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 .
Applicant’s Amendment/Request for Reconsideration-After Non-Final Rejection, filed 9/4/2025, has been entered and fully considered.
Status of Claims
Claims 7-9 are pending and are examined on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Priority of EUROPEAN PATENT OFFICE (EPO) application 17194288.1 filed 10/02/2017 is acknowledged.
Withdrawn Rejections/Objections
The claim rejections under 35 U.S.C. §103 to claim 10 in the Office action mailed 5 June 2025 are withdrawn in view of the claim amendments filed 4 September 2025.
Claim Rejections - 35 USC § 103
This rejection was withdrawn on the Office Action filed 6/5/2025. Upon further consideration, a 35 USC 103 rejection is re-installed in this Office Action, with a new combination of prior-art, and modifications.
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 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.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 7 is rejected under 35 U.S.C. 103 as being unpatentable over
Bergstrom: (“Methods for predicting treatment response based on the expression profiles of biomarker genes in notch mediated cancers”, US 20110166028 A1,
2011-07-07. Previously cited), in view of Rodilla et al. ("Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer." Proceedings of the National Academy of Sciences 106.15 (2009): 6315-6320. Newly cited) and Rustighi ("The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer." Nature cell biology 11.2 (2009): 133-142. Previously cited).
Claim 7 is directed to a method of treating a subject suffering from a disease associated with an activated Notch cellular signaling pathway. With respect to claim 7, Bergstrom discloses a method to prognose cancer treatment with the NOTCH Signaling Inhibitors, which reads on the subject matter of the current invention. More specifically, Regarding claim 7 step a and step a.i.1, Bergstrom teaches receiving expression level data for the following Notch pathway target genes: HES1, HES5, HEY2, DTX1, MYC, NRARP ([0039]; claim 74 and Fig 4a, 4b). Bergstrom’s teaching qualifies as “at least five target genes are selected from DTX1, EPHB3, HES1, HES4, HES5, HEY2, MYC, NFKB2, NRARP, PIN1, PLXND1 and SOX9”. Bergstrom’s teaching also qualifies as “at least two of the target genes are selected from DTX1, HES1, HES4, HES5, HEY2, MYC and NRARP.” Bergstrom also divides the Notch target genes into three overlapping groups (claim 102). Bergstrom does not teach any gene from the list of EPHB3, NFKB2, PIN1, PLXND1, and SOX9. In other investigations on the Notch signaling pathway in cancer, Rodilla provides “we have identified several genes downstream of TCF/ß-catenin pathway that are directly regulated by the Jagged1/Notch pathway including hes1, CD44, KLF5, NOX1, EpHB3, and SOX9” (page 6315, col 2, last para), which teaches that EpHB3, and SOX9 are Notch target genes (in addition to also identifying the HES1 gene, as in Bergstrom). Rustighi teaches that PIN1 is a Notch target (pg. 133, Title and Abstract). Rodilla and Rustighi satisfies the claim limitation “at least three of the target genes are selected from EPHB3, NFKB2, PIN1, PLXND1, and SOX9”
Regarding claim 7 step a.i and step a.i.2, Bergstrom further disclose calculating the Notch pathway activity with a calibration (NOTCH-10, [0216]). Particularly, Bergstrom provides (emphasis added):
“We used transcriptional profiling to determine if a gene signature could be identified that predicts sensitivity to GSI in T-ALL. The 16 T-ALL cell lines described in Table 1 were profiled and ten NOTCH target genes (HES-1, HES-4, HES-5, HEY-L, HEY-2, DTX1, C-MYC, NRARP, PTCRA, SHQ1) were used to assess NOTCH pathway activity (FIG. 1A). A composite expression score for NOTCH pathway activity was determined by calculating the average expression value of the ten NOTCH target genes (NOTCH-10) for each sensitivity group and comparing this to the overall average expression of these 10 genes across all 16 T-ALL cell lines. Indeed, the basal Notch pathway activity as measured with the NOTCH-10 signature correlates with sensitivity to GSI (FIG. 1A) Change in expression of the Notch-10 gene set in response to GSI treatment was also assessed We found that T-ALL cell lines with high sensitivity to GSI displayed a higher fold change in NOTCH target genes upon GSI treatment (FIG. 1B). Thus, we have identified a NOTCH gene signature that accurately predicts T-ALL cell lines with GSI sensitivity. In addition, we demonstrate that decrease in expression of this gene signature correlates and reports on the cytotoxic effects of the drug.” [0216]
Bergstrom’s 16 cell-line averaged target gene expression suggests the claim limitation “expression levels of the at least five target genes in the calibrated pathway model which define an activity level of Notch transcription factor element”. Bergstrom teaches a composite expression score for NOTCH pathway activity was determined by calculating the average expression value of the ten NOTCH target genes (NOTCH-10) for each sensitivity group and comparing this to the calibrated pathway model (overall average expression of these 10 genes across all 16 T-ALL cell lines).
Step (a.ii) is rejected similarly as discussed above regarding step (a.i), as step (a.ii) is a part of step (a.i).
Bergstrom teaches that gene expression patterns correlate with a Notch inhibitor treatment outcomes for cancers with aberrant Notch signaling pathway expression [4, 29, 34, 39].
Step (a.iii) is obvious over step (a.i-ii). Once the Notch activity level is calculated, whether the signaling pathway is abnormal can be determined.
Bergstrom further teaches (Step (b)) treating patients with Notch inhibitors (claims 80-81), based on Notch signaling levels.
