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 .
Election/Restrictions
Applicant’s election without traverse of Group I (i.e., claims 1-12 and 17) in the reply filed on 6/12/2026 is acknowledged. The traversal is on the ground(s) that Group I and Group II
are not independent or distinct as claimed; and there is no serious search burden on the Examiner. This is not found persuasive because the claims of group I and group II are distinct inventions and they lack unity of invention and the technical feature. The applicant’s arguments are incorrect and generic as these are not the criteria for unity of invention.
In addition to the rationale outlined in the restriction requirement, the examiner notes that group I is clearly directed towards a compound of general formula (I). Group II, on the other hand, is directed towards a method for a method for treating a disease in a mammal. Although the groups may share some common features, the examiner maintains that the inventions lack unity. The groups of inventions listed above do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons: Even though the inventions of these groups require the technical feature of B-L-K (I), this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Zhang, Xuan et al. ("Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity." European journal of medicinal chemistry vol. 192 (2020): 112186, Published 15 April 2020). Zhang teaches that DT2216 is a VHL-based PROTAC derived from ABT-263, and is more potent to a variety of BCL-XL dependent cancer cells with significantly less platelet toxicity than parent compound ABT-263 thereof (see figure 1; page 2, right column, main text,
paragraph 2). The requirement is still deemed proper and is therefore made FINAL.
Applicants amended of claims 1, 7, 12 and 16 is acknowledged. Applicant’s cancellation of claims 13-15 is acknowledged.
There are new claims 17-19.
Furthermore, applicant’s election of the following species “in current claim 11 and Table P-1 and example 6” for Group I
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is acknowledged.
Since, the applicant elected group I (i.e., claims 1-12 and 17), therefore, based on that election, claims 16, 18 and 19 are withdrawn as being drawn to a non-elected group.
Claims 1-12 and 17 are under consideration in this office action and will be examined on the merits.
Status of Claims
Claims 1-12 and 16-19 are pending. The preliminary amendment was filed on 03/01/2024, wherein the applicant amended claims 1, 7, 12, 17, and canceled claims 13-15. There are new claims added 17-19.
Claims 1-12 and 17 are under consideration in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/01/2024 and 10/27/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al. (“Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity” European Journal of Medicinal Chemistry 192 (2020) 112186) herein referred to as Zhang.
Regarding claims 1-11, Zhang teaches PROTAC BCL-XL degraders and potent BCL-2/BCL-XL dual inhibitor similar to the compounds of Formula I.
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536
814
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656
862
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Zhang teaches chemical structures of representative BCl-2/BCL-XL inhibitors and BCL-2 family protein degraders as depicted on page: 2 (Fig. 1) and below:
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wherein;
q1 in the instant general formula I (Ia)
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222
484
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is 1;
Z is
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90
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;
B3 in the instant formula I
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112
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is
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98
42
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;
wherein;
Rw1 is methyl; and
Rw2 is methyl.
The scope of Zhang’s compounds overlaps with Formula I of the instant claims.
Based on the foregoing reasons, the instant claims are deemed anticipated over the cited art.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Applicant Claims
2. Determining the scope and contents of the prior art.
3. Ascertaining the differences between the prior art and the claims at issue, and 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 12 and 17 are rejected under 35 U.S.C. 103(a) as being unpatentable over Zhang et al. (“Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity” European Journal of Medicinal Chemistry 192 (2020) 112186) herein referred to as Zhang in view of Park et al. ("The Goldilocks Window of Personalized Chemotherapy: Getting the Immune Response Just Right" Cancer Res;79(20) October15, 2019) herein referred to as Park.
Regarding claims 12 and 17, Zhang teaches PROTAC BCL-XL degraders and potent BCL-2/BCL-XL dual inhibitor similar to the compounds of Formula I. However, Zhang does not specifically teach the pharmaceutical composition comprises 1-1500 mg of the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof.
Park et al. teaches a mathematical modeling framework of tumor-immune dynamics. Their results suggest that optimal chemotherapy scheduling must balance two opposing objectives: maximizing tumor reduction while preserving patient immune function. Successful treatment requires therapy to operate in a "Goldilocks Window" where patient immune health is not overly compromised. By keeping therapy "just right," they show that the synergistic effects of immune activation and chemotherapy can maximize tumor reduction and control (see abstract). Furthermore, Park demonstrates that optimal chemotherapy requires identification of a Goldilocks Window in which treatment can both induce cytotoxic effects in the tumor and enhance the immune response to tumor antigens. Identifying optimal strategies for chemotherapy in each patient will likely benefit from the application of mathematical models that are parameterized by patient data pretreatment to generate an optimal treatment strategy for that patient. Importantly, these predicted strategies would most likely need to change as patient responses diverge from those predicted, leading to an iterative loop of "predict-apply-refine." With the growing drive toward precision medicine, we believe that mathematical models are critical for the future of truly personalized therapy, where no two patients will receive the same therapeutic regimen, and where treatments adapt a change based on patient responses. The model presented here is a step toward describing the complex landscape of treatment decisions regarding dosing and combination of different therapies, and we have shown how these decisions can be sensitive to patient-specific parameters and guide clinical intuition (Page 5313, Conclusion).
Additionally, with regards to the claimed range of 1-1500 mg of the compound in a pharmaceutical composition, the Examiner notes that the optimum amounts of the presently claimed active agents and excipients would have been a matter well within the insight of one of ordinary skill in the art. Such a determination would have been made in accordance with a variety of factors, such as the route of administration, pharmacological considerations, such as the activity, efficacy, pharmacokinetics and toxicology profiles of the combination regimen, as well as the age, weight, sex, diet and medical condition of the patient, and the severity of the condition. Thus, the determination of the optimum or workable amounts given the guidance of the prior art would have been generally prima facie obvious to the ordinary skilled artisan. Please see MPEP 2144.05 [R-2] (II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (“[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation."). Accordingly, the particular amounts claimed do not impart patentability to the claims, absent a showing of the criticality of the particular amounts claimed.
It would have been obvious for PHOSITA to incorporate the teachings of Zhang’s PROTAC BCL-XL degraders and potent BCL-2/BCL-XL dual inhibitor similar to the compounds of Formula I with the teachings of Park to optimize the claimed dosages. One would have been motivated to do so, with a reasonable expectation of success as it would maximize the synergy between chemotherapy and antitumor immune response, following the administration of optimal dosing as taught by Park.
Conclusion
Claims 1-12 and 17 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAHAR INAM whose telephone number is (571)272-0821. The examiner can normally be reached 7:30 am-5:00 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAHAR INAM/
Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/
Supervisory Patent Examiner, Art Unit 1622
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