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 .
DETAILED ACTION
The amendment filed December 18, 2025 in response to the Office Action of June 18, 2025 is acknowledged and has been entered.
Claims 7, 8, 10, and 42 have been amended.
Claims 1-11, 13-16, and 42-46 are pending.
Claims 1-6, 13-16, and 43-46 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 7-11 and 42 are currently under consideration as drawn to the elected invention.
In view of the claim amendments and applicant’s arguments, the 102 rejection set forth in the previous Office Action of 06/18/2025 is hereby withdrawn.
In view of the claim amendments and applicant’s arguments, the 103 rejection set forth in the previous Office Action of 06/18/2025 is hereby withdrawn.
MAINTAINED/MODIFIED REJECTIONS
Claim Rejections - 35 USC § 112
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 7-11 and 42 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 WRITTEN DESCRIPTION rejection.
Claim 7 is drawn to a method of enhancing immune function to induce solid tumor reduction and/or elimination, comprising: administering a therapeutic dose of an MCL1 inhibitor to inhibit immunosuppression of T cells; and administering an immunotherapeutic antibody to increase immune activation within the solid tumor and induce solid tumor reduction and/or elimination, wherein the MCL1 inhibitor enhances the efficacy of the immunotherapeutic antibody. Paragraph [0041] of the instant publication US 2022/0347180 A1 states: MCL1 inhibiting compound may refer to various compounds that inhibit the function of the MCL1 protein. Given BRI, the claim encompass inhibitors specific to MCL1 such as S63845, S64315, ABBV-467, AZD-5991, AMG-176, and AMG-397 and pan inhibitors of BCL2 family (such as GX15-070 a pan inhibitor of MCL-1/BCL-2/BCL-XL/BCL-W/BFL-1, see [0040 of the instant publication). Kale (Kale et al., Cell Death and Differentiation, 2018, 25, 65-80, Publication Date: 11/17/2017, of record) teaches that MCL-1 is a member of large BCL2 family including 1) anti-apoptotic proteins: BCL2, BCL-XL, BCL-W, MCL-1, BFL-1/A1; 2) pro-apoptotic pore-formers: BAX, BAK, BOK; 3) pro-apoptotic BH3-only proteins: BAD, BID, BIK, BIM, BMF, HRK, NOXA, PUMA (page 66, col. 2, para. 2). These members have different structures and functions (Fig. 2 on page 68). It is well known in the art that MCL-1 inhibitors may inhibit other members of BCL2 family. For example GX15-070 is a pan inhibitor of MCL-1/BCL-2/BCL-XL/BCL-W/BFL-1. In addition, the specification does not limit the structure of inhibitors, thus, given BRI, the inhibitors could be small molecule mimetic, peptide, antibody, oligonucleotide, genome editing system (e.g. CRISPR/Cas). These compounds vary significantly, have different structures and physical/chemical properties, and function through different mechanisms which may lead to different therapeutic effects..
The claim also encompasses a broad genus of an immunotherapeutic antibodies, which would encompass all possible known or novel immunotherapeutic antibodies. These immunotherapeutic antibodies could have different physical/chemical properties, function through different targets and/or mechanisms.
The instant specification provided limited evidence of the effect of the claimed combination comprising a MCL1 inhibitor and a therapeutic antibodies for limited cancers:
Example 3 shows combining MCL1 inhibitor S63845 and an anti-PD1 antibody strongly suppressed tumor growth in a melanoma model, better than either drug alone (Fig. 3).
Examples 14 shows combining MCL1 inhibitor S63845 and an anti-PD1 antibody strongly suppressed tumor growth in a melanoma model, better than either drug alone (Fig. 16d). It is noted that Fig. 3 and Fig. 16d are identical.
Examples 5-9, and 11-13 shows results for combinations of a MCL inhibitor (S64315 or S63845) and a BCL2 inhibitor (ABT-199), which do not comprise using a therapeutic antibody.
Taken together, the specification discloses only one specific combination: MCL1 specific inhibitor S63845 (a small molecule inhibitor) and an anti-PD1 antibody. No other combinations that have the claimed functions/properties have been disclosed. Thus, the specification lacks written description support for the claimed MCL1 inhibitors and immunotherapeutic antibody used in combination with MCL1 inhibitors.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. (See Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001, especially page 1106 3rd column). A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. MPEP 2163 II.A.3a.ii.
Regarding MCL-1 inhibitors, Kale teaches that MCL-1 is a member of BCL-2 family proteins. The BCL-2 family of proteins controls cell death primarily by direct binding interactions that regulate mitochondrial outer membrane permeabilization (MOMP) leading to the irreversible release of intermembrane space proteins, subsequent caspase activation and apoptosis (Fig. 2a and Abstract). Thus, different inhibitors with different specificity and affinity to MCL1 may lead to different therapeutic outcomes in a combination with an immunotherapeutic antibody.
