DETAILED ACTION
The present Office Action is responsive to the Amendment received on February 17, 2026.
Preliminary Remark
Claims 7-12, 14 and 15 are canceled.
Claims 22-26 are new.
Claim Interpretation
The term, “RNA-seq” is not deemed a trademark, but refers to an art-recognized process of sequencing RNA molecules in a biological sample.
Similarly, the term, “DNA-seq” is not deemed a trademark.
The term, “ATAC-seq” refers to “Assays for Transposase-Accessible Chromatin with sequencing” and is not trademarked.
Claim Rejections - 35 USC § 112 – New Grounds, Necessitated by Amendment
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 22 and 26 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.
Claim 22 is indefinite for reciting the phrase, “wherein Rij is the ratio between the amount of pre-mRNA of the first allele and the amount of pre-mRNA of the second allele, wherein Rij ≠ 1”.
Claim 22, however, does not provide a proper antecedent basis for this limitation because the claim lacks any quantification/determination step of the amounts of the first and second alleles of a gene from the sample.
Claim 26 is indefinite for the following reasons. Claim 26 is appears to be no different in scope to that of claim 4. Claim 4 depends from claim 1 (via claim 3), wherein the recited limitation involves the sequences derived from “specific alleles” by the same lists of process recited in claim 26. Because parent claim 1 specifically recite the “alleles” as being first and second alleles, claim 4 implies the specific alleles are first and second alleles) and claim 26 that explicitly recites that sequences are derived from first and second alleles, does not further distinguish the claim from claim 4.
Therefore, claim 26 is indefinite for not appearing to contain any difference in metes and bounds in scope of claim 4.
Claim Rejections - 35 USC § 101
Maintained & New – Necessitated by Amendment
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.
The rejection of claims 1-6 and 13-21 under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception as discussed in the Office Action mailed on October 16, 2025 is maintained for the reasons of record.
Applicants’ claim amendment and arguments presented in the Amendment received on February 17, 2026 have been carefully considered but they have not been found persuasive for the reasons discussed in the, “Response to Arguments” section.
The Rejection:
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception based on the analysis under the current Patent Eligibility Guidelines (herein, “PEG”) as discussed below.
The rejection is based on two different judicial exception issues as discussed below:
Step 1 Inquiry under PEG
Step 1 inquiry under Patent Eligibility Guidelines (herein, “PEG”) determines whether or not the claimed invention is drawn to one of the recognized statutory classes of invention.
Claims 1-6 and 13-21 satisfy the step 1 analysis as the claims are directed to a method.
Step 2A Inquiry under PEG
A recently revised PEG now performs step 2A inquiry under a 2-prong analysis, and the subject claims analyzed accordingly as follows:
Prong 1:
Independent claim 1 which is representative of the invention recites the steps of:
obtaining pre-mRNA of a pair of alleles of a gene for a plurality of genes;
determining the ratio (Ri,j) between the amount of pre-mRNA of one of more pairs of alleles (i, j) of the genes;
determining the nucleotide sequences of the pair of alleles; and
comparing the nucleotide sequences of the pair of alleles to identify the differences between the nucleotide sequences of said pair of alleles.
The claim also recites a judicial exception, which is a naturally existing correlation between different mutations found between the pre-mRNAs and their expression levels.
Data collection & manipulations:
Claim 1 Prong-1 inquiry under step 2A determines whether the claim(s) recites an abstract idea, a law of nature, or a natural phenomenon. Under this analysis, the claim recites the step of data collection, which is “obtaining” the pre-mRNA levels for a pair of alleles of a given gene. The claim then recites the mathematical processing step (i.e., data manipulation) in the form of comparing the amounts of pre-mRNA in the form of Ri, j, wherein “i” represents the amount of pre-mRNA for one allele of a gene and “j” represents the amount of pre-mRNA for the other allele of the same gene, wherein a conditional requirement when the levels of pre-mRNA from each allele is not equal to each other, that is, i ≠ j is conditionally attached to the sequences of the pre-mRNAs of said pair of alleles.
The claimed method therefore, tantamount to collection of data, analyzing the data by way of data comparison and establishing a relation of this data to another data, which is the sequence of the pre-mRNA for each allele of the gene.
