DETAILED ACTION
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 .
Claims Status
Claims 28, 32-33, 42, 61, and 63-64 are canceled. Claims 1-2, 27, 30-31 and 34-41 are pending and are examined on the merits.
Priority
Priority for Claim 27 and its dependent claims was previously determined to correspond to the filing date of PCT/US2020/034954 (05/28/2020) owing to the lack of disclosure for “Table 4B” in the provisional filing. In view of applicant’s amendments removing reference to Table 4B in the claims, priority for pending claims 27, 30-31, and 34-41 is considered to be that of the provisional filing 62/853,551 on 05/28/2019.
OBJECTIONS WITHDRAWN
Objections to the specification regarding hyperlinks are withdrawn in view of applicant’s amendments to the specification filed 12/09/2025.
REJECTIONS WITHDRAWN
Claims 28, 32-33, 42, 61, and 63-64 are canceled, rendering all previously made rejections thereof moot.
35 USC 102(a)(1) rejections over Claims 1-2 as anticipated by Jiang et al. 2016 (PLoS genetics, 12(4), e1005895.; of record) are withdrawn in view of applicant’s amendments requiring additional active steps not taught by Jiang.
35 USC 102(a)(1) rejections over Claims 27, 30, 35, and 38-40 as anticipated by Rudin et al. 2012 (Clinical Cancer Research, 18(11), 3163-3169.; of record) are withdrawn in view of applicant’s amendments further requiring a defined set of biomarkers.
35 USC 102/103 rejections over Claims 27-28, 30-31, and 34-40 as anticipated by and/or obvious over Rudin et al. 2012 (Clinical Cancer Research, 18(11), 3163-3169.; of record) are withdrawn in view of applicant’s amendments specifying a defined subset of biomarkers and rephrasing the claim to require the active steps of determining said biomarkers’ normalized level of expression and determining that said level of expression is not significantly different than a control.
NEW/UPDATED REJECTIONS NECESSITATED BY CLAIM AMENDMENTS
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.
Claims 1-2, 27, 30-31, and 34-41 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claims are to drawn to methods of classifying or treating an SCN or SRBCT cancer comprising biological samples from patients being classified as an SCN or SRBCT cancer as determined by a “normalized level of expression” for biomarkers DCX, LHX2, FAM57B, KCNC1, and CAMK2B. Claims 1-2 are further drawn to “mapping the normalized level of expression...to its corresponding SCN gene signature weight” and “computing a SCN score”.
The disclosure does not directly provide a “normalized level of expression” of any given biomarker, but rather Tables 1-3 of the instant specification disclose a “signature weight” calculated via principal component analysis (PCA). These weights were used to determine a “SCN Score”, which is defined as the “PC1 score after projection onto the Fig 1A varimax PCA framework” (¶00190).
Although the specification provides a threshold for “SCN-like” as a SCN score “greater than 3 standard deviations from the mean in the z-scored analysis”, determining the SCN score relied on all of the measured values rather than a subset comprising DCX, LHX2, FAM57B, KCNC1, and CAMK2B; see ¶00190: “Because of the nature of PCA, this score is determined as a linear combination of weights that includes every coding gene, and hence is not strictly dependent on solely one subset of genes”. Similarly, the specification highlights that “heterogeneity in expression precludes the use of only a small set of markers in the clinical identification of aggressive SCN” (¶00165).
This disclosed shortcoming of relying on a limited number of biomarkers is consistent with previous efforts in the prior art at establishing a diagnostic gene expression profile of a neuroendocrine cancer. For example, Tsai et al. 2017 (BMC cancer, 17, 1-21.; IDS filed 01/18/2024) reports employing statistical methods to analyze 8 published gene lists comprising gene expression in neuroendocrine prostate cancer (NEPC) to determine an expression profile diagnostic of a neuroendocrine phenotype (Pg. 2, § Background). However, Tsai reports that of the 3,567 genes with differential expression, “no genes were common to all lists”, with only 24% of downregulated and 13% of upregulated genes common to multiple lists, and the most frequent appearing on only 5 of the 8 lists – thereby reinforcing a limited expectation of success in making an SCN diagnosis based on a limited number of biomarkers.
The instant specification further discloses that a logistic regression model was trained using the top and bottom genes from this signature to establish a “compact signature predictive of samples with an SCN phenotype” (Pg. 248, Example 2). Two different signatures were derived from the top/bottom 100 or 500 genes comprising 47 and 41 genes, respectively (¶00208; Fig. 17-18), and each predicted the original training data (i.e. previously confirmed SCN cases) with 100% accuracy (¶0053-0054). The five claimed biomarkers DCX, LHX2, FAM57B, KCNC1, and CAMK2B are components of both signatures (Fig 17C, 18C) and correspond to the 5 biomarkers with the highest “signature weight” in the 41-gene signature disclosed in Fig. 18. Notably, however, the specification does not disclose the specifics of the “logistical regression model” used to compute these compact gene signatures, the accuracy of the models decay when fewer genes are in the signature (Fig 18 A-B), and there is no evidence that DCX, LHX2, FAM57B, KCNC1, and CAMK2B alone are predictive of an SCN phenotype.
