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 .
Priority
This application is a U.S. national phase of International Application No. PCT/US2020/033602, filed on 05/19/2020, which claims domestic benefit to US provision application 62/850,098, filed 05/20/2019.
Claim Status
The amendment, filed on 10/15/2025, in which 1, 8, 13, 18, 22, 25, 26, 48, and 68 are amended; claims 4-7, 9-11, 14-17, 19-21, 24, 27-36, 39-46, and 63-65 are cancelled; and claims 50-51, 61-62, 66-67, and 69 are withdrawn, is acknowledged. Claims 1-3, 8, 12-13, 18, 22-23, 25- 26, 37-38, 47-49, and 68 are currently pending.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/15/2025 has been considered by the examiner.
Withdrawn Objections and Rejections
In the office action dated 07/16/2025,
Claims 1, 8, 25, and 26 were objected to for typographical errors. Applicant’s
amendment to the claims has overcome the objections and the objections are withdrawn.
Claims 8, 18, 25, 26, 48, and 68 were rejected under 35 USC 112(b) as being indefinite. Applicant’s amendment to the claims to clarify claim limitations has overcome the rejections and the rejections are withdrawn.
Claim 22 was rejected under 35 USC 112(d) as being of improper dependent form. Applicant’s amendment to the claim to independent form has overcome the rejection and the rejection is withdrawn.
Claims 40-41 and 43-46 were rejected under 35 USC 103 as being unpatentable over Hansen and Qiu. Applicant’s cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
Claims 1 and 2 were provisionally rejected under on the ground of nonstatutory double patenting as being unpatentable over claims 47 and 48 of copending Application No. 17/612,280 in view of Kotschy and Govindan. Applicant’s amendment to claim 1 to include the limitations of claim 25 has overcome the rejections and the rejections are withdrawn.
The following grounds of objections and/or rejections are either maintained or necessitated by applicant’s amendment to the claims.
Maintained Objections - Specification
While many of the errors noted in the previous office action filed 07/16/2025 were address, several minor informalities previously reported are still present within the replacement specification submitted 10/15/2025. Therefore, the objection to the specification is maintained because of the following informalities:
“exces” should read “excess” - pg 361, ¶ [457], line 7 (previously noted at pg 360, line 5) and pg 367, ¶ [466], line 9 (previously noted at pg 366, line 2)
“intraveneous” should read “intravenous” - pg 566, Example 12 title (previously noted at pg 563, line 3) and pg 568, Example 13 title (previously noted at pg 564, last line)
Appropriate correction is required.
As stated in the previous office action dated 07/16/2025, trade names or marks used in commerce, have been noted in the instant application. While, most of the terms have been amended for proper symbols indicating use in commerce (i.e. ™, SM , or ® following the terms) within the replacement specification filed 10/15/2025, the following term has not been properly addressed: “AcQuity” - pg 548, ¶ [712], line 10 (previously noted on pg 545, ¶ [712], line 110).
Modified/New - Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-3, 8, 12, 13, 18, 25-26, 37-38, and 48-49 are rejected under 35 U.S.C. 103 as being unpatentable over Govindan (Mol Cancer Ther. 2013;12(6):968-978), Jonchère (Oncotarget. 2015;6(1):409-426), EP2886545 (herein Kotschy), and US10,898,578B2 (herein Poudel) as evidenced by US10,124,069B2 (herein Lee).
Govindan teaches CD74 is an attractive target for antibody-drug conjugates (ADCs) because of its high rate of internalization after antibody binding and its expression in more than 90% of B-cell tumors and several nonhematopoietic cancers (i.e. gastric renal urinary bladder, NSCLC, certain sarcomas, and glioblastoma – pg 967, left column, ¶ 2) making the anti-CD74 antibody an efficient carrier for the intracellular delivery of cancer therapeutics (pg 968, right column, ¶ 2; pg 969, left column, ¶ 2). Govindan teaches anti-CD74 (milatuzumab) ADCs generated through disulfide reduction of the IgG, followed by reaction with corresponding maleimide derivatives attached to CL2A- or CL2E- (self-immolative) linked via carbonate bond (-OC(=O)-) to topoisomerase I inhibitor, SN-38 (active metabolite of irinotecan), with estimated drug:IgG molar substitution ratio of 5:7 (pg 969, column spanning ¶; Figure 1 annotated below).
