are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
However, Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claim 12 objected to because of the following informalities: incorrect article. It is suggested that the claim recite “a” culture solution. Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 12, 15, and 18 are directed to non-statutory subject matter. These claims do not fall within at least one of the four categories of patent eligible subject matter because they do not contain an active step within the method. Therefore, it is not clear how to interpret the method claims because the claims are directed to an evaluation and do not require an active step.
Claims 12, 15, and 18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
Claim 12 recites “A method for evaluating a differentiation state of cells during culturing for inducing undifferentiated pluripotent stem cells to differentiate into desired cells, wherein a ratio of amounts of change over time in two or more types of amino acids contained in the culture solution, a ratio of amounts of change over time in any two or more types of the metabolites of glycolysis, or a ratio of amounts of change over time in any two or more types of the metabolites of the tricarboxylic acid cycle (TCA cycle) is used as an index of progression of induced differentiation.”
Per the 2019 Revised Patent Subject Matter Eligibility Guidance (2019 PEG) published on January 7, 2019 (84 Fed. Reg. 50), if a claim recites a limitation that can practically be performed in the human mind, the limitation falls within the mental processes grouping, and the claim recites an abstract idea. Claims recite a mental process when they contain limitations that can practically be performed in the human mind, including for example, observations, evaluations, judgments, and opinions.
The courts consider a mental process (thinking i.e. evaluating) that "can be performed in the human mind, or by a human using a pen and paper" to be an abstract idea. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1372, 99 USPQ2d 1690, 1695 (Fed. Cir. 2011). As the Federal Circuit explained, "methods which can be performed mentally, or which are the equivalent of human mental work, are unpatentable abstract ideas the ‘basic tools of scientific and technological work' that are open to all.' " 654 F.3d at 1371, 99 USPQ2d at 1694 (citing Gottschalk v. Benson, 409 U.S. 63, 175 USPQ 673 (1972)). See also Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. 66, 71, 101 USPQ2d 1961, 1965 (2012) ("‘[M]ental processes[] and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work' " (quoting Benson, 409 U.S. at 67, 175 USPQ at 675)); Parker v. Flook, 437 U.S. 584, 589, 198 USPQ 193, 197 (1978).
Regarding claim 12, the “evaluating” step is considered to embrace a mental process. See also MPEP 2106.04(a-b).
Step 1-Statutory Category: According to the 2019 Revised Patent Subject Matter Eligibility Guidelines (2019PEG), the claim is first analyzed to determine if it is directed to one of the acceptable statutory categories of invention (i.e. process, machine, manufacture, or composition of matter). Claim 12 is drawn to a method for evaluating function, status and/or activity a differentiation state of cells during culturing for inducing undifferentiated pluripotent stem cells to differentiate into desired cells. Thus, the process meets the requirements for step 1 of the analysis as it is drawn to a method.
Next the claim is assessed to determine if it is directed to a judicial exception under step 2A. Under 2019 PEG, “directed to" is determined via a two-prong inquiry: (1) Does the claim recite a law of nature, a product of nature, a natural phenomenon, or an abstract idea; and (2) Does the claim recite additional element(s) that integrate the judicial exception into a practical application. The phrase, “integration of a practical application", requires the presence of an additional claim element(s) or a combination thereof to apply, rely on or use the judicial exception in a manner that imposes a meaningful limitation on the judicial exception, such that the claim does not monopolize the judicial exception. (See MPEP § 210 6.05 for examples of integration of practical application).
Step 2A Judicial Exception-Prong 1 (claim is directed to a judicial exception): Prong 2A asks whether the claim recites an abstract idea, law of nature, or natural phenomenon (product of nature).
Regarding claim 12, recites a judicial exception in the step of “a method for evaluating a differentiation state of cells during culturing for inducing undifferentiated pluripotent stem cells to differentiate into desired cells,” which requires a mental step. The claim 12, “evaluating” step of comparing the ratio of amounts of change over time in two or more types of amino acids contained in the culture solution, as an index of progression of induced differentiation is an abstract idea involving mental processes because a simple comparison of the ratios obtained can be performed mentally. Claims can recite a mental process even if they are described in the specification and/or claimed as being performed on a device. Hence, the claim relates to an abstract idea that is related observing a natural phenomenon involving laws of nature. Thus, the claim is directed to a judicial exception.