The Federal Circuit has explained that the courts “continue to ‘treat[] analyzing information … by mathematical algorithms, without more, as essentially mental processes within the abstract-idea category.’” (Synopsys, Inc. v. Mentor Graphics Corp., 839 F.3d 1138, 1146-7 (Fed. Cir. 2016). Cf. Diamond v. Diehr, 450 U.S. 175, 191 (1981) (“A mathematical formula as such is not accorded the protection of our patent laws.”). Therefore, the claim recites collection of data, and its manipulation using mathematical relationship, which is deemed abstract in nature therefore, patent ineligible as being directed to judicial exception.
Naturally Occurring Relationship:
Additionally, the claim also recites a judicial exception, that is, the different mutations found between the alleles of the same gene in pre-mRNA resulting in allelic skew.
“inventors have now recognized that additional information from the transcriptome may be obtained using mRNA which is not limited polA+ RNA. More typically, they have recognized that, if pre-mRNA is used (e.g., polyA- mRNA, which still contains introns), then the natural variations in genome sequences which are found in introns and down-stream sequences and which are removed in polyA+ RNA can be used to determine allelic skew and so identify dyregulated genes” (page 2)
“Using the method of the invention, it becomes possible to link the skew in gene expression to genetic signals associated with traits and disease traits outside the body of the gene … also allows for the linking of the skew in gene expression to skew in sequence-based genomics assays linked to regulatory activities” (page 5)
Therefore, claim is based on Applicants’ discovery of a natural correlation that exists between the amounts of pre-mRNA of each allele from a pair of alleles for a given gene and their sequence differences. And this correlation is a consequence of natural processes, similar to Ariosa, where the invention was “directed to detecting the presence of naturally occurring thing or a natural phenomenon, cffDNA in maternal plasma or serum.” (Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1376 (Fed. Cir. 2015).
Therefore, the invention as claimed recites judicial exceptions.
Prong 2:
Prong-2 inquiry under step 2A determines whether or not the claims recite additional elements that integrate the judicial exception into a practical application in a manner that imposes a meaningful limit on the judicial exception.
Data collection & manipulations:
Some of the dependent claims recite addition elements, such as the additional conditional statement for establishing a mathematical correlation of expression to sequence differences between the alleles of a gene. Specifically, claims 2, 5, and 17 recite the “R” value, which is the level of expression of pre-mRNA, with values “i” and “j” (directed to each allele), having unequal values, is expressed i ≠ j, < 0.9, or > 1.1, or an integer value being less than 1 or greater than 1. This is simply a mathematical formula that represents the collect data (i.e., amounts of pre-mRNA) and establishing a condition that represents allelic skew. These additional steps therefore, are also deemed algorithmic steps for the manipulation of collected data and do not add significantly add more than the judicial exception itself.
Claims 3, 4, and 20 add additional steps of the sequencing means utilized for the determination of mutations in the pre-mRNAs, such as RNA-seq, ATAC-seq, DNase-seq, or ChIP-seq. However, these steps are not new means of sequencing. The claims “do not recite an inventive concept that transforms the observation of a natural phenomenon into a patentable invention” Genetic Veterinary Scis., Inc. v. Laboklin GmbH & Co. KG, 933 F.3d 1302, 1318-19 (Fed. Cir. 2019). In Genetic Veterinary, “[n]othing in claim 1’s language suggests the invention of a new method of genotyping … Rather … the genotyping method in claim 1 uses conventional or known laboratory techniques to observe the newly discovered mutations in the SUV39H2 at position 972.” Id. At 1318-19. That is, the invention was the natural phenomenon of the mutation and the Fed. Circuit found the claims fell “short of statutory patentable subject matter”, Id. At 1320.
Analogously, the natural correlation which exists (as discussed above) is analyzed technologies that were commercially available and routine (i.e., RNA-seq, ChIP-seq, etc.).
“[A] claim for a new abstract idea is still an abstract idea.” Synopsys, Inc. v. Mentor Graphics Corp., 839 F.3d 1138, 1151 (Fed. Cir. 2016). The instant claims “are directed to a natural law because they recite only the natural law together with standard techniques for observing it. That the routine steps are set forth with some specificity is not enough to change that conclusion.” Athena, 915 F.3d at 752.
