DETAILED ACTION
Applicant's response, filed 17 September 2025, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 .
Claim Status
Claims 1-15 are currently pending and under exam herein.
Claims 16-20 have been cancelled.
Specification
Note: All references to the Specification herein pertain to the PG publication: US20220251634.
The outstanding objections to the Specification are withdrawn in view of the amendments submitted herein.
Claim Interpretation
Claims 16-20 have been cancelled and thus the claim interpretation under 112(f) is moot.
Claim Rejections - 35 USC § 112(a)
With respect to claim 16-20 and 112(a), said claims have been cancelled and therefore the rejection is moot.
With respect to claims 1-15 and 112(a), the instant claims have been amended to include that the transducing and editing occurs using CRISPR. The instant Specification includes disclosure of Cas proteins including Cas9 and those derive from Streptococcus, Neisseria, Pasteurella, Francisella, and Campylobacter. Further the Specification indicates that the CRISPR system of the invention is not limited thereto [0028].
Claim Rejections - 35 USC § 112(b)-Indefiniteness
The outstanding rejections under 35 USC 112(b) with respect to claims 16-20 are moot, as said claims have been cancelled.
The outstanding rejections under 35 USC 112(b) with respect to claims 1-15 are withdrawn in view of the claim amendments submitted herein.
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 1-15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. Any newly recited portions herein are necessitated by claim amendment.
The instant rejection reflects the framework as outlined in the MPEP at 2106.04:
Framework with which to Evaluate Subject Matter Eligibility:
(1) Are the claims directed to a process, machine, manufacture or composition of matter;
(2A) Prong One: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea;
Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application (Prong Two); and
(2B) If the claims do not integrate the judicial exception, do the claims provide an inventive concept.
Framework Analysis as Pertains to the Instant Claims:
Step 1 Analysis: Are claims directed to process, machine, manufacture/composition of matter
With respect to step (1): yes, the claims are directed to a method for measuring time which has elapsed from a predetermined time point in cells.
Step 2A, Prong 1 Analysis: Do claims recite abstract idea
With respect to step (2A)(1), the claims recite abstract ideas. The MPEP at 2106.04(a)(2) further explains that abstract ideas are defined as:
mathematical concepts, (mathematical formulas or equations, mathematical relationships and mathematical calculations);
certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or
mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information).
With respect to the instant claims, under the (2A)(1) evaluation, the claims are found herein to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for observing, analyzing and organizing information) and in conjunction with mathematical concepts (in particular mathematical relationships and formulas).
The claim steps to abstract ideas are as follows:
Claim 1:
(c) measuring an indel frequency (IF) of the target sequence, which is a step performed by mathematical analysis (see, for example, the Specification at [0076]; [0085]) and is abstract.
(d) calculating any time point using the following equation:
F =1-IF =e-ℷ(t-t0) (t ≥ 0,t) ≥ 0)
(wherein F represents a relative frequency (ratio) of the copy number of an intact target sequence in the total copy number of the target sequence at any time point, IF represents an indel frequency of the target sequence measured at any time point, A is a positive constant that represents an indel generation rate of the target sequence per unit time, and to is the latent time taken to express a transgene transduced into cells), which is a mathematical calculation and therefore abstract.
Claims 2: (iii) measuring a frequency (F) of the copy number of an intact sequence in the total copy number of the target sequence; and calculating an indel generation rate constant (A) of the target sequence per unit time for the given target sequence using the following equation:
F =e-ℷt* (t* ≥ 0)
(wherein F represents a frequency of the copy number of an intact target sequence in the total copy number of the target sequence, A represents a positive constant, and t* is a positive constant that represents a predetermined time point), wherein said step represents mathematical equation/calculation and is abstract.
Hence, the claims explicitly recite numerous elements that, individually and in combination, constitute abstract ideas.
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined herein to each cover performance either in the mind (calculations by hand or pen and paper) and performance by mathematical operation (calculation for assessment of time points as per the recited specific equations in said claims). There are no specifics as to the methodology involved in “measureing” or in “calculating” and thus, under the BRI, one could simply, for example, perform said operation with pen and paper, or, alternatively with the aid of a generic computer as a tool to perform said calculations. These recitations are similar to the concepts of collecting information, analyzing it and providing certain results from the collection and analysis (Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), organizing and manipulating information through mathematical correlations (Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) and comparing information regarding a sample or test to a control or target data in (Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)) that the courts have identified as concepts that can be practically performed in the human mind with pen and paper, and can include mathematical concepts.