Regarding claim 15, dependent on claim 12, recites “wherein the desired cells are neuronal cells, and the progression of induced differentiation is determined using glycine and threonine contained in the culture solution”. Claim 15 just describes the cell type and the assay substance. Therefore, claim 15 does not remedy the deficiency of claim 12. Hence, the claim relates to an abstract idea that is related observing a natural phenomenon involving laws of nature. Thus, the claim is directed to a judicial exception.
Regarding claim 18, dependent on claim 12, recites “wherein the desired cell are neuronal cells, and the progression of induced differentiation is determined using any of a-ketoglutaric acid (AKG), succinic acid (Sue), and fumaric acid (Furn) as the metabolites of the tricarboxylic acid cycle (TCA cycle)”. Claim 18 just describes the cell type and the assay substance. Therefore, claim 18 does not remedy the deficiency of claim 12. Hence, the claim relates to an abstract idea that is related observing a natural phenomenon involving laws of nature. Thus, the claim is directed to a judicial exception.
Furthermore, there is nothing about claims 12, 15, and 18 that include additional elements that are sufficient to amount to significantly more than the judicial exception since the invention as claimed does not introduce or recite any step of compositions that is beyond that which is well understood, routine and conventional.
Step 2A Judicial Exception-Prong 2 (Judicial exception is integrated into a practical application): The phrase, "integration of a practical application", requires the presence of an additional claim element(s) or a combination thereof to apply, rely on or use the judicial exception in a manner that imposes a meaningful Iimitation on the judicial exception, such that the claim does not monopolize the judicial exception. (See MPEP § 2106.05 for examples of integration of practical application). Prong 2 asks whether a claim recites additional elements that integrate the judicial exception into a practical application.
In claim 12, there is no additional step after the claim recites “a method for evaluating a differentiation state of cells during culturing for inducing undifferentiated pluripotent stem cells to differentiate into desired cells, wherein a ratio of amounts of change over time in two or more types of amino acids contained in the culture solution, a ratio of amounts of change over time in any two or more types of the metabolites of glycolysis, or a ratio of amounts of change over time in any two or more types of the metabolites of the tricarboxylic acid cycle (TCA cycle) is used as an index of progression of induced differentiation” for requiring a practical application (e.g. applying a treatment, or action step). The claim does not recite any additional elements or a combination thereof that integrated the judicial exception identified in prong 1 as being integrated into a practical application. Therefore, this judicial exception is not integrated into a practical application because there are no additional limitations that might integrate the mental processes and laws of nature into a practical application.
Regarding claim 15, dependent on claim 12, recites “wherein the desired cells are neuronal cells, and the progression of induced differentiation is determined using glycine and threonine contained in the culture solution”. The claim does not recite any additional elements or a combination thereof that integrated the judicial exception identified in prong 1 as being integrated into a practical application. Therefore, this judicial exception is not integrated into a practical application because there are no additional limitations that might integrate the mental processes and laws of nature into a practical application.
Regarding claim 18, dependent on claim 12, recites “wherein the desired cell are neuronal cells, and the progression of induced differentiation is determined using any of a-ketoglutaric acid (AKG), succinic acid (Sue), and fumaric acid (Furn) as the metabolites of the tricarboxylic acid cycle (TCA cycle)”. The claim does not recite any additional elements or a combination thereof that integrated the judicial exception identified in prong 1 as being integrated into a practical application. Therefore, this judicial exception is not integrated into a practical application because there are no additional limitations that might integrate the mental processes and laws of nature into a practical application.
Thus, claims 12, 15, and 18 meet the requirements of step 2A as being directed to a judicial exception.
Step 2B Significantly More: The "significantly more" analysis determines that a claim is patent eligible if the claims recite structures or functions that transform the natural product in a manner that make the product markedly different from the judicial exception. The nature-based product is analyzed to determine whether it has markedly different characteristics from any naturally occurring counterpart(s) in their natural state.
