DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. This action is in response to the papers filed February 6, 2026. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
Applicant’s election of Group III and the combination of CRH, FST, GLI1, RELN, and STK32B in the reply filed on December 10, 2025 is reiterated for the record. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-3, 5-6, and 8-13 are currently pending.
Claims 1-3, 5-6, and 10-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 10, 2025.
Claim Rejections - 35 USC § 101
3. 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 8-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4 Monday, January 7, 2019).
Step 1: The claims are directed to the statutory category of a composition of matter.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
Claim 8 is drawn to a reagent kit for detecting markers for the identification and classification of DPC cells, including primers designed based on marker genes or biological precursors of marker genes, wherein the marker genes are CRH, FST, GLIl, RELN, and STK32B.
Claim 9 is drawn to the reagent kit of claim 8, comprising one or more sets of primers with a nucleotide sequence of SEQ ID NO: 1-2, SEQ ID NO: 3-4, SEQ ID NO: 5-6, SEQ ID NO: 11-12, and SEQ ID NO: 21-22.
The markedly different characteristics analysis has been used to determine if the nature-based products (the primers) are an exception. The nature-based products have been compared to their natural counterparts. There is no indication that the primers have any characteristics that are different from the naturally occurring nucleic acids. There is no difference in function, structure, or other properties. It is noted that the claims state that the primers are in a “reagent kit”. The primers do not necessarily interact with each other in the reagent kit. There is no indication that the primers being present in a “reagent kit” changes the function, structure, or other properties of the primers. Because the claimed primers do not have markedly different characteristics, they are a product of nature exception.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims recite the additional element of a “reagent kit”. A “reagent kit” broadly encompasses a collection of reagents. It fails to meaningfully limit the claims and is equivalent to adding the words “apply it” to the judicial exception. Accordingly, there are no additional elements that integrate the recited judicial exceptions into a practical application.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
The claims recite the additional element of a “reagent kit”. At the time the invention was made, kits comprising primers for performing nucleic acid amplification assays were well-established, routine, and conventional. Thus, the claims as a whole do not amount to significantly more than each “product of nature” by itself, and the claims do not quality as eligible subject matter.
Response To Arguments
4. In the response the Applicants traversed the rejection under 35 USC 101.
Regarding Step 2A, Prong One, the Applicants argue that the analysis should focus on the result of the combination of the natural components, rather than on each natural component individually. They argue that the claims recite a combination of five specific marker genes, CRH, FST, GLIl, RELN, and STK32B and that the Office Action improperly dissects this combination as a whole and treats it as a mere aggregation, instead focusing on the alleged lack of differences between each individual primer and its natural counterpart.
This argument has been fully considered but is not persuasive. The claims are drawn to a kit including primers for CRH, FST, GLIl, RELN, and STK32B. The claimed primers have been considered individually and as a combination. The primers are fragments of naturally occurring acids and are therefore nature based products. The markedly different characteristics analysis has been used to determine if these nature based products are an exception. The individual primers do not have any characteristics (structural, functional, or otherwise) that are different from the naturally occurring nucleic acids. The claim says that the primers are present in a kit but this does NOT mean that they are in the same test tube within the kit. If they are in separate test tubes, their inclusion in the same kit does not change their characteristics. Even if all the primers were mixed in the same tube, there is no indication that the mixture would have any characteristics that are different from the naturally occurring nucleic acids. There would be no difference in function, since the primers would still hybridize to the genes it always hybridized to. There would be no different in structure (mere aggregation of primers together in a mixture does not change the structure of the primers). There would be no difference in other properties. Because the claimed primers, when considered individually and as a mixture, do not have markedly different characters, they are a product of nature expectation.
Additionally the Applicants argue that the claims recite a set of marker gene combinations identifying and distinguishing among three possible target cell types (DPC, NSC, and iPSC) that may be present in iPSC-derived DPC products. The argue that the claimed marker gene combination exhibits different expression levels compared to individual marker genes in the same target cells, and also exhibits different expression level patterns across different target cells. These differences in expression levels across different target cells practically solve a technical problem that cannot be solved by naturally occurring individual marker genes. Therefore, the claimed marker gene combination is markedly different from naturally occurring single genes and does not fall within the product of nature exception.
