DETAILED CORRESPONDENCE
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 .
This action is in response to the papers filed July 22, 2026. Currently, claims 1-5, 8-13 are pending. All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow. This action is made FINAL.
Any objections and rejections not reiterated below are hereby withdrawn.
Priority
This application is a 371 of PCT/JP2022/031772, filed August 23, 2022 and claims priority to Japan 2021/1135550, filed August 23, 2021.
It is noted that a translation of the foreign document has not been received.
Drawings
The drawings are acceptable.
New Matter
Claims 1-5, 9 are rejected under 35 U.S.C. 112, first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
In the amended claims, reference to “enriching comprises selecting the tumor cell population based on expression of at least one biomolecule encoded by a gene from the group….” are included. The amendment proposes that the new claim language is supported in paragraphs 12-13 and 40 of the specification. Paragraph 12 and 13 are directed to separating tumor cells using magnetic beads and magnetism. This is not enrichment based upon gene expression. The specification then talks about detecting gene alterations, but this is not enrichment by gene expression. The specification, para 4, discusses tumor cell enrichment by microdissection. However, the specification does not describe or discuss “enriching comprises selecting the tumor cell population based on expression”. The description of macrodissection does not support enriching comprises selecting the tumor cell population based on expression. The concept of “enriching comprises selecting the tumor cell population based on expression” does not appear to be part of the originally filed invention. Therefore, “enriching comprises selecting the tumor cell population based on expression” constitutes new matter.
Applicant is required to cancel the new matter in the reply to this Office Action.
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.
Newly amended and added Claims 1-5, 8-13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Question 1
The claimed invention is directed to a process that involves a natural principle and a judicial exception.
Question 2A Prong I
The claims are taken to be directed to an abstract idea, a law of nature and a natural phenomenon.
Newly amended Claim 1 has been amended to require a comparison between the sequencing results and a reference sequence of a target. The comparison is considered an abstract idea.
Claim 8 is directed to “a method for distinguishing between a somatic mutation and a germline mutation” by determining sequencing results, VAF from a tumor cell population and a residual cell population. Claim 8 is directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of “distinguishing between a somatic mutation and a germline mutation”, comparing to a threshold and “classifying the target mutation as a germline mutation”) and a law of nature/natural phenomenon (i.e. the natural correlation between variant allele frequencies and somatic/germline mutations).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Claims 1 and 8 each recite a comparison between the sequencing result and a reference sequence of a target gene or a threshold that is deemed an abstract idea (see MPEP 2106.04(a)(2)(III)(A); • claims to “comparing BRCA sequences and determining the existence of alterations,” where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014)).
Further, claim 8 involves the patent-ineligible concept of an abstract process. Claim 8 requires performing the step of “distinguishing between a somatic mutation and a germline mutation” and “classifying the target mutation as germline”. Neither the specification nor the claims set forth a limiting definition for " distinguishing between a somatic mutation and a germline mutation " and the claims do not set forth how “distinguishing” is accomplished. As broadly recited, the distinguishing recitation may be accomplished mentally by thinking about a subject’s variant allele frequency and assessing whether the mutation is somatic or germline. Thus, the determining step constitutes an abstract process idea. This allele frequency is a simple mathematical formula and is thus an abstract concept.
Question 2A Prong II
The exception is not integrated into a practical application of the exception. The claim does not recite any additional elements that integrate the exception into a practical application of the exception. While the claim recites dissociating, separating and collecting and sequencing, this is not an integration of the exception into a practical application. Instead, these elements are data gathering required to perform the method. Thus, the claim is “directed to” the exception.
Accordingly, the claims are directed to judicial exceptions.
Question 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non patent ineligible elements, are sufficient to “’transform the nature of the claim’ into a patent eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
The claims are not sufficiently defined to provide a method which is significantly more from a statement of a natural principle for at least these reasons:
The claims do not include applying the judicial exception, or by use of, a particular machine. The claims do not tie the steps to a “particular machine" and therefore do not meet the machine or transformation test on these grounds. The use of machines generally does not impose a meaningful limit on claim scope.
The claims also do not add a specific limitation other than what is well-understood, routine and conventional in the field. The dissociating, separating and collecting and sequencing are mere data gathering step that amounts to extra solution activity to the judicial exception. It merely tells the users of the method to determine the variant allele of a sample without further specification as to how the sample should be analyzed. The claim does not recite a new, innovative method for such determination. The determining step essentially tells users to determine the markers through whatever known processes they wish to use.
The steps of dissociating, separating and collecting and sequencing were well known in the art at the time the invention was made. The steps are recited at a high level of generality. The claim merely instructs a scientist to use any analysis assay to sequence the nucleic acids. The claim does not require the use of any particular non-conventional reagents. When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine and conventional activities engaged in by scientists prior to applicant’s invention and at the time the application was filed.