Regarding claim 12, does not add significantly more than the judicial exception. The claim recites “wherein a ratio of amounts of change over time in two or more types of amino acids contained in the culture solution, a ratio of amounts of change over time in any two or more types of the metabolites of glycolysis, or a ratio of amounts of change over time in any two or more types of the metabolites of the tricarboxylic acid cycle (TCA cycle) is used as an index of progression of induced differentiation (lines 3-7).” Therefore, this step does not have an additional practical step performed in this embodiment. Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements claimed. Therefore, claim 12 does not meet the requirement of step 2B and therefore does not meet patent subject matter eligibility requirements.
Regarding claim 15, dependent on claim 12, recites “wherein the desired cells are neuronal cells, and the progression of induced differentiation is determined using glycine and threonine contained in the culture solution”. Therefore, this step does not have an additional practical step performed in this embodiment. Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements claimed. Therefore, claim 15 does not meet the requirement of step 2B and therefore does not meet patent subject matter eligibility requirements.
Regarding claim 18, dependent on claim 12, recites “wherein the desired cell are neuronal cells, and the progression of induced differentiation is determined using any of a-ketoglutaric acid (AKG), succinic acid (Sue), and fumaric acid (Furn) as the metabolites of the tricarboxylic acid cycle (TCA cycle)”. Therefore, this step does not have an additional practical step performed in this embodiment. Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements claimed. Therefore, claim 18 does not meet the requirement of step 2B and therefore does not meet patent subject matter eligibility requirements.
Accordingly, the "mental processes" abstract idea grouping is defined as concepts performed in the human mind, and examples of mental processes include observations, evaluations, judgments, and opinions (see MPEP 2106.04(a)(2)(III)).It is well established that data gathering steps required to use the method do not add a meaningful limitation to the method as they are insignificant activity (see also MPEP 2106.05(g)).
In conclusion, claims 12, 15, and 18 recite abstract ideas which are not considered to disclose eligible subject matter under 35 U.S.C. 101, and therefore are deemed not patent eligible.
Claim Rejections - 35 USC § 112b
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 12, 15 and 18 are 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.
Claims 12, 15, and 18 are indefinite because they do not recite an active step. It is unclear if the claims drawn to a process which comprises an active step, and therefore a person of ordinary skill in the art would not have a clear indication of what type of subject matter is being claimed. Thus, the metes and bounds of the invention cannot be determined (MPEP 2173.05(q)).
Claim 12 recites the term “desired” (line 2), which is a relative term which renders the claim indefinite. The term “desired” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In the instant case, the word “desired” is a relative term because it implies that the “desired cell” is dependent on a person or situation. Thus, a "desired cell" may be considered unclear because a person of ordinary skill in the art would not know when a desirable result may be or is achieved.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 12 is rejected under 35 U.S.C. 102(a)(2) as being anticipated by Suzuki, et al. (US2019/0119650 A1, published April 25, 2019, cited IDS 6/14/2022, hereinafter as “Suzuki 2019”).
Regarding Claim 12, Suzuki discloses a method for evaluating a differentiation state of cells during culturing for inducing undifferentiated pluripotent stem cells to differentiate into desired cells (see e.g. abstract, claim 1, para. 11, 22, 36), wherein a ratio of amounts (i.e. test cells/control cells) of change over time (i.e. Day 3 -Day 6)(see e.g. fig. 4, see Results section) in two or more types of amino acids (e.g. alanine and cystine) contained in the culture solution (see e.g. para. 56-58 and results section and Table 11-12) as an index of progression of induced differentiation.
Thus, the prior art of Suzuki anticipates the instant claims.
Claim 12 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Suzuki, et al. (US2017/0052171 A1, published 2017, cited IDS 6/14/2022).
Regarding Claim 12, Suzuki discloses a method for evaluating a differentiation state of cells during culturing for inducing undifferentiated pluripotent stem cells to differentiate into desired cells (see e.g. abstract, claim 1, para. 3-4, 11, 15, 22-25, 36), wherein a ratio of amounts (i.e. test cells/control cells) of change over time (i.e. zero to six day)(see e.g. fig. 2-3, Tables 1-4, Example 1) in two or more types of amino acids (e.g. ascorbic acid, threonic acid or cystine) contained in the culture solution (see e.g. abstract, tables, para. 12-17, Example 1) as an index of progression of induced differentiation.
Thus, the prior art of Suzuki anticipates the instant claims.