Indeed, the contribution/coefficient of each biomarker’s “signature weight” varies between the two disclosed “compact signatures” (compare Col. 2 values between Fig 17C and 18C for the same genes). Moreover, the “signature weight” of a particular gene does not appear to strongly correlate with its predictive power in the regression models. For example, the 41 gene model of figure 18C includes the genes LHX2 and ZNF711, which have a signature weight of 0.031425 and 0.017519 (rank 39 and 421), respectively. However, despite the higher signature weight for LHX2, its contribution to the regression model was substantially lower than that of ZNF711 (output coefficient of 0.005529027 vs 0.137096713).
It is therefore not clear how the “signature weight”, much less “normalized level of expression”, correlates with a particular biomarker’s predictive value for either SCN diagnosis or drug sensitivity, nor whether measuring the combined expression of DCX, LHX2, FAM57B, KCNC1, and CAMK2B would be alone sufficient to categorize an SCN cancer. Accordingly, armed only with the information provided by the instant disclosure and expression levels for DCX, LHX2, FAM57B, KCNC1, and CAMK2B, one of ordinary skill in the art would be unable to determine whether any particular tumor was an SCN or SRBCT cancer without an undue amount of experimentation, and there would be a limited expectation of success when relying on only a small number of biomarkers.
Response to Arguments
Applicant's arguments filed 12/09/2025 have been fully considered but they are not persuasive because:
Applicant has amended the claims to require a defined set of biomarkers comprising DCX, LHX2, FAM57B, KCNC1, and CAMK2B and comparison of said biomarkers to a control level of expression determined from an SCN or SRBCT cancer. Applicant argues that because “the claims now recite a core set of genes instead of ‘one-or-more’, the relevant threshold can easily be determined by a person of ordinary skill in the art”.
In response, the above 35 USC 112(a) rejections have been updated to reflect the new scope of the claims. However, the main thrust of rejection remains the same. Namely, the specification does not provide evidence that a direct comparison of expression levels between a subset of 5 biomarkers can be used to determine SCN identity. Instead, the specification highlights “heterogeneity in expression precludes the use of only a small set of markers in the clinical identification of aggressive SCN” (¶00165), and further teaches classification of SCN identity based on a principal component analysis of all measured genes: “Because of the nature of PCA, this score is determined as a linear combination of weights that includes every coding gene, and hence is not strictly dependent on solely one subset of genes” (¶00190).
Although the instant disclosure demonstrates that SCN classification employing a more “compact” gene signature was possible by “training a logistic regression model” (Example 2), the specifics of these algorithms are not disclosed, the “compact” signatures of the disclosure each required contribution from over 40 genes (Fig. 17C, 18C), and no examples of SCN classification based solely on DCX, LHX2, FAM57B, KCNC1, and CAMK2B are provided.
Accordingly, the instant disclosure is does not enable the classification of SCN or SRBCT as claimed.
NEW REJECTIONS
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 1-2 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon and abstract mental steps without significantly more. The rationale for this determination is explained below:
Claims 1-2 are drawn to judicial exceptions comprising both a natural phenomenon and abstract mental steps. The natural phenomenon is the correlation between small cell neuroendocrine (SCN) identity and expression levels of biomarkers CDX, LHX2, FAM57B, KCNC1, and CAMK2B. The abstract mental steps are “mapping”, “computing”, and “classifying” as recited in steps c-e. As explained below, there are no additional elements that amount to significantly more than the judicial exceptions, and the judicial exceptions are not integrated into a practical application.
Regarding Claim 1 steps a-b, “obtaining a biological sample” and “obtaining a normalized level of expression of biomarkers” are data gathering steps necessary to observe the natural phenomenon, and method of measuring expression levels are routine and conventional for one of ordinary skill in the art. For example, Jiang et al. 2016 (PLoS genetics, 12(4), e1005895.; of record) employs RNASeq to measure differential expression levels of potential biomarkers in tumor samples obtained from small-cell lung cancer patients (Abstract). Claim 2 further specifies the patient subpopulation in which the natural phenomenon is observed, but does not introduce any additional active steps.
Because the remaining steps c-e recited in Claim 1 are directed to mental processes, and there are no additional active steps incorporating the observed natural phenomenon into a practical application required by either Claim 1 or 2, the claims do not constitute “significantly more” than the judicial exceptions to which they are drawn.
Conclusion
No claim is 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.
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/BRYAN WILLIAM HECK/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643