This argument has been fully considered but is not persuasive. The genes themselves are not present in the kit, it is only primers for the genes that are in the kit. As explained above the primers have been considered individually and as a combination and do not have any characteristics (structural, functional, or otherwise) that are different from the naturally occurring nucleic acids. Because there are no different characteristics, there are no markedly different characteristics. Further it is noted that the intended use of the kit is irrelevant to this analysis because the intended use to change any characteristics of the primers. Thus the claims are directed to a product of nature exception.
Regarding Step 2A, Prong Two, the Applicants argue that the present application provides a practical and feasible inventive concept, namely adopting a specific combination of five marker genes, CRH, FST, GLIl, RELN, and STK32B. This specific gene combination not only enables differentiation between iPSCs and NSCs (see Fig. 4A), but also enables differentiation between highly similar DPCs and NSCs (see Fig. 4B). Based on this solution, identification and quality control of DPC products can be achieved, avoiding situations in which NSCs as intermediate forms or iPSCs as starting materials are present in DPC products but cannot be identified, thereby affecting clinical applications. Therefore, the present application truly proposes a technical solution and genuinely solves a specific and practical technical problem in the field, rather than merely applying an "apply it" label to a natural product without any substantive limiting effect.
This argument has been fully considered but is not persuasive. Having made the determination that the claims recite a judicial exception, we next examiner whether there are additional elements beyond the judicial exception in the claim that integrate the judicial exception into a practical application. The only other element recited in the claim is the “kit”. The fact that the primers are present in a kit does not change the structure, function, or any other properties of the kit. Thus the kit does not add significantly more to the exception.
Regarding Step 2B, the Applicants argue that the present application effectively solves the specific technical problem that impurities (iPSCs and/or NSCs) in iPSC-derived DPC products are difficult to identify, resulting in an inability to control DPC product quality and thereby affecting subsequent clinical applications. This clearly constitutes a practical and useful improvement in the technical field of stem cell regenerative medicine. They argue that the Office Action focuses on the reagent kit as an additional element while ignoring the fundamental inventive concept of the present application and disregarding the actual and effective improvement and contribution made by the technical solution to the relevant technical field.
This argument has been fully considered but is not persuasive. In Step 2B, we look to whether the claims adds a specific limitation beyond the judicial exception that is not well understood, routine, or conventional in the field. The only other element recited in the claim is the “kit”. At the time the invention was made, kits comprising primers for performing nucleic acid amplification assays were well-established, routine, and conventional. Thus it is maintained that the claims do provide an inventive concept. Additionally the examiner does not agree that the claims recite an additional element that reflects an improvement to technology. The recitation that the primers are in a “kit” does not result in an improvement to any technology.
Additionally the Applicants argue that a number of granted U.S. patents demonstrate that when multiple naturally occurring genes are combined in a specific manner to solve a specific technical problem (i.e., integrated into a practical application), such technical solutions based on specific gene combinations should be regarded as meeting the requirements of 35 U.S.C. § 101. They list US Patent Nos: US9097715B2, US10988811B2, and US 11401560B2 as examples.
This argument has been fully considered but is not persuasive. It would be improper for the Examiner to comment on the patentability of the issued Patents. Each case is examined on its own merits. The 101 rejection is maintained.
Claim Rejections - 35 USC § 102
5. 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.
Claims 8-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by the NEB catalog (1998/1999 pages 121, 284).
As noted in MPEP 2111.02, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” In the present situation, the structural limitations are able to stand alone and the preamble limitation is not accorded patentable weight. Accordingly, the claim language of “a reagent kit for the identification and classification of DPC, NSC, and iPSC” merely sets forth the intended use of the kit, but does not limit the scope of the claims.