An invention would have been obvious to one of ordinary skill in the art if some motivation would have led that person to substitute a few Notch target genes in the prior art teachings to arrive at the claimed invention. Prior to the first day of filing of the current invention, said person would have been motivated to substitute the genes in Bergstrom’s teaching of measuring the NOTCH signaling activity level, with the additional NOTCH target genes taught by Rodilla and Rustighi.
Because Bergstrom’s Notch target genes are T-cell acute lymphoblastic leukemia (T-ALL) -based ([011, 216]), which means these target genes are expected to be turned on in the T-cells by the Notch (this doesn’t mean Bergstrom’s genes are not turned on in other cancerous tissues). To develop a robust method/product appliable to a wide cancer research, substituting a few Notch target genes with Rodilla’s SOX9 and EPHB3, which is known to be expressed in the colorectal cancer (Rodilla: page 6315, Title and Abstract), plus Rustighi’s PIN1, which is known to be expressed in breast cancer (Rustighi: page 133, Title and Abstract), will enhance the NOTCH signaling activity level measuring method/kit when applied to a wider cancer research.
A person with ordinary skill in art could reasonably have expected success as this is a classic example of:
“Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art” (MPEP §2141.III.(F)).
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over
Bergstrom, Rodilla and Rustighi, as applied to claim 7 above, and further in view of Espinoza: (“Notch inhibitors for cancer treatment”, Pharmacology & Therapeutics, Volume 139, Issue 2, August 2013, Pages 95-110. Previously cited).
With respect to claims 8-9, Bergstrom teaches treating patient with Notch inhibitors (claims 80-81), based on Notch signaling levels. However, Bergstrom does not teach administering the Notch inhibitors to human patients. To review the clinical activities that treat cancer with Notch inhibitors, Espinoza teaches treating cancer in humans with elevated Notch activity with the Notch inhibitors such as PF-03084014, MK-0752, RO-4929097 (pg. 102-103, Table 1).
An invention would have been obvious to one of ordinary skill in the art if some motivation would have led that person to modify prior art teachings to arrive at the claimed invention. Prior to the time of invention, said person would have been motivated to modify the combined Bergstrom, Rodilla and Rustighi on NOTCH signaling and inhibition/activation, with Espinoza’s teaching of several specific NOTCH inhibitor, because Espinoza systematically reviewed the successful NOTCH inhibitors that made the way to clinical trials till the time of the instant invention was filed. We can reasonably expect the success as combined Bergstrom, Rodilla, Rustighi, and Espinoza are all about measuring Notch pathway activities and treat the disease with corresponding inhibitors/activators.
Reasons to Re-Install the rejection under 35 USC 103
In the Appeal Brief filed 12/05/2024, Applicant argued (page 16, paras 2-3) that “the claims do not recite a list of genes; rather, the claims recite a very specific combination of genes, namely:
1. Two (or more) genes selected from DTX1, HES1, HES4, HESS, HEY2, MYC, and NRARP; and
2. Three (or more) genes selected from EPHB3, NFKB2, PIN], PLXND1, and SOX9.
To render the claimed invention obvious, according to the MPEP, the prior art must suggest the recited specific combination of genes, specifically two (or more) genes selected from DTX1, HES1, HES4, HESS, HEY2, MYC, and NRARP, and three (or more) genes selected from EPHB3, NFKB2, PINI, PLXND1, and SOX9. Thus, rather than simply reciting all the genes in this list, the prior art must suggest or render obvious this specific combination of target genes.” (page 16, paras 2-3)
To response, this argument is not persuasive. Bergstrom teaches receiving expression level data for the following Notch pathway target genes: HES1, HES5, HEY2, DTX1, MYC, NRARP ([0039]; claim 74 and Fig 4a, 4b). Bergstrom’s teaching qualifies “at least five target genes are selected from DTX1, EPHB3, HES1, HES4, HES5, HEY2, MYC, NFKB2, NRARP, PIN1, PLXND1 and SOX9”. Bergstrom’s teaching also qualifies as “at least two of the target genes are selected from DTX1, HES1, HES4, HES5, HEY2, MYC and NRARP.”
Bergstrom also divides the Notch target genes into three overlapping groups (claim 102).
The only thing that Bergstrom is missing is the third gene list of EPHB3, NFKB2, PIN1, PLXND1, and SOX9.
Rodilla and Rustighi add to Bergstrom in this regard. In other investigations on the Notch signaling pathway in cancer, Rodilla provides “we have identified several genes downstream of TCF/ß-catenin pathway that are directly regulated by the Jagged1/Notch pathway including hes1, CD44, KLF5, NOX1, EpHB3, and SOX9” (page 6315, col 2, last para), which teaches that EpHB3, and SOX9 are Notch target genes (in addition to the above identified HES1 gene). Rustighi teaches that PIN1 is a Notch target (pg. 133, Title and Abstract).
Hence, Rodilla and Rustighi satisfies the claim limitation “at least three of the target genes are selected from EPHB3, NFKB2, PIN1, PLXND1, and SOX9” in the third listed gene group.
Upon further consideration, Bergstrom does teach the pathway calibration model. Van Ooijen (previously cited for pathway calibration model) is no longer required in this rejection.
For the above reasons, the 103 rejections are re-installed with modifications.
Conclusion
No claims are allowed.
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/GL/
Patent Examiner
Art Unit 1672
/Anna Skibinsky/
Primary Examiner, AU 1635