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.
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 5 and 19 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Claims 3, 6, 8, 12-14, 16, 18, and 20 have been withdrawn from consideration due to an election/restriction requirement.
Withdrawn Rejections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 claim 5 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite due to dependency on a canceled claim is hereby withdrawn due to amendment.
The rejection of claim 19 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite due to dependency on a canceled claim is hereby withdrawn due to amendment.
Maintained/Modified Rejections
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, 15, 17, and 19 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.
response to applicant’s arguments
Applicants argue that the BIM of Chen et al is not exogenous, but rather from the sample, that Chen et al does not use a sample isolated from a subject, that it is not a simple substitution to replace the test of Chen et al with a TIRF assay, that Li et al does not measure MCL-1 expression, mut rather, mRNA expression, and that Li et al is concerned about relapse, rather than efficacy.
Applicant's arguments filed 10 Aug, 2026 have been fully considered but they are not persuasive.
Applicants argue that Chen et al uses BIM from the sample. While the reference is curt in description of the experiment, applicant’s interpretation is not consistent with the language used in the reference. The “co” in co-immunoprecipitation requires two compounds added, in this case, MCL1 and BIM – note that the drug is described separately. Furthermore, applicant’s interpretation of the reference is a displacement, not a precipitation –this difference in language would lead a person of sill in the art away from applicant’s interpretation. Applicant’s support for their argument is that the authors also looked at other proteins binding to MCL1, but that is easily explained as repeating the experiment with a different co partner.
Applicants argue that switching the test of Chen et al for TIRF is not a simple substitution, because that reference is measuring displacement rather than binding. This is merely a matter of semantics; a difference in the order of binding, which is easily measurable by TIRF.
Applicants argue that Li et al does not measure levels of MCL1, but rather MCL1 mRNA. However, this is a common, well known, and frequently used proxy. Buccitelli et al (Nat. Rev. (2020) 21 p630-644) states that mRNA levels generally scale with protein levels (p641, 2nd column, 2nd paragraph); this is obvious from how Li et al uses their data. If mRNA had no relationship with protein levels, then the measurement of Li et al would make no sense, because the drug used by Li et al does not bind to mRNA. In other words, while Li et al do not measure absolute protein levels, the mRNA measurements give relative protein levels, which meets the claim limitations.
Applicants argue that Li et al is looking at disease resistance vs. efficacy. However, these are different sides of the same coin; if the cancer is resistant, the drug will be ineffective.
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 FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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