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 . 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.
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 29 Sept, 2025 has been entered.
Election/Restrictions
Applicant’s election of the MCL1-BIM interaction using an antibody based measurement for efficacy of an MCL1 inhibitor in a cancer patient without traverse in the reply filed on 28 March, 2022 and the phone call on 21 April, 2022 with Stephen Alteri, applicant’s representative.
Claims Status
Claims 1, 3, 5, 6, 8, and 12-20 are pending.
Claims 1, 3, 5, and 6 have been amended.
Claims 3, 6, 8, 12-14, 16, 18, and 20 have been withdrawn from consideration due to an election/restriction requirement.
Withdrawn Rejections
The rejection of claims 1, 3, 5, 7, 9-10, 15, 17, 19, and 21 under 35 U.S.C. 103 as being unpatentable over Cardone (US 20160178634, cited by applicants) in view of Li et al (Oncotargets and therapy (May 2019) 12 p3295-3304, previously cited) and Fish (Curr. Protoc. Cytom. (2009) 0 12: unit 12:18) is hereby withdrawn due to amendment.
New Rejections
Claim Rejections - 35 USC § 112(b)
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.
first rejection
Claim 5 is 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 5 depends from claim 2, which has been canceled. This makes it unclear what limitations the rejected claim has from the canceled claim.
second rejection
Claim 19 is 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 19 depends from claim 11, which has been canceled. This makes it unclear what limitations the rejected claim has from the canceled claim.
Claim Rejections - 35 USC § 103
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.
Claims 1, 5, 7, 9-10, 15, 17, 19, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Cardone (US 20160178634, cited by applicants) in view of Li et al (Oncotargets and therapy (May 2019) 12 p3295-3304, previously cited), Chen et al (Blood (2018) 132 (Suppl 1):951) and the Conduct Science page on total internal reflection fluorescence microscopy (April, 2019).
Cardone discusses using antibodies to detect the presence of heterodimers of BCL-2 proteins to predict sensitivity to treatment (abstract). Note that this reads on applicant’s elected detection method of antibody detection. This method comprising a tissue sample, contacting the sample with an antibody that detects heterodimers, and detecting a signal indicative binding (paragraph 10). This sample can be a tissue sample (reading on cells) (paragraph 10). Among the interactions discussed, that could be measured is MCL1/BIM (paragraph 10), applicant’s elected protein interaction pair. Note that the antibody detects heterodimers, not the individual BCL-2 proteins in the heterodimer (paragraph 73) – this reads on step (b)ii of claim 1. The result of the antibody test can be used to determine the likelihood of response to therapy (paragraph 95) which is interpreted as decision making based on cutoff values. The drug can be an inhibitor of MCL1 (paragraph 115), applicant’s elected drug species. Prognosis is based on the presence or absence, correlated to responder/non-responder status (paragraph 82), relevant to part (c) of claim 1. Among the disorders discussed is acute myeloid leukemia (AML) (paragraph 103). An example is given where multiple heterodimers are examined (paragraph 165).
The difference between this reference and the claims is that this reference does not discuss measuring the levels of one or more BCL-2 family proteins in the context of drug efficacy, does not discuss measuring interactions with MCL1 and an exogenous protein, nor does it discuss total internal reflectance microscopy.
Li et al look at the prognosis of AML related to MCL1 expression (title) tied to use of an MCL1 protein inhibitor (p3296, 1st column, 1st paragraph). Patients with high expression levels had a worse response to chemotherapy, with a large difference in MCL1 levels between patients that went into remission and those that did not (fig 3, p3299, 1st column, middle of page). Relapse was also higher in patients with higher expression levels of MCL1 (fig 6, p3301, 1st column, top of page). The expression levels of MCL1 is discussed as a predictor of treatment outcome (paragraph 3302, 1st column, 1st paragraph). Other references discussing similar findings in other cancers is discussed (p3301, 2nd column, 1st paragraph). This reference teaches a negative relationship between MCL1 expression levels and therapeutic response (interpreted as drug efficacy).
Chen et al discusses MCL1 point mutations and how they affect function (title). Binding of MCL1 and BIM, measured by immunoprecipitation in the presence of an anti MCL1 drug (i.e. BIM is exogenous) correlated to sensitivity to an anti MCL1 drug (2nd page, 3d paragraph). This reference shows that the ability of the drug to displace BIM from MCL1 correlates to drug efficacy, i.e. step b(i) of the claims, although using a different detection method.
The conduct science page on total internal reflection fluorescence microscopy (TIRF) can be used to measure protein-protein interactions (2nd page, 3d paragraph). This is based on the evanescent field created by total internal reflection of light in a cover slip (2nd page, 6th and 7th paragraphs). An example is given where fluorescent antibodies were used to view cytoskeletal elements (6th page, 2nd paragraph). This reference discusses using TIRF to measure protein binding.
Therefore, it would be obvious to add the absolute MCL1 levels of Li et al to the heterodimer levels of Cardone, to provide more information as to therapy response. As both references discuss cancer response to therapy, an artisan in this field would attempt this therapy with a reasonable expectation of success.
Furthermore, it would be obvious to include testing the binding of MCL1 from the patient with exogenous BIM, in the presence of the drug, as a further test of the patient’s sensitivity to the drug, as described by Chen et al. As that reference shows that an inability of the drug to displace BIM binding indicates a lack of sensitivity to the drug, a result consistent with the mechanism of action of the drug, an artisan in this field would attempt this test with a reasonable expectation of success.
Finally, it would be obvious to use TIRF to measure the binding of MCL1 to BIM, as a substitution of one known element (the precipitation of Chen et al) for another (the TIRF of the conduct science webpage) yielding expected results (measurement of binding of MCL1 to BIM). As both methods are used to determine protein-protein binding, an artisan in this field would attempt this process with a reasonable expectation of success.
Cardone et al discusses preparing a sample from a subject, subjecting it step b (ii), with the cells bound to a cover slip (protein attached to a substrate), and looks at multiple BCL related proteins (wherein a complex formed by the interaction in b(i) is different from a complex formed by the interaction in b(ii)). Li et al renders obvious measuring the absolute expression level of the BCL protein, step b(iii). Chen et al renders obvious examining binding of MCL1 from the patient with exogenous BIM in the presence of the drug. The conduct science web page renders obvious using TIRF to measure the interaction with a fluorescent probe – note the combination of Chen et al and the conduct science web page together disclose step b(i). Chen et al discusses comparison with reference values, presumably from experimentation with responsive and non-responsive patients, to determine if the patient is responsive. Thus, the combination of references renders obvious every step of claim 1 with MCL1 and BIM, anticipating the claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658