The NEB catalog offered for sale a random primer mix of 6, 9, 12 and 24 mer primers. As the calculation below shows, about 3.2 x 108 molecules of every single 12-mer are present in each tube of 12 mer nucleotides. No calculation is provided for the 6 or 9 mers as they will necessarily contain more of every n-mer than that calculated for the 12 mer. With regard to the 24mers, about 9 molecules of every 24 mer are statistically expected to be present in each tube.
a.Molecular weight of 12-mer:12 x 325 daltons/nucleotide = 3,900 daltons = 3,900 g/molb.Total number of possible 12-mers:412 = 1.6 x 107 moleculesc.How many/molecules of 12-mer in a vial sold bv NEB:1 A260 unit = 33 mg = 3.3 x 10-5 g3.3 x 10-5 g / 3,900 g/mol = 8.4 x 10-9 mol(8.4 x 10-9 mol) x (6.02 x 1023 molecules/mol) = 5 x 1015 moleculesd.How many/molecules of each 12-mer in a single vial:5 xl015 molecules / 1.6 x 107molecules = 3.2 x 108 molecules of each 12-mer per viale.Molecular weight of 24-mer:24 x 325 daltons/nucleotide = 7,800 daltons = 7,800 g/molf.Total number of possible 24-mers:424 = 2.8 x 1014 moleculesg.How many/molecules of 24-mer in a vial sold bv NEB:1 A260 unit = 33 mg = 3.3 x 10-5 g3.3 x 10-5 g / 7,800 g/mol = 4.2 x 10-9 mol(4.2 x 10-9 mol) x (6.02 x 1023 molecules/mol) = 2.5 x 1015 molecules
h.
How many/molecules of each 24-mer in a single vial:2.5 xl015 molecules / 2.8 x 1014molecules = 9 molecules/vial
Regarding Claim 8 the 24-mer vial sold in the NEB catalog will inherently and necessarily contain nucleic acid primers that would amplify CRH, FST, GLIl, RELN, and STK32B.
Regarding Claim 9 the 12 mer vial sold in the NEB catalog will inherently and necessarily contain nucleic acid primers with a nucleotide sequence of SEQ ID NOs: 1-6, 11-12, and 21-22. Here it is noted that the recitation of “a nucleotide sequence” encompasses nucleic acids that comprise the full length sequence of the recited SEQ ID NOs: or any portion of the recited SEQ ID NOs.
Response To Arguments
6. In the response the Applicants traversed the rejection under 35 USC 102. The Applicants argue that amended claim 8 explicitly emphasizes that the marker genes are the combination of CRH, FST, GLIl, RELN, and STK32B, thereby excluding other marker genes not listed therein. Therefore, the primer combination corresponding to the specific marker gene combination recited in amended claim 8 is clearly different from the commercially available random mixed primers provided in the NEB catalog. This is because the commercially available random mixed primers correspond to genes that include, but are not limited to, these five marker genes, and also include many other genes. The combinations formed by these other genes are highly unlikely to satisfy the required expression level differences in the aforementioned target cells (DPC, NSC, and iPSC), because such a disordered system introduces many genes that exhibit insufficient or even no expression level differences in the target cells. As a result, commercially available random mixed primers cannot identify and distinguish among the three possible target cell types present in iPSC-derived DPC products based on differences in gene expression levels, and therefore cannot solve the technical problem that the present application is specifically designed to address.
This argument has been fully considered but is not persuasive. The examiner does not agree that the claims are limited to only the five recited genes. The claims as amended recite the following:
A reagent kit for detecting markers for the identification and classification of DPC, NSC and iPSC cells, including primers designed based on marker genes or biological precursors of the marker genes, wherein the marker genes are the combination of CRH, FST, GLIl, RELN, and STK32B.
The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps (see MPEP 2111.03). In view of the open claim language (“including”) the reagent kit can have primers for additional genes. Further the recitation that the kit is “for the identification and classification of DPC, NSC, and iPSC” merely sets forth the intended use of the kit, but does not limit the scope of the claims. Therefore the prior art is not required to teach use of the NEB kit for this purpose. The rejection is maintained.
7. THIS ACTION IS MADE FINAL. 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 extension fee 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Shen can be reached at 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682