Further, see MPEP § 2106.04(a)(2), subsection III. The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation (see, e.g., Benson, 409 U.S. at 67, 65, 175 USPQ at 674-75, 674: noting that the claimed "conversion of [binary-coded decimal] numerals to pure binary numerals can be done mentally," i.e., "as a person would do it by head and hand."); Synopsys, Inc. v. Mentor Graphics Corp., 839 F.3d 1138, 1139, 120 USPQ2d 1473, 1474 (Fed. Cir. 2016): holding that claims to a mental process of "translating a functional description of a logic circuit into a hardware component description of the logic circuit" are directed to an abstract idea, because the claims "read on an individual performing the claimed steps mentally or with pencil and paper"). Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer. As the Federal Circuit has explained, "[c]ourts have examined claims that required the use of a computer and still found that the underlying, patent-ineligible invention could be performed via pen and paper or in a person’s mind" (see Versata Dev. Group v. SAP Am., Inc., 793 F.3d 1306, 1335, 115 USPQ2d 1681, 1702 (Fed. Cir. 2015); Mortgage Grader, Inc. v. First Choice Loan Servs. Inc., 811 F.3d 1314, 1324, 117 USPQ2d 1693, 1699 (Fed. Cir. 2016): holding that computer-implemented method for "anonymous loan shopping" was an abstract idea because it could be "performed by humans without a computer").
Step 2A, Prong 2 Analysis: Integration to a Practical Application
Because the claims do recite judicial exceptions, direction under (2A)(2) provides that the claims must be examined further to determine whether they integrate the abstract ideas into a practical application (MPEP 2106.04(d). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the abstract idea is integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the abstract idea, the claim is said to fail to integrate the abstract idea into a practical application (MPEP 2106.04(d).III).
With respect to the instant recitations, the claims recite the following additional elements:
Claim 1: (a) transducing a composition into cells and editing target genes using a CRIPSR system to generate indels, followed by culturing of the cells; (b) harvesting some of the cultured cells at any time point (t) which has elapsed from a predetermined time point, followed by sequencing of a target sequence from the genomic DNA of the cells, which are operations that are routine laboratory operations and serve to get the data for computations in the abstract idea.
Claims 2: further comprising estimating a lambda constant (A), which includes the following steps prior to the step (b): (i) harvesting some of the cultured cells at predetermined time point (f);(ii) sequencing the target sequence from the genomic DNA of the cells, which are operations that are routine laboratory operations and serve to get the data for computations in the abstract idea.
Claims 3-15 further limit the types of “compositions” (claims 3-4); further limits to the transduction for editing step (claim 5); limits to the induction (claim 6); limits to the derivation of Cas9 protein and Cpf1 protein (claims 7-8); base sequences compositions (claim 9-11); vector types and constructions (claim 12-14); and method for sequencing (claim 15), wherein each of said limiting steps further serves to gather the data for computations in the abstract idea using routine laboratory methods.
Further with respect to the additional elements in the instant claims, those steps directed to data gathering perform functions of collecting the data needed to carry out the abstract idea. Data gathering does not impose any meaningful limitation on the abstract idea, or on how the abstract idea is performed. Data gathering steps are not sufficient to integrate an abstract idea into a practical application. (MPEP 2106.05(g).
The courts have recognized the following laboratory techniques as insignificant extra-solution activity. See further, the MPEP at 2106.05(d)II.): determining the level of a biomarker in blood by any means (Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017)); detecting DNA or enzymes in a sample (Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017)).
Step 2B Analysis: Do Claims Provide an Inventive Concept
The claims are lastly evaluated using the (2B) analysis, wherein it is determined that because the claims recite abstract ideas, and do not integrate that abstract ideas into a practical application, the claims also lack a specific inventive concept. Applicant is reminded that the judicial exception alone cannot provide the inventive concept or the practical application and that the identification of whether the additional elements amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they provide significantly more than the judicial exception. (MPEP 2106.05.A i-vi).