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780
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Govindan does not teach an ADC utilizing Mcl-1 inhibitor comprising Formula (I) as the payload nor covalent linkage to a drug within the genus of Formula (I) via specific R groups (e.g. R03, R09, or R012 as recited in the instant claim) nor a hydrophilic moiety (-L3-R2 group) attached to the self-immolative linker.
Jonchère teaches that cancers can develop resistance to irinotecan treatment and ‘escape’ senescence (pg 410, left column, ¶ 2; Figure 2). Jonchère further teaches these persistent cancers are dependent on Mcl-1 pro-survival signaling (Figure 5, 6, and 9 – shown below).
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Kotschy teaches Mcl-1 inhibitor compound species within scope of Formula (I) (listed in the table below with comparison to species claimed in instant claim 38) and teaches these may be linked to anticancer agents including antibodies (pg 17, ¶ [0045]; claim 46), monoclonal or fragments thereof (pg 17, ¶ [0049]) in pharmaceutical compositions with one or more pharmaceutically acceptable excipients (claim 47).
Instant (claim 38)
Kotschy ID
Structure
(1)
Examples 30, 826-828, 871
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326
681
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(3)
Example 744
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234
488
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(6)
Example 728
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279
540
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(8)
Example 482
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255
537
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(11)
Example 107
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253
542
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(12)
Example 77
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280
539
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Poudel teaches that ADCs comprising self-immolative compounds with hydrophilic substituents, ortho to the benzylozycarbonyl group, can have improved stability in serum for (column 4, ¶ 2; R4 moiety in Formula (II) shown below analogous to instant (L3-R2); Table A (e.g. (Ia-09)-(Ia-11) R4 groups containing hydrophilic formamide group and polyethylene glycol)).
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237
568
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Poudel also references teachings of Lin et al., which showed improved solubility of PABC group molecule when attaching hydrophilic group to the benzylic position (column 3, lines 21-23). Poudel teaches that many different antibodies can be conjugated to a compound of Formula (I) – as shown in Formula (II) – where preferably the antibody targets tumor associated antigens (column 32, lines 31-34), and teaches a specific example of preparing conjugates with a molar ratio of antibody:enzyme of 5:1 (column 34, Example 3). Poudel further teaches R3 of Formula (II) connecting the self-immolating moiety to a drug could be a tertiary amine secondary to the payload/toxic moiety (L) (column 6, lines 47-65), which can include piperazine ring amine groups as evidenced by peptidomimetic linker drug moieties as taught by Lee (ADC Examples 1-86) - annotated example 1 shown below).
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1201
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One of ordinary skill in the art would recognize that utilizing anti-CD74 ADC as taught by Govindan would be advantageous for inhibitors that require cell internalization, such as those targeting intracellular signaling pathways (i.e. irinotecan derivatives or mcl-1 inhibitors). Furthermore, incorporating a serum stable self-immolative group as taught by Poudel would increase efficacy of cancer targeted biologics. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to adapt elements of the ADC utilizing anti-CD74 antibodies as taught by Govindan, by adding a hydrophilic moiety to the self-immolative linker as taught by Poudel and covalently linking through tertiary amine present on Mcl-1 inhibitor compounds as taught by Kotschy (covalent linkage to piperazine group analogous to R03 group of the instant invention as evidenced by Lee) to achieve a therapeutic within scope of the instant invention that has enhanced serum stability and ADC solubility as taught by Poudel and reduces the likelihood of cancer drug resistance as taught by Jonchère.
Claim 47 is rejected under 35 U.S.C. 103 as being unpatentable over Govindan, Jonchère, Kotschy, Poudel and Lee as applied to claim 1 above, and further in view of Qiu (MAbs. 2019;11(7):1266-1275 – prior art to PCT/US2020/033602, filed on 05/19/2020, which is the first appearance of specific anti-CD74 antibody CDRs).
Govindan, Jonchère, Kotschy, and Poudel as evidenced by Lee teach claim 1 as discussed above.
Govindan teaches milatuzumab as the anti-CD74 antibody (instant SEQ ID NOs: 1, 2, 3, 16, 70, and 18; Table C). This sequence differs from the instant claimed CDRs elected (v) by a single amino acid residue mutation (see alignment below; each CDR separated by “xxxx”).
