DETAILED ACTION
The present Office Action is responsive to the Amendment received on July 16, 2026.
Preliminary Remark
Claims 3-8, 12-17, 24, 28-59, 61-71, and 73-78 are canceled.
Drawings
The replacement drawings received on July 16, 2026 are acceptable.
Claim Objections
The objection made to claims 1-13, 15-23, 25-27, 60, and 72 for reasons discussed in the Office Action mailed on January 16, 2026 is withdrawn in view of the Amendment received on July 16, 2026.
Claim Rejections - 35 USC § 101
The rejection of claims 1-13, 15-23, 25-27, 60, and 72 under 35 U.S.C. 101 for reasons discussed in the Office Action mailed on January 16, 2026 is withdrawn in view of the Amendment received on July 16, 2026.
Claim Rejections - 35 USC § 112
The rejection of claims 6-8, 13, 15, 17, 20, 23, 26, 27, and 72 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particularly point out and distinctly claim the subject matter, made in the Office Action mailed on January 16, 2026 is withdrawn in view of the Amendment received on July 16, 2026.
The rejection of claims 2-8, 12, 13, and 15-17 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement made in the Office Action mailed on January 16, 2026, is withdrawn in view of the Amendment received on July 16, 2026.
Rejection – 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 10, 11, 18, 19, 20, 21, and 22 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 10 is indefinite for reciting the limitation, “the expression signature”. There is an insufficient antecedent basis for this limitation in the claim.
Claim 10 is also indefinite because it is unclear what the claimed step is achieving for the following reasons.
Claim 10 recites that the expression levels of the recited genes and miRNAs are within a predetermined amount of a mean expression level in metastases of a cohort of patients having one of the: canonical, immune, or stromal metastatic phenotypes. It is unclear how a sample being measured can be required to have the required expression levels. While a sample can be measured to determine whether its expression level of genes/miRNAs are within a pre-established levels correlated with certain phenotypes, the present claim appears to require that the expression levels of the genes and miRNAs are within the predetermined amount of such pre-established levels correlated with the three recited phenotypes.
For the purpose of prosecution, the claim has been construed to mean that the expression levels of the genes and the miRNAs are compared against the predetermined amounts.
Claims 11, 18, 19, 20, 21, and 22 are indefinite by way of their dependency on claim 10.
Rejection - Maintained
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The rejection of claims 1, 9-11, 18-23, 25-27, and 60 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, made in the Office Action mailed on January 16, 2026 is maintained for the reasons of record.
Applicants’ arguments received on July 16, 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 claim(s) contains 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 or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description Rejection.
The written description requirement ensures that, “an applicant invented the subject matter which is claimed. Further, the written description requirement for a claimed genus may be satisfied through a sufficient description of a representative number of species by 1) reduction to practice; 2) reduction to drawing; or 3) disclosure of relevant identifying characteristics (i.e., structure of other physical and/or chemical properties, functional characteristics coupled with a known or disclosed correlation between function and structure) (MPEP 2163 at II(A)(3)(a)(ii)).
Reduction to Practice
The present invention is directed to the metastases of a particular type of metastases and the ability to determine a sub-phenotype based on the expression levels and/or signature of one or more markers.