Further it is noted that 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.
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For these reasons the claims are rejected under section 101 as being directed to non-statutory subject matter.
Response to Arguments
The response traverses the rejection. The response asserts the invention is a defined laboratory procedure and a calculable computational procedure. The response argues the process includes determining VAF values, calculating and classifying and determining whether the calculated value is less than a threshold. The response argues these limitations are specific, novel and innovative portions of the invention. This argument has been considered but is not convincing because the standard for patent eligible subject matter is not specific, novel and innovative. The analysis provided above is the framework set forth by the courts for determining eligibility. As discussed above, the claims are directed to multiple judicial exceptions and the steps in addition to the judicial exceptions are well understood routine and conventional.
The response further argues that although Claim 8 includes mathematical calculations, the claim is not directed to merely the mathematical concept itself. This argument has been reviewed but is not persuasive. Example 49 of the July 2024 Subject Matter Eligibility Examples are relevant here. The guidelines provide a method that requires collecting and genotyping a sample, performing a mathematical analysis and administering a treatment. The guidelines find the claim is ineligible because it recites a judicial exception (an abstract idea) and the claim as a whole does not integrate the exception into a practical application (and is thus directed to an abstract idea) and the claim does not provide significantly more than the exception (does not provide an inventive concept). Here, the claims similarly perform insignificant extra solution activity that is well-known and the additional limitations are directed to judicial exceptions.
Thus for the reasons above and those already of record, the rejection is maintained.
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.
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.
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.
Claim(s) 1-5, 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Manaresi et al. (US 2015/0126396, May 7, 2015) in view of Huang et al. (WO2014/110163, July 2014)
Manaresi teaches a method for identification and selection of tumor cells. Manaresi teaches sampling FFPE tumor biopsy and processing the biopsy so as to obtain a suspension of cells in a fluid (para 35). The suspension of cells is obtained by subject the FFPE biopsy to deparaffinization and then dissociating single cells with dispase/collagenase solution(para 35). Manaresi teaches labeling suspended cells with antibodies for identifying cells. Manaresi teaches marking tumor cells with keratin and stroma cells with vimentin (para 76). Manaresi also teaches CD45 MACS depletion (para 143-150) and differentiation between tumor cells, lymphocytes (para 170-171). Manaresi teaches the cells recovered can be analyzed using sequencing for identification of mutations (para 51).
With respect to Claim 3, DNA was analyzed (page 12, para15).
With respect to Claim 4, Manaresi teaches sequencing carried out by targeted next-generation sequencing on standard sample preparation.
With respect to Claim 5, the separation may be performed with MACS that uses paramagnetic beads (para 91 and 101).
With respect to Claim 9, Manaresi teaches the frequency of any given mutation may be identified however, Manaresi teaches TP53 (para 223, 224).
With respect to Claim 8, Figure 12B illustrates 5 distinct populations are present. Vim+/Ker- and Vim-/Ker+ samples were clearly studied and frequencies were determined. Figure 16 illustrate tumor and stromal samples and the frequency of different alleles to identify germline mutations.
Manaresi does not teach enriching tumors based upon MELK gene. However, Huang teaches MELK is highly enriched in developed breast tumors.
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention to have modified the enrichment method of Manaresi that enriched tumor cells based upon vimentin, MUC1, PSA, IGFR, cytokeratin, etc. Manaresi teaches enriching of cells may be based upon expression of surface antigens. Therefore, the ordinary artisan would have been motivated to have enriched a sample for tumor cells using any known gene that was differentially expressed in cancer cells. Huang teaches MELK is highly enriched in breast cancer tumors. Thus, the ordinary artisan would have been motivated to have enriched tumor cells using the known MELK gene.
Conclusion
No claims allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Bolognesi et al. (Scientific Reports, Vol. 6, No. 20944, February 11, 2016). Bolognesi teaches sorting pure cell populations for genetic analysis of formalin-fixed paraffin-embedded tumors by next generation sequencing. Specifically, Bolognesi teaches sampling FFPE sample, dewaxing the section which allows a cell suspension to be obtained (page 10, para 6). Bolognesi teaches dissociation was monitored by swirling the sample and then was stopped by putting the sample on ice (page 12, para 1). Bolognesi teaches the cell suspension was stained with anti-keratin and anti-vimentin. Next generation sequencing was then conducted on the cell lysates (page 12).
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEANINE ANNE GOLDBERG whose telephone number is (571)272-0743. The examiner can normally be reached Monday-Friday 6am-3:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng (Winston) Shen can be reached on (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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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
August 20, 2026
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