However, in view of the above, the specification discloses only a few MCL1 inhibitors such as the inhibitors recited by claim 8. Only one of them (S63845) has been tested in a combination with only one immunotherapeutic antibody (anti-PD-1 antibody) in treating melanoma (Examples 3 and 14). These disclosed MCL1 inhibitors would not teach other MCL-1 inhibitors which can be used in combination with an immunotherapeutic antibody and function as claimed.
Regarding to “immunotherapeutic antibody”, the specification and prior art (see 103 rejection below) teaches anti-PD1 or anti-PD-L1 antibodies can be combined with an MCL-1 inhibitor to treat solid tumors such as melanoma. However, anti-PD1 antibodies would not teach other immunotherapeutic antibodies encompassed by the claims, which can be used in combination with MCL1 inhibitors and function as claimed. Immunotherapeutic antibodies can target specific extracellular proteins, including cell surface receptors, soluble ligands, and immune checkpoints, to treat cancers. Major targets include HER2, CD20, EGFR, TNF-α, VEGF and checkpoint inhibitors, etc., which function through different mechanisms such as inducing direct cytotoxicity, blocking growth signals, or modulating the immune system. One of ordinary skill in the art would not be able to readily recognize/visualize other immunotherapeutic antibodies in combination with a MCL1 inhibitor would lead to the same therapeutic outcomes as the anti-PD-1 antibody disclosed in the specification.
In addition, the claim and dependent claims identify the MCL-1 inhibitors by function only, where the function is to:
inhibit MCL-1;
inhibit immunosuppression;
enhance the efficacy of an immunotherapeutic antibody;
inhibit immunosuppression of CD8+ T cells (claim 9);
inhibit immunosuppression of T cells by targeting myeloid-derived suppressor cells (claim 10);
treat melanoma (claim 11).
The claim and dependent claims identify the immunotherapeutic antibody by function only, where the function is to:
increase immune activation within a solid tumor;
induce solid tumor reduction and/or elimination;
work better with an MCL-1 inhibitor.
However, the instant specification has not provided a sufficient description about the correlation between the recited functions and the structure of the MCL-1 inhibitor or the immunotherapeutic antibody. Based on the specification and prior art, one of ordinary skilled in the art would not be able to “visualize or recognize” other members of the genus, excepted the ones described in the specification with the recited functions.
The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification discloses only a few MCL-1 inhibitors, and only MCL-1 inhibitor and immunotherapeutic antibody combination, with claimed properties/ functions. A definition by function does not suffice to define the genus because it is only an indication of what the MCL-1 inhibitor or an immunotherapeutic antibody do, rather than what they are.
Taken together, the instant specification has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between functions and the structure of the inhibitors (e.g. MCL1 inhibitors) by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus of MCL1 inhibitors, the genus of immunotherapeutic antibody, and combinations broadly encompassed by the claimed invention. Logically, the claims lack the written description support for a method of using them.
Response to Arguments
For the WRITTEN DESCRIPTION rejection under 35 U.S.C. 112(a), Applicant argues:
As amended, claim 7 recites "an MCL1 inhibitor" rather than a "BCL2 family member inhibitor" and states that the immunotherapeutic is an antibody. As noted by the Office, the specification provides clear support for MCL1 inhibitors, describing how "a BCL2 family member inhibitor" "may be an MCLl inhibitor, that may inhibit immunosuppression of CD8+ T cells to facilitate reducing or eliminating solid tumors." US Publ. 2022/0347180, paragraph [0011 ]. Antibody immunotherapeutics, noted by the Office at pp. 14 and 15 of the O.A., are also well supported by the specification, which notes that "the disclosed compounds and methods may aid in therapies involving treating a patient with a therapeutic compound, such as an immunotherapeutic compound, for example an antibody, that is directed to a cancer cell." Id. at [0051].
Applicant’s arguments have been considered, but have not been found persuasive. As set forth above, the amended claim 7 still encompasses a broad genus of MCL1 inhibitors (both MCL1 specific inhibitors and pan BCL2 family inhibitors) and a broad genus of immunotherapeutic antibodies, which would encompass all possible known or novel immunotherapeutic antibodies. These immunotherapeutic antibodies could have different physical/chemical properties, function through different targets and/or mechanisms. In addition, the specification does not limit the structure of MCL1 inhibitors, thus, given BRI, the inhibitors could be small molecule mimetic, peptide, antibody, oligonucleotide, genome editing system (e.g. CRISPR/Cas). These compounds vary significantly, have different structures and physical/chemical properties, and function through different mechanisms which may lead to different therapeutic effects. As set forth above, the instant specification provided limited evidence of the effect of the claimed combination comprising a MCL1 inhibitor (e.g. S63845) and a therapeutic antibodies (e.g. anti-PD-1 antibody).