In particular, the metastases is “oligometastases” where cancer metastasis is limited in number and organ involvement, which has a better prognosis:
“Metastases are the leading cause of cancer-related deaths and are frequently widely disseminated, which has led to the prevailing view that metastases are always widespread. The oligometastasis hypothesis, in contrast, suggests that metastatic spread is a spectrum of virulence where some metastases are limited both in number and organ involvement and potentially curable with surgical resection or other loco-regional therapies. This paradigm is in stark contrast to the outcomes of patients with solid tumors where widespread metastases are largely fatal despite recent advances in systemic therapy. To date, the oligometastasis concept has been challenged, in large part, due to the lack of supporting molecular data to identify metastases associated with restricted spread. (section [0003])
The instant specification seeks to improve the inventors’ previous findings of a group of markers that are indicative of sub-phenotypes of a primary colorectal cancer metastases to liver, so as to allow fewer markers that are indicators of sub-phenotypes:
“Expression signatures based on mRNA or miRNA expression levels in metastatic tissue have been developed. Ptiroda … Nature Communications 9:1793 (2018) … describes identification of three subtypes of liver metastases from colorectal cancer primary tumors using expression levels of mRNA and miRNA in metastatic tissue (see also PCT Publication WO2019/204576 to Pitroda et al. …). Classification of the subtypes depend on mRNA or miRNA signatures requiring analysis of approximately 50 to 200 miRNAs or mRNAs, and it was only possible to classify patients into one of two groups (one SNF2 group, and one SNF1 + SNF3 group).” (section [0005])
“The inventors’ prior studies found that mRNA data alone or miRNA data alone were insufficient to classify patients into three molecular subtypes of CRCLM. By contrast, integration of both mRNA and miRNA data accurately classified the molecular subtypes of CRCLM. In the present study, the inventors aimed to minimize the number of input mRNA and miRNA features while maintaining a high accuracy for classification into the three molecular subtypes. The inventors first overlapped the mRNA and miRNA features that were present in the Pitroda 2018 Publication with the data from the UK randomized trial Xcel platform. This provided the full set of potential input mRNA and miRNA features. The inventors utilized a neural network classifier (a machine learning algorithm) to derive a classifier in the cohort from the Pitroda 2018 Publication that could then be validated in the UK validation cohort. In this context, 2018 study cohort was split into a training a testing set (60% and 40% of samples respectively) from which a signature was discovered and iteratively optimized. The model was first derived by training the neural network containing a hidden layer of 25 neurons and using as the input standardized z-scores of 400 mRNAs were selected from approximately 20,000 mRNAs on the basis of having the highest principal component (PC1 and PC2) using a principal component analysis. The 41 miRNAs were selected as being present in both platforms used in the 2018 study and the UK study. At this initial stage the average model accuracy using 400 mRNAs and 41 miRNAs as input features was 83% in the 2018 cohort testing set. In order to improve the model prediction, a recursive feature elimination was performed where input features that did not contribute significantly to the model accuracy were successively eliminated. The final model contained only 24 mRNAs (listed in Table 1 below) and 7 miRNA (listed in Table 2 below), for a total of only 31 features.” (section [0071])
In addition, in this finding, the instant specification discloses that data which pertains to the metastasis of a particular type of primary cancer, colorectal cancer to a particular type of organ, that is liver.
All of the markers which have been trained and determined to be indicative of three different types of metastatic phenotypes (canonical, immune, and stromal) pertains to colorectal cancer metastasis observed in liver.
Therefore, the specification does not contain any discussion nor show evidence of reduction to practice for a method comprising measurement of expression levels of one or more genes or miRNAs that pertain to metastasis of any origin of primary cancer to any organ.
While the specification does disclose that this method can be applied in, “metastatic cancers beyond only colorectal liver cancer” and that, “methods disclosed herein can be used to identify molecular subtypes of other metastatic cancers and to guide prognosis and treatment decisions for patients having such cancers, section [0007]), the application as filed does not contain any such markers which are correlated to such metastatic cancers to which the claims embrace.
Neither is the claim reproducing the assertion made in the specification justify written description as the Federal Circuit reiterated that mere use of the same words in the specification and the claim (an in ipsis verbis test) is not sufficient to establish written description.
Reduction to Drawing
The specification makes reference to various Figures which pertain to the markers and their correlation to colorectal cancer metastasis to liver. There are no figures which show demonstration of markers being correlated with any other primary cancer and its metastasis to any other organs.
Disclosure of Relevant Identifying Characteristics
While one could argue that a skilled artisan would be able to identify the “representative number of species” of such markers that correlate with other primary cancers and their metastasis to other organs, such argument would not satisfy the written description for the genus claims when, “the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art” (MPEP 2163(I)(A)). For the claims at issue, such essential or critical feature is markers and their demonstrated correlation. Applicants have not disclosed enough number of species within the claimed genus so as to justify the present claims directed to the subject-genus.