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Qiu teaches deamidation of asparagine (Asn; N) residues can significantly impact protein structure and function (pg 1266, left column, ¶ 2). Antibody CDR loops in particular are susceptible to Asn deamidation when followed by a Gly, Ser, Thr, or Asn (pg 1266, column 2, ¶ 2). Similar to instant LCDR1 for milatuzumab (SEQ ID NO:16), the LCDR1 of anti-CD52 antibody MAB1 as taught by Qiu contains Asn33-Gly34, which was found to be prone to deamidation (Figure 1). Mutagenesis studies revealed three mutations including G34Q showed increased resistance to deamidation while maintaining antigen binding capacity (abstract).
Routine optimization of known milatuzumab CDRs in an ADC as taught by the combined teachings of Govindan, Jonchère, Poudel, and Kotschy would have led to the generation of a G34Q mutant as suggested by Qiu. A person of ordinary skill in the art would have found it obvious to optimize CDR residues to utilize an LCDR1 with G34Q mutation as taught by Qiu because Qiu teaches this a common site for antibody deamidation and that G34Q has been shown to increase antibody stability without greatly affecting antigen binding.
Claim 68 is rejected under 35 U.S.C. 103 as being unpatentable over Govindan, Jonchère, Kotschy, Poudel and Lee as applied to claim 1 above, and further in view of Yu (J Hematol Oncol. 2019;12(1):94 – prior art to PCT/US2020/033602, filed on 05/19/2020, which is the first appearance of an Fc silent antibody).
Govindan, Jonchère, Kotschy, and Poudel as evidenced by Lee teach claim 1 as discussed above.
Kotschy (¶ [0049]) and Poudel (column 9-10 spanning ¶) further teach the antibody portion of an ADC can include antigen binding fragments without Fc domains (e.g. scFv) (i.e. inherently Fc silent).
Yu teaches utilizing IgG antibodies in ADCs, which have intrinsic antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), may add additional toxicities to the cytotoxic payloads (pg. 1-2, page spanning ¶). Yu further teaches that this can be avoided by introducing mutations to the Fc domain to silence intrinsic effector functions (i.e. direct Fc silencing) (pg. 2, left column, ¶ 1).
Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify an ADC as taught by the combined teachings of Govindan, Jonchère, Kotschy, and Poudel as evidenced by Lee (ADC using full length antibody - milatuzumab) with an Fc silent antibody, either by virtue of lacking an Fc domain as suggested by Kotschy and Poudel or through Fc silencing mutations as taught by Yu, because Yu teaches this can reduce the potential of additional off-target toxicities.
Response to Arguments - 35 USC § 103
Applicant's arguments filed 10/15/2025 have been fully considered but they are not persuasive.
Applicant states:
“…independent claim 1 has been amended to recite that the Mcl-1 inhibitor comprises a compound of Formula (I)” (Remarks, pg 70)
“To arrive at the presently claimed ADCs from the ADC of Govindan, a person skilled in the
art needs to make at least following modifications: 1) replace doxorubicin or SN-38 in the ADC with a specific Mcl-1 inhibitor - a compound of Formula (I); 2) add a spacer moiety with a hydrophilic moiety (-L3-R 2) onto the linker; and 3) connect the compound of Formula (I) with the linker through a specific position - one of the R03, R09, or R012 groups in the compound of Formula (I).
Jonchère, Poudel, and Kotschy do not cure the deficiency.” (Remarks, pg 71)
“See Poudel, column 4, paragraph 2.
Nothing in this paragraph suggests that certain substituents on a PABC group are
hydrophilic. Furthermore, nothing in Poudel teaches or suggests that the modified self-immolating moiety is suitable for connecting an anti-CD7 4 antibody with a specific Mcl-1 inhibitor represented by Formula (I), let alone connect the specific Mcl-1 inhibitor represented by Formula (I) through one of the R03, R09, or R012 groups.” (Remarks, page 72)
“Nothing in Jonchère teaches or suggests that the Mcl-1 inhibitor should be the compound of Formula (I) as required by present claim 1, let alone connect the specific Mcl-1 inhibitor represented by Formula (I) with an anti-CD74 antibody to form an ADC. Furthermore,
Jonchère is completely silent on the linker and the connecting points between the linker and drug moieties.” (Remarks, pg 72)
“nothing in Kotschy teaches or suggests what kind of linker should be used to link the Mcl-1 inhibitor with an antibody, let alone link the Mcl-1 inhibitor at the specific point as required by the present claims. In addition, Kotschy is silent on the anti-CD74 antibody and hydrophilic moiety (-L3-R2) required by the present claims.” (Remarks, pg 73)
In response to applicant’s argument regarding the amended claim 1, the current rejection has been modified to address the amended claim limitations as discussed above. Subsequent arguments regarding deficiencies in the analysis of the amended base claim 1, with respect to dependent claims (i.e. claims 25-26 and 37-38 (Remarks, pg 74)) or made on the basis that additional references do not cure the primary deficiency (i.e. claim 47 (Remarks, pg 74-75)), are deemed unpersuasive.