Naturally Occurring Relationship:
As explained by the Supreme Court, in order to transform a judicial exception into a patent-eligible application, the additional element or combination of elements must do ‘more than simply stat[e] the [judicial exception] while adding the words ‘apply it’”. Alice Corp. v. CLS Bank, 573 U.S. __, 134 S. Ct. 2347, 2357, 110 USPQ2d 1976, 1982-83 (2014) (quoting Mayo Collaborative Servs. V. Prometheus Labs., Inc., 566 U.S. 66, 72, 101 USPQ2d 1961, 1965). Thus, for example, claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. Alice Corp., 134 S. Ct. at 2358, 110 USPQ2d at 1983. See also 134 S. Ct. at 2389, 110 USPQ2d at 1984 (warning against a § 101 analysis that turns on “the draftsman’s art”) (MPEP 2106.05(f))
As stated above, additional elements recited in the form of sequencing that involve commercially available platforms (discussed above), also fails to add more to the judicial exception itself and for the same reason, lacks patent eligibility.
Step 2B Inquiry under PEG
Step 2B inquiry of the PEG determines whether or not additional elements are provided and whether such elements amount to significantly more than the judicial exception in the claims.
Data Collection & manipulation & B) Naturally Occurring Relationship:
Presently, the additional elements which are provided in the claims that recite that the judicial exceptions are claimed in the form of employing commercially known platforms for sequencing nucleic acids, and the number of genes for which pair of alleles are analyzed. However, they fail to further add more than the judicial exception because expansion of analyzing additional genes for which allelic skew exists utilizing commercially sold sequencing platforms do not specifically limit the presently recited judicial exception as they are widely applicable and routinely included in the field of molecular diagnostics.
Therefore, the present claims lack patent eligibility.
Response to Arguments:
Applicants traverse the rejection.
Applicants state that claim 1 has been amended to recite active steps – namely, extracting pre-mRNAs from target eukaryotic cells, measuring amounts of the pre-mRNAs and performing phased sequencing of the pre-mRNAs (page 10, Response).
Applicants contend that under paten eligibility framework, step 1 is satisfied because claims are directed towards a process, and under step 2A, claims recite active, physical steps which are not directed to a judicial exception (page 10, Response).
The Office respectfully disagrees.
As stated in the above rejection, the patent eligibility rejection was based on the claims embracing two different types of judicial exception, that is, by way of simple data capture and manipulation (see Prong-1A, Prong-2B(A) analyses) and capture of judicial exception of naturally existing phenomenon (see Prong-1B, Prong-2B(B) analyses).
To reiterate, claim 1 recites a judicial exception in that the presence of a mutation fond between the alleles of a gene in pre-mRNA results in allelic skew. This is admitted by Applicants in their own disclosure:
“inventors have now recognized that additional information from the transcriptome may be obtained using mRNA which is not limited polA+ RNA. More typically, they have recognized that, if pre-mRNA is used (e.g., polyA- mRNA, which still contains introns), then the natural variations in genome sequences which are found in introns and down-stream sequences and which are removed in polyA+ RNA can be used to determine allelic skew and so identify dysregulated genes” (page 2)
“Using the method of the invention, it becomes possible to link the skew in gene expression to genetic signals associated with traits and disease traits outside the body of the gene … also allows for the linking of the skew in gene expression to skew in sequence-based genomics assays linked to regulatory activities” (page 5)
Therefore, claim is based on Applicants’ discovery of a natural correlation that exists between the amounts of pre-mRNA of each allele from a pair of alleles for a given gene and their sequence differences. And this correlation is a consequence of natural processes, similar to Ariosa, where the invention was “directed to detecting the presence of naturally occurring thing or a natural phenomenon, cffDNA in maternal plasma or serum.” (Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1376 (Fed. Cir. 2015).
While the Office acknowledges the addition of “active steps” recited in claim 1 in the form of “extracting pre-mRNA from a target eukaryotic cell”, “measuring the amounts of the pre-mRNAs”, and performing phased sequencing of pre-mRNAs, these are not deemed to amount to add significantly more than the judicial exception for the following reasons.
The situation is analogous to that which was present in Mayo (citation omitted), the representative claim duplicated below:
A method of optimizing a therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising:
(a) administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and
(b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder,
wherein the level of 6-thioguanine less than about 230 pmol per 8x108 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and
wherein the level of 6-thioguanine greater than about 400 pmol per 8x108 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject, [from litigated patent 6,355,623]
As seen, the claims of Mayo recited two active steps in the form of “administering” a drug and “determining” the level of said drug metabolite. The judicial exception is also recited in the claims in the form of the two “wherein clauses.”
