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 .
2. This action is in response to the amendment filed on 25 February 2026. 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 All rejections not reiterated herein are hereby withdrawn.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 declaration under 37 CFR 1.130(a) filed 25 February 2026 is sufficient to overcome the rejection of claims 1, 5, 6 and 10 under 35 U.S.C. 103 as unpatentable over Mong et al. (Arterioscler Thromb Vasc Biol. June 2018. 38: 1321-1332; cited in the IDS) in view of Weingart et al (Oncotarget. 2014. 6(5): 3165-3177) and the rejection of claims 1, 5, 6 and 10 under 35 U.S.C. 103 as unpatentable over Mong et al (USF Health. Feb 2018 poster; “LIN28B/let-7 correlates with infantile hemangioma stages and response to propranolol”; cited in the IDS), in view of Weingart et al (Oncotarget. 2014. 6(5): 3165-3177).
Claim Status
3. Claims 1, 5, 6, and 10 are pending and have been examined herein.
Priority
4. The present claims are entitled to the current filing date of 07 November 2018. Note that a claim as a whole is assigned an effective filing date rather than the subject matter within a claim being assigned individual effective filing dates. U.S. provisional application 62/582,506 does not provide support for the presently claimed methods for treating a human subject or a non-human subject with propranolol having any type of brain cancer or having breast or cervical cancer, the methods comprising detecting the expression level of LIN28A and/or Let-7 in a sample from a subject and identifying a tumor as responsive to propranolol treatment when the expression of LIN28A is higher in the sample as compared to the reference control, or when the expression of let-7 is lower in the sample as compared to a reference control, and further administering a therapeutically effective amount of propranolol to the subject having the tumor that is identified as being responsive to propranolol. The ‘506 application provides examples in which the expression level of LIN28A was shown to be increased in skin tissue samples from infantile hemangiomas (IH) and let-7a and let-7c was decreased in skin tissue samples from subjects with IH discloses that propranolol treatment reduced expression of LIN28A and increased let-7a and let-7c expression. However, the teachings in ‘506 are limited to human subjects having IH. This disclosure does not provide basis for the broadly claimed methods of treating any brain cancer, or breast cancer or cervical cancer in a human or non-human subject. Further the ‘506 application does not provide support for each of the recited methods for quantifying the level of expression in claims 6 (i.e., methods other than qRT-PCR).
If Applicant asserts that the present claims are entitled to priority to the provisional applications, Applicant should point to specific teachings (e.g., by page and line number) in the priority applications to establish priority for each of the recitations set forth in the claims.
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 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.
Claims 1, 5, 6, and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Baillie et al (U.S. 2017/0234884; cited in the IDS).
The following rejection applies to the claims to the extent that the claims encompass methods that determine the expression level of LIN28A alone in a sample from a subject.
Baillie teaches a method comprising obtaining a biological sample derived 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 (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 LIN-28A is an embryonic stem cell biomarker (para [0093-0094]).
Ballie states that:
[0107] The present invention provides methods for preventing, treating, and/or managing cancer, the method comprising administering to a subject in need thereof a course of therapy that stabilises, reduces, or eradicate the cancer stem cell population. In certain examples, the stabilisation, reduction, or elimination of the cancer stem cell population is achieved by administering a therapy that targets the growth and proliferation of the cancer stem cells.
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 further 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 teaches that discrete cancer stem cell populations are present in brain cancers and that the methods disclosed therein are applicable to the treatment of brain cancer (e.g., para [0016], [0089] and [0105]).
Accordingly, Ballie teaches a method of treating a subject having a tumor that is brain cancer comprising obtaining a biological sample derived from the subject having brain cancer; and quantifying the level of the biomarker of LIN28A relative to a reference control, wherein it is an inherent property of the biomarker LIN28A that it necessarily is associated with responsiveness of the tumor to propranolol treatment.
Ballie does not expressly teach that the method further comprises a step of determining that the brain cancer will be responsive to propranolol treatment based on the detection of an increase in the level of LIN28A, as compared to a control level, and then administering propranolol to those subjects determined to be responsive to propranolol.
However, again, Ballie does teach the association between elevated expression levels of stem cell biomarkers, including LIN28A, as indicative of cancer stem cell populations and responsiveness to therapeutic agents that target growth and proliferation of cancer stem cell populations, and particularly agents that target RAS, including the beta blocker of propranolol (para [0090], [0094], [0097], [0109], [0113] and [0141- 0150)).
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 Ballie so as to have included a step of determining that the subject having brain cancer will be responsive to propranolol, a therapeutic agent that selectively targets cancer stem cell populations, based on the detection of an increase in the level of LIN28A as compared to a control level, and then to have administered propranolol to those subjects determined to be responsive to propranolol in order to have provided an effective therapy for subjects having brain cancer and having an elevated LIN28A expression level.
Regarding claim 5, Ballie teaches that the sample is a tissue sample or blood sample (e.g., para [0075], [0080] and [0183]).
Regarding claim 6, Ballie teaches that detection of LIN28B expression levels any be accomplished by performing quantitative reverse-transcription PCR (e.g., para [0229].