Furthermore, regarding applicant's arguments against the references individually (i.e. ‘nothing in [reference] teaches or suggests [all remaining deficiencies of Govindan]’), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Briefly, a skilled artisan would be motivated to modify an ADC utilizing anti-CD74 antibodies conjugated to an irinotecan derivative via self-immolative linker (PABC group) as taught by Govindan, with substituting SN38 with an Mcl-1 inhibitor (e.g. known inhibitors taught by Kotschy who further teaches these molecules can be ADCs), because Jonchère teaches this can avoid potential cancer drug resistance. Poudel further teaches the self-immolative linker (PABC group as disclosed by Govindan ADC) can be modified to include a hydrophilic R4 group (examples shown in Table A) and a skilled artisan would be motivated to do so to increase stability and/or solubility of an ADC. Furthermore, Poudel teaches said linker can be covalently bonded to a tertiary amine, including tertiary amines within piperazine ring groups as evidenced by Lee (i.e. those equivalent to instant R03 or Mcl-1 inhibitors taught by Kotschy).
Applicant states:
“…The Examiner's analysis, which picks and chooses the elements that are scattered around in Govindan, Jonchère, Poudel, and Kotschy, is hindsight using the presently claimed ADCs as a blueprint. Such analysis should not be allowed in the obviousness reasoning” (Remarks, pg 73)
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made (i.e. the modularity of ADCs and combination of elements known in the art), and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant states:
“Absent any teachings or suggestions, a person skilled in the art could not reasonably expect that connecting the compound of Formula (I) with an anti-CD74 antibody through a specific position could lead to ADCs that are highly potent inhibitors in multiple cancer cell lines.” (Remarks, pg 74)
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., anti-tumor activities) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Modified - Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 17/613,006
Claims 1-3, 8, 12, 13, 18, 22-23, 25-26, 37-38, 48-49 and 68 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 38, 52, 54-55, 68 and 69 of copending Application No. 17/613,006 (herein US006). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1 and 52 of US006 claims an ADC with identical Formula (1) wherein the L-D comprises species of molecules within scope of genus of ADCs elements recited in instant claims 1-3, 8, 12, 13, 18, 22-23, 25-26, and 37-38. Claim 54 of US006 further claims the ADC of claim 1 wherein the antibody or antigen binding fragment binds to a target cancer antigen. Claim 55(1)(i) of US006 additionally claims the target antigen of US006 claim 54 to include CD74. Therefore a skilled artisan would recognize the instant species of a CD47-ADC to be within scope of the genus of ADC as recited in US006.
Claim 38 of US006 further claims the ADC of US006 claim 1, wherein A is a bond and/or R is a -CH3, patentably indistinct from instant claim 23
Claim 68 of US006 further claims the ADC of US006 claim 1, wherein the ADC has identical ranges of average drug loading (average p) compared to instant claim 48.
Claim 69 of US006 further claims a pharmaceutical composition of the ADC of US006 claim 1, and a pharmaceutically acceptable carrier, patentably indistinct from instant claim 49.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments - Double Patenting
Applicant's arguments filed 10/15/2025 have been fully considered but they are not persuasive.
Applicant states:
“Nothing in claims 1, 23, 25-26, 30, 32, 34, 37-39, 43, 52, 54-55, 68 and 69 of the '006
application teaches or suggests the use of an anti-CD74 antibody for preparing the instantly claimed ADC. In addition, nothing in the cited claims of the '006 provides any suggestion or motivation to select an anti-CD74 antibody for making an ADC.” (Remarks, page 76)
In response to applicant’s argument, US006 claims the antibody or antigen binding fragment of the claimed ADC can be selected from various species including CD74 (Claim 55, line 2), thus, while the aforementioned claims are not identical, they are not patentably distinct.
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 HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647