Applicant cites paragraphs [0011] and [0051] of the instant publication to argue that the compounds and method are supported by the specification. However, those paragraphs only provide the functional definition of the compounds which does not tell the structures of the compounds. A definition by function does not suffice to define the genus because it is only an indication of what the MCL-1 inhibitor or an immunotherapeutic antibody do, rather than what they are.
Furthermore, the instant specification has not provided a sufficient description about the correlation between the recited functions and the structure of the MCL-1 inhibitor or the immunotherapeutic antibody. Based on the specification and prior art, one of ordinary skilled in the art would not be able to “visualize or recognize” other members of the genus, excepted the ones described in the specification with the recited functions.
Applicant further argues:
Amended claim 8 recites that the MCL1 inhibitor is selected from the closed list of "S63845, S64315, ABBV-467, AZD-5991, AMG-176, and AMG-397," which is supported by the specification's explicit disclosure that "the disclosed compounds inhibiting MCL1 may include S63845, S64315, ABBV-467, AZD-5991, AMG-176, AMG-397." US Publ. 2022/0347180, paragraph [0041]. Claim 42 is amended to depend from claim 8 and recites two specific MCLl inhibitors: S63845 and S64315. The specification further provides extensive experimental data demonstrating that "MCLl inhibitors S63845 or S64315 blocked tumor growth, drastically decreased the frequency of myeloid-derived suppressor cells (MDSCs) and increased the frequency of tumor-infiltrating CD8+T cells." Id. paragraph [0097].
Applicant’s arguments have been considered, but have not been found persuasive. It’s acknowledged that the specification provides written description support for the MCL1 inhibitors listed in claims 8 and 42, however, claims 8 and 42 also encompass a broad genus of immunotherapeutic antibodies. As set forth above, the claims lack written description support for encompassed immunotherapeutic antibodies.
Because one of skill in the art would reasonably understand, from the Specification's
disclosure of specific compounds, their mechanisms of action, and extensive experimental data
demonstrating their efficacy in the claimed methods, that Applicant was in possession of the subject matter recited in claims 7-11 and 42, withdrawal of the present rejection under 35 U.S.C. § 112(a) is respectfully requested.
Applicant’s arguments have been considered, but have not been found persuasive. First, the specification provides very limited data about the claimed combinations. In addition, the instant specification has not provided a sufficient description about the correlation between the recited functions and the structure of the MCL-1 inhibitor or the immunotherapeutic antibody. Based on the specification and prior art, one of ordinary skilled in the art would not be able to “visualize or recognize” other members of the genus, excepted the ones described in the specification with the recited functions. Thus, contrary to applicant argument, one of ordinary skill in the art would not think that applicant was in possession of the subject matter recited in claims 7-11 and 42.
Thus, the rejection is maintained for the reasons of record.
NEW GROUNDS OF REJECTIONS
Claim Rejections - 35 USC § 103
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.
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.
Claim 7-11 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Kotschy (Kotschy et al., Nature, Vol. 538, 477-482, Publication Date: 10/19/2016, cited in IDS of 03/29/2024) and in view of Moreno (Moreno et al., Seminars in Oncology, Vol 42, No 3, 466-473, Publication Date: June 2015) and Pierson (Pierson et al., Nature Immunology, Vol. 14, No. 9, 959-965, Publication Date: September, 2013).
Kotschy teaches MCL1 is essential for the growth of diverse tumors including solid tumors. Certain compounds that broadly inhibit gene transcription (for example, anthracycline and CDK9 inhibitors) or protein translation (for example puromycin and emetine) are thought to exert their cytotoxic effects in tumor cells, at least in part, by down regulating MCL1 (page 477, col. 2, para. 1).
Kotschy teaches a potent selective MCL1 inhibitor: S63845. S63845 exhibited low nanomolar cytotoxicity to multiple cancers in vitro and in vivo. Normal tissue can tolerate doses of S63845 (page 477, col. 2, para. 3).
Kotschy teaches that S63845 is 1,000-fold more potent in killing H929 cells than the previously described MCL1 inhibitor A-121047; and more than 10-fold more potent in killing RS4;11 cells than A-121047 (Fig. 1C).
Kotschy teaches S63845 kills cancer cells through on-target activity, that is, activation of the BAX/BAK-dependent mitochondrial apoptotic pathway by direct inhibition of MCL1 (page 478, col. 2, para. 4).
