DETAILED ACTION
The present Office Action is responsive to the Amendment received on October 30, 2025.
Preliminary Remark
Claims 7-13 are canceled.
Information Disclosure Statement
The IDS received on October 30, 2025 is improper. An IDS submitted after a non-final office action must be accompanied by wither a fee under 37 CFR 1.17(p) or a statement under 37 CFR 1.98(e).
The IDS does not have a fee under 37 CFR 1.17(p) and the statement made under 37 CFR 1.704(d) does not satisfy the necessary requirement for 37 CFR 1.98(e).
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As seen, the statement under CFR 1.704(d) specifically states that this statement “will not satisfy the requirement of 37 CFR 1.97(e) and that, “the information disclosure statement must be accompanied by a statement under 37 CFR 1.97(e) notwithstanding any statement filed under 37 CFR 1.704(d).”
As well, 37 CFR 1.704(d) is improper since the section requires that the time period under the section does not provide “three months” of filing as asserted by Applicants (see letter filed on 10/30/2025), but only thirty days.
The IDS has not been considered therefore.
Claim Rejections - 35 USC § 112
The rejection of claims 1-9 and 14-20 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to particularly point out and distinctly claim the subject matter, made in the Office Action mailed on July 30, 2025 is withdrawn in view of the Amendment received on October 30, 2025.
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 Rejections - 35 USC § 101
The rejection of claims 7-9, 12, and 13 rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception of naturally existing correlation (i.e., natural phenomenon) as discussed in the Office Action mailed on July 30, 2025 is withdrawn in view of the Amendment received on October 30, 2025, by way of their cancellation.
Rejection - Maintained
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 16 -20 under 35 U.S.C. 101 because the claimed invention is directed to judicial exception of naturally existing correlation (i.e., natural phenomenon) as discussed in the Office Action mailed on July 30, 2025 is maintained for the reasons of record.
Applicants’ arguments presented in the Amendment received on October 30, 2025 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 recite the natural correlation that exists between the expression levels of a group of genes with a prognosis of a HER2+ breast cancer patients or the natural correlation that exists between the expression levels of said group of genes and the likelihood of a patient to an anti-HER2 therapy; or a kit of reagents which is for the detection of said group of genes, which embrace primers that are portions of sequences found in nature. This judicial exception is not integrated into a practical application because the recited claims do not add a meaningful limitation by application of the judicial exception.
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.
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 1-9 and 14-20 satisfy the present inquiry as being drawn to a method; and claims 12 and 13 satisfy the present inquiry as being drawn to a product.
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:
Prong-1 inquiry under step 2A determines whether the claim(s) recites an abstract idea, a law of nature, or a natural phenomenon. As stated above, independent claims 1 and 2 recite a naturally existing correlation of the level of expression of gene genes and the prognostics of a subject having a HER2 positive (i.e., HER2+) breast cancer or the predisposition to respond so anti-HER2 therapy. Claims 8 and 9 are directed to “use” claims. These claims are recited as a method claim and therefore, analyzed similarly to claims 1 and 2.
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.
Preliminarily, claims 12 and 13 is directed to a kit of comprising a generically recited “reagent” for measuring the level of expression of the recited genes. However, such broad recitation of the term, “reagent” embraces nucleotide homologs of the recited genes that can be used primers for detection.
Such sequences are found as a portion of a naturally existing gene because primers are homologous sequence to the gene sequences. Therefore, the sequences of a primer is a judicial exceptions (i.e., naturally existing product) and the combination of such judicial exceptions (i.e., combination of primers for such genes) falls under judicial exception, thus not patent eligible.
In University of Utah Research foundation, The trustees of the University of Pennsylvania, HSC Research and Development Limited Partnership, Endorecherche, Inc., and Myriad Genetics, Inc. v. Ambry Genetics Corporation, 2014, 1361, 1366, herein, “Ambry”), the court stated the below:
“primers necessarily contain the identical sequence of the BRCA sequence directly opposite to the strand to which they are designed to bind. They are structurally identical to the ends of the DNA strands found in nature” (page 7)
“it makes no difference that the identified gene sequences are synthetically replicated … neither naturally occurring compositions that are structurally identical to the naturally occurring compositions, are patent eligible.” (page 8)
“One of the primary functions of DNA’s structure in nature is that complementary nucleotide sequences bind to each other. It is the same function that is exploited herein – the primer binds to its complementary nucleotide sequence. Thus, just as in nature, primers utilize the innate ability of DNA to bind to itself” (page 9)
“A DNA structure with a function similar to that found in nature can only be patent eligible as a composition of matter if it has a unique structure, different from anything found in nature … Primers do not have such as different structure and are patent ineligible” (page 9)
As to claims 1 and 2, claim 1 is directed to a method of prognosis of a patient having a HER2 positive breast cancer; and claim 2 is directed to the patient’s propensity to response to an anti-HER2 therapy based on the expression levels of a combination of the recited group of genes. The correlation that exists between the expression levels of the groups of genes and the said prognosis and propensity, however, is a naturally existing phenomenon (i.e., a judicial exception), be it discovered by Applicants.