With respect to the instant claims, the additional elements of data gathering described above do not rise to the level of significantly more than the judicial exception. As directed in the Berkheimer memorandum of 19 April 2018 and set forth in the MPEP, determinations of whether or not additional elements (or a combination of additional elements) may provide significantly more and/or an inventive concept rests in whether or not the additional elements (or combination of elements) represents well-understood, routine, conventional activity. Said assessment is made by a factual determination stemming from a conclusion that an element (or combination of elements) is widely prevalent or in common use in the relevant industry, which is determined by either a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims, the prior art gene editing systems such as CRISPR- Cas9 systems, for example, is well established in the art. See, as exemplary art the art to Shalem et al. disclosing genome-scale CRISPR-Cas9 knockout screening in human cells (Science (2014) Vol. 343:84-87) wherein the prior art provides that each of said laboratory steps as disclosed herein are directed to are data gathering elements as shown under 2A, prong 2 and that under the assessment herein under 2B, encompass steps that are routine, well-understood and conventional in the art.
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity (see MPEP 2106.05(d)II.): determining the level of a biomarker in blood by any means (Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017)); detecting DNA or enzymes in a sample (Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017)).
The dependent claims have been analyzed with respect to step 2B and none of these claims provide a specific inventive concept, as they all fail to rise to the level of significantly more than the identified judicial exception.
For these reasons, the claims, when the limitations are considered individually and as a whole, are rejected under 35 USC § 101 as being directed to non-statutory subject matter.
Response to Applicant’s Arguments
1. Applicant states that “as amended, claim 1 recites a method for measuring time which has elapsed from a predetermined time point in cells comprising, among others, transducing a composition into cells and editing target genes using a CRISPR system to generate indels. The limitation "editing target genes with a CRISP[A] system to generate indels" imposes a meaningful limit to the method, because, as described in the specification, indel generation by the CRISP[A] system can occur at steady rates, in contrast to typical dynamic biological reactions, and the accumulated indel frequency can be a function of time”.
It is respectfully submitted that this is not persuasive. Applicant correctly notes that the steps directed to (a)-(b) are those steps that are the “additional elements” in the claim. However, said steps are those that are directed to data gathering and are steps that we well-known in the art of CRISPR systems. For example, it was demonstrated above that the prior art to Shalem et al. disclosed genome-scale CRISPR-Cas9 knockout screening in human cells. Further to the generation of indels, as indicated in the above argument, Shalem et al. disclose that CAS9 can induce DNA double-strand breaks (DSBs) at specific genomic loci through sgRNA, which when targeted to coding regions can create indels (page 85-Shalem et al.). As such the system by which transduction and harvesting of cells is one that is well-known, routine and conventional in the art and cannot, thus be an additional element herein that provides for significantly more. Rather, said operations merely provide data gathering operations for the performance of the recited judicial exceptions in the claim (measuring IF, which includes mathematical function and calculating, as per the formula recited).
2. Applicant states that, “claim 1provides an inventive concept under the Step 2B evaluation for an eligible subject matter. As the Examiner acknowledges in the Office Action (page 8, lines 9-10), the art is particularly silent with respect to the technology of claim 1 using transduced compositions for editing in the realm of time measurements”.
It is respectfully submitted that the Office Action dated 17 June 2025 does recite the following: “the closest prior art is represented in the above citations 1-5, wherein the prior art fails to teach or fairly suggest the steps of the instant claims that are directed to the measurements of indel frequency (IF) and calculations of time using the formulas as disclosed herein”. Applicant will note that the claim limitations directed to the judicial exceptions, steps (c) and (d), are those that are indicated as not being taught by the closest prior art. It is further important to note, the judicial exceptions alone cannot provide the improvement. See, for example Diamond v. Diehr, 450 U.S. 175, 187 and 191-92, 209 USPQ 1, 10 (1981)). As such, it if the judicial exception is integrated into a practical application (under 2A, prong two) or wherein if said additional elements alone or in combination provide significantly more, then under 2B an inventive concept may be distinguished. Neither are present in the instant claims.
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.
Inquiries
Papers related to this application may be submitted to Technical Center 1600 by facsimile transmission. Papers should be faxed to Technical Center 1600 via the PTO Fax Center. The faxing of such papers must conform to the notices published in the Official Gazette, 1096 OG 30 (November 15, 1988), 1156 OG 61 (November 16, 1993), and 1157 OG 94 (December 28, 1993) (See 37 CFR § 1.6(d)). The Central Fax Center Number is (571) 273-8300.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lori A. Clow, whose telephone number is (571) 272-0715. The examiner can normally be reached on Monday-Thursday from 11:00AM to 9:00PM ET.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Karlheinz Skowronek can be reached on (571) 272-9047.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/Lori A. Clow/Primary Examiner, Art Unit 1687