DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 16 June 2026 has been entered.
3. Applicant's arguments and amendments to the claims have been fully considered but do not place the application in condition for allowance. All rejections not reiterated herein are hereby withdrawn.
In particular, the claims as amended in the reply of 16 June 2026 recite (in part) “b) quantifying an expression level of a biomarker in the biological sample derived from the subject relative to a reference control, wherein the biomarker consists of LIN28A, or let-7, wherein the reference control is a biological sample derived from a non-diseased subject; c) determining the tumor as responsive to propranolol treatment if the expression level of the biomarker LIN28A is higher in the biological sample derived from the subject compared to the reference control, or d) determining the tumor as responsive to propranolol treatment if the expression level of let-7 is lower in the biological sample derived from the subject compared to the reference control; and e) administering a therapeutically effective amount of propranolol to the subject determined to have the tumor that is responsive to propranolol in c) or d)…”. Thus, the claims are considered to require that the step of determining responsiveness to propranolol (and then administering propranolol to the subject) is based on the expression level of LIN28A alone or let-7 alone.
The closest prior art of Baillie et al (U.S. 2017/0234884; cited in the IDS) is discussed in detail in the Office action of 23 March 2026. In particular, Ballie teaches a method comprising obtaining a biological sample from a subject having cancer, quantifying the expression level of the stem cell biomarker LIN28A in the sample from the subject relative to that of a reference control and administering a therapy to the subject having an elevated level of expression of LIN28A relative to the reference control and having an elevated level of one or more biomarkers associated with the Renin-Angiotensin System (e.g., para [0018], [0025], [0093-0094], [0097], [0099] and [0141-0150]). Ballie teaches that the methods of treatment disclosed therein are applicable to cancers having differential expression of embryonic stem cell biomarkers and that LIN28A is an embryonic stem cell biomarker (para [0093-0094]). Ballie teaches that the therapy includes a therapy that targets the growth and proliferation of cancer cells (para [0097]). Ballie (para [0109]) further states that "therapy that targets the growth and proliferation of cancer stem cell populations comprises administering a therapeutic agent that selectively targets components of the RAS and/or Pro/Renin Receptor Systems (PRRS) expressed by the cancer stem cells." It is stated that such a therapy that targets the growth and proliferation of cancer stem cell populations includes administering a beta-blocker (para [0100], and that propranolol is a preferred type of beta-blocker (para [0113]).
Ballie also states (para [0090]):
"Accordingly, the expression of the components of RAS by these cancer stem
cell populations provides a novel and unique therapeutic approach by targeting the
cancer stem cells associated with various tumours from the extensive array of drugs
that target RAS such as, Angiotensin-Converting Enzyme Inhibitors (ACEis),
Angiotensin Receptor Blockers (ARBs), Direct Renin Inhibitors (DRIs), Beta-Blockers,
Cyclo-oxygenase 2 Inhibitors, Chymase Inhibitors, Inhibitors of Cathepsin B, Cathepsin
D and Cathepsin G, Calcium Supplements, Vitamin D and Calcium Channel Blockers."
Thus, as argued by Applicant in the response of 16 June 2026, Ballie teaches that the selection of a beta-blocker, such as propranolol, to treat cancers expressing the
stem cell biomarker (i.e.,, LIN28A) is based on the co-expression of a stem cell biomarker and a biomarker associated with the Renin-Angiotensin system (RAS) in the cancer stem cells.
Ballie does not teach or suggest the presently claimed method of quantifying the expression level of only the biomarker LIN28A in a sample from a subject having a tumor, determining that the tumor will be responsive to propranolol if the expression level of LIN28A alone is higher in the sample from the subject as compared to a subject without a tumor or a cancer, and administering propranolol to the subject determined to have the tumor that is responsive to propranolol.
New Claim Rejections - 35 USC § 112(a) - New Matter
4. 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, 5, 6, and 10 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 written description requirement. 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 new matter rejection.
The disclosure as originally filed does not provide basis for the amendment to the claims to recite “wherein the tumor is a benign tumor.”
The response points to Example 1 as providing basis for this amendment. However, Example 1 discusses the expression level of LIN28B and let-7, in response to propranolol, in infantile hemangiomas. As stated in the specification (p. 19, lines13-15) “Infantile hemangiomas (IH) are the most common benign vascular neoplasms of infancy.” The specification (p. 19, lines 27-29) also states “This work uncovers the role of the LIN28B/let-7 switch in IH pathogenesis and provides a novel mechanism by which propranolol induces IH involution.” This disclosure relating to a specific benign tumor - i.e., infantile hemangiomas - does not provide basis for the broadly claimed methods of treating a subject having any type of benign tumor. The specification does not refer to benign tumors elsewhere, other than to define infantile hemangiomas as a benign tumor. The specification does not provide any indication that Applicant was in possession of the broadly claimed method of treating any benign tumor with propranolol after determining that any type of benign tumor would be responsive to propranolol treatment based on the detection of an increase in the level of expression of LIN2A or a decrease in the level of expression of let-7, as compared to a control level.
If Applicant maintains that the originally filed disclosure provides basis for the amended claims, Applicant should point to specific teachings (e.g., by paragraph number) in the present application to establish basis for each of the recitations set forth in the claims.