To this end, 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))
To this end, claims 1 and 2 generically recite that the levels of the recited groups are genes are “measured” and compared against a reference level of expression and based on this comparison, prognosis/prediction (of response to anti-HER2 therapy is made). The claims do not recite what this reference level of expression is nor does the claim recite what source the reference level of expression is derived from. Based on conventional and well-known means employed in the art, the reference expression level is established from a control sample(s) and existing relationship is deemed a judicial exception.
Because claims 1 and 2 (thus, claims 8 and 9) do not recite any additional element, claims are deemed non-patent eligible.
Claims 3, 4, 16, and 17 recite additional genes, but are also based on their judicial exception of naturally existing correlation without additional meaningful application, and therefore non-patent eligible.
Claims 5-7 and 18-20 also lack additional elements that practically apply the judicial exception because the claims simply recite the sample from which the judicial exceptions are produced, or the types of anti-HER2 cancer drugs that are correlated with the judicial exception.
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.
With regard to claims 12 and 13, no specifically elements are recited as being part of the kit and therefore, the claims fail to recite additional elements.
With regard to claims 3-9 and 16-20 no additional elements are recited as being part of the method so as to meaningfully apply the judicial exception of the claimed methods.
Therefore, these elements are not deemed significantly more than inclusion of that are commonly used, routine and conventional.
Therefore, the present claims lack patent eligibility.
Response to Arguments:
Applicants traverse the rejection (page 9, Response).
On page 10 of Applicants’ response (herein, “Response”), Applicants state that the subject matter eligibility of an in vitro HER2+ breast cancer prognosis method or anti-HER2 therapy response comprises a step of measuring the level of expression of the recited genes with a correlation of the expression levels of the two separate groups of genes are used as prognosticator of the patient’s potential outcome, and this renders the claim patent eligible concept under pathway A of section 101 test.
The Office respectfully disagrees.
For claim 1 (and analogously for claim 2), the method is directed to a prognosis of a patient suffering from HER2+ breast cancer, wherein the prognosis is based on expression levels of two combination of gene groups. The fact that Applicants have discovered this correlation does not negate the fact that the correlation existed in nature, that is to say, the relative expression levels of the genes in the subject and the likelihood of the subject having a good or bad prognosis was naturally existing.
Therefore, this judicial exception must be claimed with additional elements, not by creative claim drafting, so as to meaningfully apply the judicial exception into patent eligibility.
Claim 1 simply does not.
Rather, claim 1 is highly identical to the claims in Mayo v. Prometheus. In Mayo, the claimed method was directed to optimizing a therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder comprising the steps:
(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.
These steps were followed by the two wherein clauses:
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.
The claims were comprised to two active steps, which are, administration of the drug; and determining the level of drug metabolite (6-thioguanine).
The natural correlation, or judicial exception was recited as levels associated with the effective amount to be administered.
In Mayo, the court considered whether the above claim added significantly more than simply describing the natural relations:
“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.”
“Second, the ‘wherein’ clauses simply tell a doctor about the relevant natural laws, at most adding a suggestion that he should take those laws into account when treating his patient. That is to say, these clauses tell the relevant audience about the law while trusting them to use those laws appropriately where they are relevant to their decision making (rather like Einstein telling linear accelerator operators about his basic law and then trusting them to use it where relevant).”
Similarly, instant claim recites an active step of measuring the expression levels of a group of genes, which are followed by the recitation of the judicial exception that naturally exist in nature, which are the expression levels of the genes and their correlation to the prognosis of a patient suffering from HER2+ breast cancer. The wherein clauses, like in Mayo, does nothing more than to tell the doctor (or a practitioner) about the natural correlation and adds the suggestion (at most) that the natural correlation should be taken into account when making prognosis.
As such was insufficient in Mayo, such is the case here. Therefore, the claim, as a whole does not demonstrate patent eligibility in a self-evident way (and similarly applied to claim 2).
Next, on page 11 of Response, Applicants state that independent claims 1 and 2 are directed to clear improvements to technology and are eligible for a streamlined analysis.
Applicants contend that claims represent a technological improvement and not merely the identification of a naturally existing correlation because the claims focus on use of a combined prognostic score based on 17 clinicopathological and genomic variables in early-stage HER2+ breast cancer to identify breast cancer patients that do not need further anti-HER2+ therapy (page 11).
The Office respectfully disagrees.
Analogous to Mayo, claims 1 and 2 do not recite any special means to obtain the gene expression levels, but generically recites that such levels are obtained. To this end, the court (Mayo) stated:
“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)).”
As to the improvements (based on prognostic score based on 17 clinicopathological and genomic variables) to which Applicants refer to, the Offices not see any single prognostic score that is computed from the purported sources.
Rather, the above-discussed judicial exception is combined with other known means of identifying HER2+ prognosis (of treatment prognosis), all of which are also based on naturally existing correlation. And combination of a naturally existing combination does not render that combination patent eligible.