In Mayo, the court stated:
“Still, as the Court has also made clear, to transform an unpatentable law of nature into a patent-eligible application of such a law, one must do more than simply state the law of nature while adding the words, ‘apply it.’ See, e.g., Benson, supra, at 71-72.”
“The case before us lies at the intersection of these basic principles. It concerns patent claims covering processes that help doctors who use thiopurine drugs to treat patients with autoimmune diseases determine whether a given dosage level is too low or too high. The claims purport to apply natural laws describing the relationships between the concentration in the blood of certain thiopurine metabolites and the likelihood that the drug dosage will be ineffective or induce harmful side-effects. We must determine whether the claimed processes have transformed these unpatentable natural laws into patent-eligible applications of those laws. We conclude that they have not done so and that therefore the processes are not patentable.”
“The question before us is whether the claims do significantly more than simply describe these natural relations. To put the matter more precisely, do the patent claims add enough to their statements of the correlations to allow the processes they describe to qualify as patent-eligible processes that apply natural laws? We believe that the answer to this question is no.”
“What else is there in the claims before us? The process that each claim recites tells doctors interested in the subject about the correlations that the researcher discovered. In doing so, it recites an ‘administering’ step, a ‘determining’ step, and a ‘wherein’ wherein step. These additional steps are not themselves natural laws but neither are they sufficient to transform the nature of the claim.”
“If a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than drafting effort designed to monopolize the law of nature itself.”
Similarly, the instant claim 1, while amended to add active steps in the form of an extraction step and the measurement of the pre-mRNAs from the sample, and performing phased sequencing to determine the sequence of the pre-mRNAs, these steps are not deemed to add more than the judicial exception, as discussed by the court because claims simply tells the practitioner interested in the subject about the correlation that has been discovered while reciting steps that are insufficient to transform the nature of the claim.
The steps of extracting and measuring are recited utilizing a highly generic language which is analogous the language utilized in the recited steps in Mayo (i.e., administering and determining (or measuring)), for which the court also found as not satisfying:
“The upshot is that the three steps simply tell doctors to gather data from which they may draw an inference in light of the correlations. To put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well-understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately. For these reasons we believe that the steps are not sufficient to transform unpatentable natural correlations into patentable applications of those regularities.”
The sequencing means recited as “phased sequencing” is also means known in the art for determining a nucleic acid sequence and therefore, is an application of means routinely engaged by the scientific community, an insignificant pre- solution activity:
“Third, the ‘determining’ step tells the doctor to determine the level of the relevant metabolites in the blood, through whatever process the doctor or the laboratory wishes to use. As the patents state, methods for determining metabolite levels were well known in the art. ‘623 patent, col. 9, ll. 12-65, 2. App. 11. … Thus, this step tells doctors to engage in well-understood, routine, conventional activity previously engaged in by scientists who work in the field. Purely ‘ conventional or obvious’ ‘[pre]-solution activity’ is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law. Flook, 437 U.S., at 590; see also Bilski, 561 U.S., at __ (slip op., at 14) (‘[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ … adding ‘insignificant post-solution activity’’ (quoting Diehr, supra, at 191-192)).”
Therefore, the invention as claimed recites judicial exceptions and Applicants’ arguments are not found persuasive.
Rejection – New, Necessitated by Amendment (i.e., addition):
Claim 22-26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception under the same rationale of record and discussed above.
Claims 22-26 recite the same judicial exception (i.e., natural correlation) of mutation among alleles of a gene that attributes to an allelic skew (i.e., dysregulation of the expression levels of the alleles of the gene), while utilizing generically recited steps of “extracting,” “phased sequencing,” which as discussed immediately above, is insufficient to meaningfully apply the judicial exception.
Therefore, the claims lack patent eligibility.
Conclusion
No claims are allowable. Claims are free of prior art.
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
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
Papers related to this application may be submitted to Art Unit 1681 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 CFR 1.6(d)). NOTE: If applicant does submit a paper by FAX, the original copy should be retained by applicant or applicant’s representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED, so as to avoid the processing of duplicate papers in the Office. All official documents must be sent to the Official Tech Center Fax number: (571) 273-8300. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
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.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/YOUNG J KIM/Primary Examiner
Art Unit 1637 April 24, 2026
/YJK/
Prosecution Insights