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 12, 15, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Suzuki, et al. (WO2017/068727A1, published 2017, hereinafter as “Suzuki”), in view of Shibuya, et al. (US2015/0192568 A1, published 2015), Folmes, et al. (Cell metabolism 14.2 (2011): 264-271, published 2011), Takashi Suzuki, et al.,(Shimadzu Review: 123-131,published 2014, hereinafter as “Suzuki 2014”), and Winkle, et al., (Frontiers in Cell and Developmental Biology 7: 300, published 2019).
Regarding Claim 12, 15, and 18, Suzuki discloses a method for evaluating a differentiation state of cells during culturing for inducing undifferentiated pluripotent stem cells to differentiate into desired cells (see e.g. abstract, claims and results, wherein a ratio of amounts (i.e. test cells/control cells) of change over time (i.e. Day 3 -Day 6)(see e.g. fig. 4, and Results section) in two or more types of amino acids (e.g. alanine and cystine) contained in the culture solution (see e.g. see results section and Table 11-12) as an index of progression of induced differentiation.
Suzuki does not explicitly state the desired cells are neuronal cells or the metabolites are from glycolysis or the tricarboxylic acid cycle (TCA cycle).
However, the prior art of Shibuya discloses a method for determine the degree of differentiation of stem cells using an analytical step of analyzing metabolites of the TCA cycle in the culture solution (see e.g. abstract, claim 1), and discloses that pluripotent stem cells in the method may grow to become nerves in the brain called neural stem cells (see e.g. page 3-4). Further, the prior art of Folmes discloses that the pluripotent stem cell transition requires glycolysis for pluripotency and to facilitate nuclear reprogramming (see e.g. page 264-267).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of Suzuki to incorporate wherein the desired cells are neuronal cells or the metabolites are from glycolysis or the tricarboxylic acid cycle (TCA cycle) as taught by Shibuya and Folms because Shibuya discloses that metabolites of the TCA cycle can determine the degree of differentiation (see abstract), and Folms discloses that glycolysis is required for nuclear reprogramming (see e.g. page 264-267). Thus, it would have been obvious to combine prior art elements according to known methods to yield predictable results. Incorporating neuronal cells or the metabolites that are from glycolysis or the tricarboxylic acid cycle (TCA cycle) as taught by Shibuya and Folms would have led to predictable results with a reasonable expectation of success because both teach utilizing metabolites for understanding differentiation and pluripotency, as discussed above. Therefore, a person of ordinary skill in the art would have combined the cell types (i.e. stem cells) and metabolites (i.e. from glycolysis or TCA cycle), which would have led to predictable results with a reasonable expectation of success. Moreover, an artisan of ordinary skill in the art of (i.e. stem cell differentiation) 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 15 and 18, as stated supra, Suzuki does not explicitly state wherein the metabolites are glycine, threonine, succinic acid (Suc) or fumaric acid (Fum).
However, the prior art of Suzuki 2014 discloses a metabolome analysis for undifferentiated and differentiated pluripotent stem cells (see e.g. page 6-8), and discloses glycine, threonine, succinic acid (Suc), and fumaric acid (Fum)(see e.g. table 1, page 1-5) in the culture solution.
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods as taught by Suzuki to incorporate the metabolites as taught by Suzuki 2014 because Suzuki 2014 discloses that the analysis method involving metabolites that are involved in glycolysis and citric acid cycle can distinguish between undifferentiated and differentiated states of pluripotent stem cells (see e.g. page 7). Thus, a person of ordinary skill in the art would have a predictable and reasonable expectation of success. Further, the prior art of Winkle discloses that threonine is converted to glycine and acetyl Co-A, and glycine is metabolized specifically to regulate trimethylation of lysine (H3K4me3), which is needed to regulate and maintain stem cell proliferation and pluripotency (see e.g. page 1). Therefore, through the scientific nexus it would have been obvious for one of ordinary skill in the art to analyze the metabolites of glycine and threonine. Further, Winkle discloses that understanding of this regulation (i.e. stem cells that require these one-carbon units to produce H3K4me3 and remain undifferentiated) is essential for treatment of human diseases and disorder (see e.g. page 5). Moreover, an artisan of ordinary skill in the art of (i.e. stem cell differentiation) 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).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
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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