Kotschy teaches S63845 is effective against haematological cancer-derived cell lines in vitro and in vivo (Fig. 2). In particular, Treatment with 25 mg/kg S63845 (i.v.) for five consecutive days was able to cure 70% of immuno-competent C57BL/6 mice bearing Eμ -Myc mouse lymphomas (Fig. 2e and Extended Data Fig. 6f, g), with no side-effects evident in normal tissues (also see page 479, col. 1, para. 4).
Kotschy teaches that S63845 shows cytotoxicity to some of the solid cancer cells lines; including melanoma cell lines SK-MEL-2, HT-144 and UACC-62 (Extended Data Fig. 8a; and page 480, col. 1, para. 1).
Kotschy teaches that S63845 in combination with various anti-tumor agents can significantly enhance the therapeutic activity of the treatment (Fig. 4).
Kotschy teaches as set forth above. However, Kotschy does not teach the method also comprising administering an immunotherapeutic antibody, or an MCL1 inhibitor to inhibit immunosuppression of T cells.
Moreno teaches that action of the PD-1 pathway include an enhancement of T-regulatory cell proliferation and suppressive activity, and a decrease in the lytic activity of both B and natural killer cells. Tumor infiltrating lymphocytes (TILs) in melanoma tumors expressed high levels of PD-1 (the bridging paragraph of cols. 1-2 on page 467). Antibodies directed against PD-1 or PD-L1 block the inhibition signaling allowing the T cell to attack the melanoma cells (Fig. 1).
Moreno teaches that anti-PD-1 antibodies nivolumab and pembrolizumab have been approved by FDA for treating melanoma (page 469, col. 1, paras. 2 and 4).
Moreno teaches that combinations with other anti-melanoma agents may result in additional benefits (§ Abstract; and § Conclusion).
Pierson teaches that Foxp3+ regulatory T (Treg) cells are a crucial immunosuppressive population of CD4+ T cells (Abstract).
Pierson teaches that the importance of Mcl-1 expression for Treg cell survival suggested that regulation of Mcl-1 may be important in setting the homeostatic balance of Treg cell (page 963, col. 2, para. 1).
Pierson teaches that MCL-1 is essential for Treg cell survival. Furthermore, MCL-1 appears to represent a rheostat for controlling the Treg cell homeostatic niche, with positive regulation via IL-2 and antagonism by Bim during homeostatic perturbation (the last paragraph of the article).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use an MCL1 inhibitor S63845 for treating cancer such as melanoma because Kotschy teaches S63845 are effective for various cancers in vivo and for several melanoma cancer cell lines in vitro; and to further add an anti-PD-1 antibody such as nivolumab or pembrolizumab in the treatment because Moreno teaches: 1) melanoma has high expression of PD-1; 2) antibodies directed against PD-1 or PD-L1 block the inhibition signaling allowing the T cell to attack the melanoma cells; 3) both nivolumab and pembrolizumab have been approved by FDA for treating melanoma; 4) combination with other anti-melanoma agent may bring additional benefit. Kotschy further teaches that S63845 can be combined with other agents to further enhance the anti-tumor activity. Based on the teachings of the references, one of ordinary skill in the art would have a reasonable expectation that a combination of an MCL1 inhibitor (such as S63845) and an anti-PD-1 antibody (such as nivolumab or pembrolizumab) would have an enhanced anti-tumor activity in melanoma, because the combination brings two mode of actions and two different anti-tumor mechanisms together. The motivation would have been to develop a more powerful cancer treatment. Based on the teaching of Pierson and Moreno, one of ordinary skill in the art would have recognized that MCL1 inhibitor S63845 would lead to reduction of Treg cells (inhibit immunosuppression of T cells); anti-PD-1 antibody would block the inhibition signaling allowing the T cell to attack the melanoma cells (increase immune activation within the solid tumor and induce solid tumor reduction and/or elimination).
Further noted: S63845 is the same MCL1 inhibitor used in the only working example of the specification. Thus, S63845 has the recited properties, such as inhibit immunosuppression of T cell; enhancing immune function (claim 1).
Regarding claims 9 and 10, Kotschy, Moreno and Person teaches the same combination (MCL inhibitor (S63845) + immunotherapeutic antibody (anti-PD-1 antibody)) as the only working example in the instant specification (Example 14). Thus, S63845 has the properties recited by claims 9 and 10: inhibits immunosuppression of CD8+ T cells (claim 9), and inhibits immunosuppression of T cells by targeting myeloid-derived suppressor cells (claim 10), (as evidenced by Fig. 16b of the instant specification).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHENG LU/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/ Supervisory Patent Examiner, Art Unit 1642