Regarding claim 10, Ballie teaches that the subject is a human subject (e.g., para [0082]).Response to Remarks:
The response argues:
“Baillie discloses embryonic stem cell biomarkers, such as the core transcription factors OCT4, SOX2, PSTAT3, and NANOG (see Baillie, claim 4), and also requires the expression of one or more biomarkers associated with the Renin-Angiotensin System (see Baillie, claim 1)….Baillie doesn't define the specific reason for detecting LIN28A as a biomarker and fails to disclose using propranolol based on LIN28A.”
These arguments have been fully considered but are not persuasive. The fact that Ballie teaches determining the expression level of a stem cell biomarker (i.e., LIN-28A) together with a biomarker associated with a renin-angiotensin system does not render the claimed method unobvious since the present claims also encompass methods wherein additional biomarkers can be detected and can be considered when determining if a patient should be treated with propranolol. As set forth in the rejection, Ballie teaches methods comprising detecting the level of LIN-28A as indicative of the need to treat the patient with an agent for treating cancer, wherein the agent targets growth and proliferation of cancer stem cell populations, and particularly wherein the agent targets the RAS and is the beta blocker of propranolol. For instance, Ballie (para [0018]) teaches:
In another aspect of the present invention there is provided a method for preventing, treating, or managing cancer in a patient in need thereof, the method comprising administering a therapeutic agent to the patient in an amount sufficient to selectively eradicate, or inhibit the growth, proliferation and/or differentiation of cancer stem cells within the cancer, wherein the cancer stem cells are characterised by (i) the expression of one or more stem cell biomarker selected from the group consisting of… LIN-28A…”.
Ballie further states:
[0109] Accordingly, 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. FIGS. 1 and 2 show the types of inhibitors/drugs that target these systems, useful in accordance with the compositions and methods according to the present invention.
[0110] Examples of known therapeutics that target the Renin-Angiotensin System include, but are not limited to, ACEIs, ARBs, DRIs, Beta-Blockers
[0113] Examples of Beta-Blockers include, but are not limited to, …Propranolol (Inderal LA).”
Thus, the teachings of Ballie suggest methods that quantify the expression level of biomarkers in a biological sample derived from the subject relative to a reference control, wherein the biomarker comprises LIN28A, determining that the subject having brain cancer will be responsive to propranolol, a therapeutic agent that selectively targets cancer stem cell populations, based on the detection of an increase in the level of LIN28A as compared to a control level, and then administering propranolol to those subjects determined to be responsive to propranolol.
The response argues “Baillie doesn't teach the outcomes or experimentation of the currently claimed invention.
However, there is no requirement for Ballie to teach the same experiments set forth in the present application. The present claims are not directed to methods that include each of the steps of the experiments recited in the specification.
The response argues that:
“Ballie does not expressly teach that the method further comprises a step of determining or identifying that the tumor will be responsive to propranolol treatment based on the detection of an increase in the level of LIN28A, as compared to a control level, and then administering propranolol to those subjects determined to be responsive to propranolol.”
These arguments have been fully considered but are not persuasive. It is noted that the rejection was applied under 35 U.S.C. 103, and not under 35 U.S.C. 102. As set forth in the rejection, Ballie does teach that elevated expression levels of stem cell biomarkers, including LIN28A, are indicative of cancer stem cell populations and teaches that cancer stem cell populations are responsiveness to therapeutic agents that target growth and proliferation of cancer stem cells, and particularly agents that target RAS, including the beta blocker of propranolol (para [0090], [0094], [0097], [0109], [0113] and [0141- 0150)). It is maintained that 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 Ballie so as to have included a step of determining that the subject having brain cancer will be responsive to propranolol, a therapeutic agent that selectively targets cancer stem cell populations, based on the detection of an increase in the level of LIN28A as compared to a control level, and then to have administered propranolol to those subjects determined to be responsive to propranolol in order to have provided an effective therapy for subjects having brain cancer and having an elevated LIN28A expression level.
The response argues that Baillie requires a combination of multiple biomarkers and “fails to provide any direction as to which of these many possible combinations would likely be successful in treating a subject having cancer.”
These arguments have been fully considered but are not persuasive. The method of Baillie does not require selecting which combination of biomarkers works since Baillie teaches that all of the possible combinations listed therein will work - i.e., that a subject expressing any of the listed stem cell biomarkers (which list includes LIN-28A) can be effectively treated with any of the listed agents that target the growth and proliferation of cancer stem cells (which list of agents includes propranolol).
The response argues that “the claims as amended only consist of the LIN28A and/or let-7 biomarker as required for ‘determining the tumor as responsive to propranolol treatment.”
However, the claims have not in fact been amended to recite that the biomarker consists of LIN28A and/or let-7 Note that the present claims recite “quantifying the expression level of biomarkers…, wherein the biomarker comprises LIN28A, or let-7.” In view of the open claim language of “comprises” the claims include detecting the expression level of additional biomarkers. The claims do not exclude detecting expression level of other biomarkers in addition to LIN28A (or let-7) and considering the expression level of the other biomarkers when (mentally) determining if a patient will be responsive to propranolol treatment.
The rejection is maintained for the reasons of record.
Conclusion
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.
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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/CARLA J MYERS/Primary Examiner, Art Unit 1682