As stated in University of California v. Eli Lilly and Co. at page 1404:
An adequate written description of a DNA ... "requires a precise definition, such as by structure, formula, chemical name, or physical properties," not a mere wish or plan for obtaining the claimed chemical invention. Fiers v. Revel, 984 F.2d 1164, 1171, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). Accordingly, "an adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself." Id. at 1170, 25 USPQ2d at 1606.
Therefore, for the foregoing reasons, the genus embraced by the claims is not sufficiently described by the number of species disclosed in the specification, and therefore, the specification lacks written description of the claims.
Response to Arguments:
Applicants argue that the rejection has been addressed by the amendments (page 9, Response).
Applicants also argue that the specification expressly describes a method of diagnosing and treating a patient having a metastasis from a primary colorectal cancer tumor utilizing the markers of Tables 1 and 2 and identifying the metastasis as canonical, immune, or stromal (page 9, Response), and while the specification indicate that the, “metastasis tested could be liver, it may also be in other parts of the body besides the liver, including peritoneum, brain, or bone” and that the tissue tested is the metastatic tissue, not the liver tissue (page 9, Response).
These arguments have been carefully considered but have not been found persuasive.
The specification discloses that while the method of the disclosure “can be used specifically in the context of metastatic colorectal cancer” with the metastasis being a liver metastasis (see page 4), a list of metastasis to other parts of the body besides the liver are listed (page 4, includes lung, peritoneum, brain, bone, testicular, gastric, head and heck, cervical, kidney, etc.)
However, the actual expression signatures as claimed and discussed in the specification are identified from a specific cancer metastasis, that is, colorectal cancer metastasis molecular subtypes:
“These studies present validation of a 31-gene expression signatures that accurately predicts the colorectal liver metastases molecular subtypes …” (section [0078])
“The discovery cohort was comprised of 93 patients who underwent predominantly peri-operative 5-fluorouracil and platinum-based chemotherapy and hepatic resection, while the validation cohort was comprised of 147 patients randomized in the phase III … both cohorts were representative of patients who underwent hepatic resection for limited liver metastases from colorectal adenocarcinoma in the setting of per-operative chemotherapy” (section [0079])
The Federal Circuit reiterated that mere use of the same words in the specification and the claim (an in ipsis verbis test) is not sufficient to establish written description.
As discussed above, it is clear that the recited combination of markers is tied to the primary cancer being colorectal to the metastasis being liver, and the specification does not appear to provide any reasonable number of species that such markers are implicated with metastasis to other organs.
Therefore, the rejection is maintained for the reasons of record.
Claim Rejections - 35 USC § 102
The rejection of claims 1 and 26 under 35 U.S.C. 102(a)(1) as being anticipated by Liu et al. (World J. Gastroenterol., October 2010, vol. 16, no. 39, pages 4986-4991), made in the Office Action mailed on January 16, 2026 is withdrawn in view of the Amendment received on July 16, 2026.
The rejection of claims 1-7, 9-13, 15, 23, 25-27, and 60 under 35 U.S.C. 102(a)(1) as being anticipated by Pitroda et al. (WO 2019/204576 A1, published October 2019; IDS ref), made in the Office Action mailed on January 16, 2026 is withdrawn in view of the Amendment received on July 16, 2026.
Claim Rejections - 35 USC § 103
The rejection of claims 16-22 and 72 under 35 U.S.C. 103 as being unpatentable over Pitroda et al. (WO 2019/204576 A1, published October 2019; IDS ref) in view of Mandal et al. (International J. of Emerging Engineering Research and Technology, July 2015, vo. 3, no. 7, pages 172-178), made in the Office Action mailed on January 16, 2026 is withdrawn in view of the Amendment received on July 16, 2026.
Conclusion
Claim 2 is objected to for being dependent on a rejected base claim.
Claim 72 is allowable.
Claims are free of prior art as the prior art does not teach, suggest, or provide motivation to assay for all of the genes in Table 1 and all of the miRNAs listed in Table 2 from a tissue from a metastasis from a primary cancer tumor.
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.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 September 28, 2026
/YJK/