See MPEP 2163 II at “(b) New Claims, Amended Claims, or Claims Asserting Entitlement to the Benefit of an Earlier Priority Date or Filing Date under 35 U.S.C. 119, 120, 365, or 386” which states:
“To comply with the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, or to be entitled to an earlier priority date or filing date under 35 U.S.C. 119, 120, 365, or 386, each claim limitation must be expressly, implicitly, or inherently supported in the originally filed disclosure.”
New Claim Rejections - 35 USC § 103
5. 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 (i.e., changing from AIA to pre-AIA ) 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.
Claim(s) 1, 5, and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chang et al (Pediatric Research. Published online 11 October 2017, 83(11): 175-182; previously cited).
The following rejection applies to the claims to the extent that the claims encompass methods that determine the expression level of let-7 alone in a sample from a subject.
Chang et al discloses that “Propranolol is the first-choice treatment for severe infantile hemangioma (IH). However, 10–30% of lesions relapse after propranolol treatment” (see abstract). Chang teaches methods for identifying biomarkers indicative of responsiveness to propranolol wherein the methods comprise: obtaining a biological sample from a subject; and assaying the biological sample for biomarkers whose expression is altered in samples that are responsive to propranolol as compared to samples that are not responsiveness to propranolol (see abstract and p. 181). Chang reports that let-7 levels in serum are increased in IH patients who developed recurrent IH following propranolol treatment, as compared to patients with non-recurrent IH following propranolol treatment (p. 177, col. 1 and p. 181, col. 1; and Tables 2 and 3). Chang concludes “On the basis of our results pertaining to fold changes in the expression of specific miRNAs, we selected five underexpressed miRNAs (hsamiR-122- 3p, hsa-miR-122-5p, hsa-miR-483-3p, hsa-miR-758-3p, and hsa-miR-494-3p) and one overexpressed miRNA (hsa-let-7c-5p) from the recurrent group as potential biomarkers” (p. 181, col. 1). Thus, Chang teaches that overexpression of let-7 prior to treatment was correlated with a lack of response to propranolol treatment, whereas lower expression levels of let-7, prior to treatment, were correlated with a positive response to propranolol treatment – i.e., IH did not recur in those patients having lower serum levels of let-7 prior to treatment.
Chang does not teach as a single embodiment a method that includes the steps of determining that the subject’s IH (i.e., benign tumor) will be responsive to propranolol based on the detection of a lower level of expression of let-7, as compared to a control level, and then administering propranolol to those subjects determined to be responsive to propranolol.
However, as discussed above, the teachings of Chang indicate that a lower level of expression of let-7 is correlated with a positive responsive (i.e., lack of recurrence of IH) to propranolol treatment, as compared to the level of let-7 in non-responsive/recurrent IH. Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Chang so as to have included the steps of determining that the subject’s IH (i.e., benign tumor) will be responsive to propranolol based on the detection of a lower level of expression of let-7, as compared to a control level, and then administering propranolol to those subjects determined to be responsive to propranolol. One would have been motivated to have done so because Chang teaches that subjects having IH and having lower levels of let-7, as compared to a control, are more responsive to IH. Thereby such a modification of the method of Chang would have provided the benefit of identifying those subjects with IH who will be most responsive to propranolol treatment and then effectively treating those subjects by administering propranolol.
Regarding claim 5, Chang teaches that the biological sample is a serum sample (e.g., p. 177, col. 1 “Differential miRNA Expression in Recurrent Cases”), and thereby a type of blood sample.
Regarding claim 10, Chang teaches that the subject is a human subject (e.g., p. 175, col. 2 “Patients and Therapy”).
6. Claim(s) 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chang et al (Pediatric Research. Published online 11 October 2017, 83(11): 175-182; previously cited) in view of Applied Biosystems (“TaqMan Advanced miRNA Assays—superior performance for miRNA detection and quantification,” available via url: < documents.thermofisher.com/TFS-Assets/GSD/Technical-Notes/TaqMan-Advanced-miRNA-Performance-White-Paper.pdf>, 2016, p. 1-6).
The teachings of Chang are presented above.
Regarding claim 6, Chang teaches that the expression level of let-7 was detected using next-generation sequencing (e.g., p. 176, col. 1 “Differential miRNA Expression in Recurrent Cases” and p. 177 “Differential miRNA Expression in Recurrent Cases”). Chang does not teach detecting the expression level of let-7 by performing a PCR assay.
However, Applied Biosystems teaches a TaqMan quantitative RT-PCR assay for detecting miRNAs (p. 1, col. 2; and Figure 1), and particularly let-7 (p. 3, col. 1 and Table 1). It is stated that the assay “improves the sensitivity of the assay significantly, without affecting sequence specificity” (p. 1, col. 2). The reference (p. 3, col. 1) states:
“In particular, we examined specificity by measuring cross-reactivity between the highly conserved let-7 miRNA family, limit of detection by performing serial dilution experiments, and accuracy by measuring small differences of miRNA concentrations in serum.”
In view of the teachings of Applied Biosystems, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Chang so as to have detected let-7 expression levels using the TaqMan quantitative RT-PCR assay of Applied Biosystems. One would have been motivated to have done so for the advantages set forth by Applied Biosystems that this assay can detect and distinguish between all members of the let-7 miRNA family and provides a highly sensitive and specific means for detecting let-7 miRNAs.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARLA J MYERS whose telephone number is (571)272-0747. The examiner can normally be reached M-Th 6:30-5:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached on 571-272-0731. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682
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