On page 12 of Response, Applicants argue that claims 1 and 2 are also patentable under step 2A. Applicants contend that the claims utilize a combined prognostic score (“HER2DX”) based on 17 clinicopathological and genomic variables in early-stage HER2+ breast cancer using tumor samples, wherein these variable genes and clinical pathological variables are MMP11, pN1, pT2-4 PAM50, CDC6, CDH3, TMEM45B, EXO1, FGFR4, RRM2, TILs, MLPH, KRT5, KRT14, MYC, PHGDH, and BAG1. Applicants sate that they evaluated the prognostic score in a combined dataset of patients and led to the “claimed relationship between response to therapy in the neoadjuvant setting and long-term survival outcome …” (page 12).
Applicants state that the claims focus on technical advancements in the medical and patient care industry, significantly improving traditional methods for prediction and treatment of HER2+ breast cancer and therefore do not merely constitute the identification of a naturally existing correlation (page 12).
These arguments have been carefully considered but have not been found persuasive because Applicants’ arguments stem from their “discovery” of a combination of “variables”, but each of the variables is nevertheless naturally correlated with the observed outcome. That Applicants discovered a subset of such variable that may result in an “improved” diagnostic does not negate the fact that their correlation existed in nature.
The correct question to ask would be, what have Applicants added to the natural correlation that existed between the group of variables and their property of therapy response? As presently recited, the claims generically recite the means of obtaining the expression levels, followed by the recitation of their natural correlation by the wherein clauses.
On page 13 of Response, Applicants state that claims 1 and 2 have been amended to clarify the meaning of reference expression level and establish that it is not a judicial exception.
Applicants contend that claims recite additional elements beyond the judicial exception in that the claim recite that a pre-established reference level of expression comprises geometric mean level of ACTB, MRPL19, PSMC4, RPL0 and SF3A1 gene expression levels, thus no longer using “generalized use of a naturally existing condition” (page 13, bottom paragraph, Response).
However, the expression levels of the collection of reference genes are no different than the measurement of the expression levels of the collection of prognosticators of HER2+ breast cancer in that they are simply observation of the naturally existing levels. The expression levels of simply observed as in their naturally expressed state.
On page 14 of Response, Applicants contend that claims 1 and 2 satisfy step 2B because the claims amount to significantly more (i.e., Step 2B analysis) than the exception itself because combination of elements and/or steps for the prognosis of patients suffering from HER2+ breast cancer and for the prediction of response to anti-HER2+ therapies in patients suffering from HER2+ breast cancer includes an inventive concept thus rendering the claims eligible.
The Office respectfully disagrees the claims do not recite any additional elements than the judicial exception itself. The claims comprise a singular active step of “measuring the level of expression” of genes that correlate with anti-HER2+ therapy response with a reference level of housekeeping genes. The claims do not recite any active calculation, comparison and active determination. Rather the claims simply recites an observation of the levels of the genes with a singular active step of measuring their expression.
And even if one were to consider that these genes were to be actively required, the combination of such genes have been well-known to be useful in normalization of expression of marker genes.
For example, Ellis et al. (US 2009/0299640 A1) evidences that housekeeping genes recited in instant claims 1 and 2 have long been used as normalization standard for cancer diagnostics:
“intrinsic genes disclosed herein can be normalized to control housekeeping genes and used in a qRT-PCR diagnostic assay … For example, MRPL19 (SEQ ID NO: 1), PSMC4 (SEQ ID NO: 2), SF3A1 (SEQ ID NO: 3, PUM1 (SEQ ID NO: 4), ACTB (SEQ ID NO: 5) AND GAPD (SEQ ID NO: 6). Other genes include GUSB, RPLP0 … intrinsic genes can be used in any combination or singularly” (sections [0072] and [0073])
Therefore, the Office respectfully disagrees that claims recite additional elements in the claims other than the judicial exception itself or at best involve additional group of housekeeping genes for normalization of expression levels that have been known in the art to be routine, conventional and well-known.
The rejection is maintained therefore.
Claim Rejections - 35 USC § 103
The rejection of claims 12 and 13 under 35 U.S.C. 103 as being unpatentable over Fu et al. (WO 2019/232485 A1, published December 2019), made in the Office Action mailed on July 30, 2025 is withdrawn in view of the Amendment received on October 30, 2025, by way of their cancellation.
The rejection of claims 12 and 13 under 35 U.S.C. 103 as being unpatentable over Harbig et al. (Nucleic Acid Research, 2005, vol. 33, no. 3, e31, pages 1-9) made in the Office Action mailed on July 30, 2025 is withdrawn in view of the Amendment received on October 30, 2025, by way of their cancellation.
Conclusion
Claims 14-16 are allowed.
The Office advises Applicants to amend the claims to actively recite the step of measuring the expression levels of the combination of recited reference genes, actively recite the step of arriving at the geometric mean level of said reference combination of reference genes; actively recite the step of comparing the measured levels of the marker gene combination to the geometric mean level for satisfying the patent eligibility.
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 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.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 February 2, 2026
/YJK/