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 .
Claim Status
Claims 1-47 have been cancelled; claim 92 has been amended; and, claim 93 has been newly added, as requested in the amendment filed on 12/01/2025. Following the amendment, claims 48-93 are pending in the instant application.
Claims 55-58, 64-70, and 72-82 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species in the Response filed 08/23/2024, there being no allowable generic or linking claim.
Claims 48-54, 59-63, 71, and 83-93 are under examination in the instant office action.
Priority - Updated
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 48-54, 59-63, 71, and 83-93 have an effective filing date of October 12, 2018 corresponding to PCT/CN2018/110155.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/01/2025 is in compliance with the provisions of 37 CFR 1.97.
Additionally, upon further review, the IDS submitted 05/16/2025 is in compliance with the provisions of 37 CFR 1.97.
Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections - 35 USC § 112 - Withdrawn
Claim 92 was rejected under 35 U.S.C. 112(d) for being of improper dependent form. It is noted that Applicant’s argument against the rejection at Page 185 of Remarks (12/01/2025) has been cut off/is incomplete, however after further review and consideration the rejection of claim 92 under 35 U.S.C. 112(d) is withdrawn as claim 92 is considered further limiting wherein claim 92 requires that the identified bond must be a single bond, which is narrower in scope than independent claim 48 from which it depends wherein the identified bond may be a single bond or absent.
Claim Objections - New
Claim 92 is objected to because of the following informalities: with regard to the identified bond, it is noted that the leading quotation marks are missing. In other words, the claim currently reads "wherein in formulae (IIa)-(IIc), [bond]" is a single bond", but should read "wherein in formulae (IIa)-(IIc), "[bond]" is a single bond". Appropriate correction is required.
Claim Rejections - 35 USC § 112 – Maintained/Updated
Claims 48-54, 59-63, 71, and 83-92 stand as rejected and new claim 93 is newly 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.
It is maintained that the wording of claim 48 as pertains to substituents that may be absent from the conjugates renders the claim indefinite/ambiguous. Claim 48 still recites that “Y1, Y2, R1, R2, R3, R4, Z1 or Z2 can be independently absent, provided that Y1, Y2, R1, R2, R3, R4, Z1 and Z2 may not be absent at the same time”, which is regarded as indefinite as indicated in the previous Office Action (08/27/2025). New claim 93 is further included in this rejection as it depends from claim 48 and fails to remedy the previously identified deficiencies with respect to indefiniteness.
Applicant argues on Pages 186-191 of Remarks (12/01/2025) that, generally, the broadest reasonable interpretation of the claims asserted by the Office is inconsistent with the use of the claim term in the specification and is inconsistent with the interpretation that those skilled in the art would reach. Applicant notes that if the assertion that when, for example, Y1 and Y2 are absent the adjacent bonds are broken and Drug1 and Drug2 cannot necessarily form a bond with R1 and R2, then Formula (IIa) would contain three separate moieties and thus would not represent a conjugate compound, which is “contrary to what is intended in the application” (emphasis added). Applicant argues the Office’s interpretation of “absent” is inconsistent with the usage of the term in the instant specification and the interpretation one of ordinary skill in the art would reach: “what is meant is that when an internal group in Formula (Ila), e.g., Y1, is absent, Formula (Ila) does not contain Y1 moiety and Drug1 and R1 are directly linked to each other by a single bond” (emphasis added). Applicant further argues that when describing variables in chemical structures, phrases such as "absent," "missing" or a number of an internal moiety being 0 are commonly used in the art and in voluminous issued U.S. patents (wherein some patents have been presented as examples); it is well established that information which is well known in the art need not be described in detail in the specification. With regard to the patents presented as examples to support Applicant’s arguments, it is noted that the presented patents do not have the same fact patterns as the instant case, and Applicants may be their own lexicographers. It is noted that the only exceptions to giving the words in a claim their ordinary and customary meaning in the art are (1) when the applicant acts as their own lexicographer; and (2) when the applicant disavows or disclaims the full scope of a claim term in the specification. To act as their own lexicographer, the applicant must clearly set forth a special definition of a claim term in the specification that differs from the plain and ordinary meaning it would otherwise possess. CCS Fitness, Inc. v. Brunswick Corp., 288 F.3d 1359, 1366, 62 USPQ2d 1658, 1662 (Fed. Cir. 2002). See MPEP 2111.01(III-IV). It is particularly noted that without a special definition of “absent” in the instant specification, the broadest reasonable interpretation of the term to one of ordinary skill in the art (i.e., a chemist) must be applied. The term “absent” as would be applied under the broadest reasonable interpretation in a chemical context is that: when “absent”, the functional group required for the sharing of elections to form a covalent bond (e.g., with adjacent functional groups) is no longer present, and as such electrons are no longer shared and the covalent bond(s) no longer exist. Such an interpretation is supported by the instant claims and specification, wherein it is noted that the substituent groups that may be absent are not all defined the same, and as such when one substituent group is removed the remaining adjacent substituents do not necessarily comprise the functional groups required to form a new covalent bond in place of bonds formed by the now absent substituent group. Specifically, it is noted that claim 48 indicates that Y1, Y2, Z1, and Z2 are “independently a function group that link a cell binding molecule Q, or Drug1 or Drug2, in a form of a disulfide, ether, ester…”. Thus the claims themselves indicate that Y1 and Y2 are necessary to form a bond with Drug1 and Drug2, respectively, and Z1 and/or Z2 are required to form a bond with Q; as such it is maintained that the recitation in claim 48 that “Y1, Y2, R1, R2, R3, R4, Z1 or Z2 can be independently absent, provided that Y1, Y2, R1, R2, R3, R4, Z1 and Z2 may not be absent at the same time” is interpreted, under the broadest reasonable interpretation, such that any combination of the above listed substituents can be absent, so long as not all of the substituents are absent. For example, Y1, Y2, R1, R2, R3, R4, and Z1 can all be absent at the same time, so long as Z2 is still present; if Y1 and Y2 are absent at the same time, the conjugate would not comprise a drug and, in the same respect, if Z1 and Z2 were absent the conjugate would not comprise a cell-binding agent. Thus, it is maintained that the previously identified claim limitation as currently worded allows for structures that frustrate the purpose of the invention and renders instant claims 48-54, 59-63, 71, and 83-93 indefinite.
Claim Rejections - 35 USC § 103 - Maintained/Updated
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 48-54, 59-63, 71, and 83-92 stand as rejected, and new claim 93 is newly rejected, under 35 U.S.C. 103 as obvious over WO 2018/185526 A1 (previously cited on PTO-892; herein after referred to as "Zhao") in view of non-patent literature by Levengood et. al. (Angew. Chem. Intl. Ed., 2017, 56, 733-737; previously cited on PTO-892; herein after referred to as “Levengood”).
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With regard to new claim 93, claim 48 is rendered obvious by Zhao and Levengood as detailed in the previous Office Action (08/27/2025). With regard to new claim 93, it is noted that in Formula I of Zhao, reproduced below, X and Y are defined as representing the same or different, and independently, a functional group that links a cytotoxic drug via a disulfide, thioether, thioester, peptide, hydrazone, ether, ester, carbamate, carbonate, amine (secondary, tertiary, or quartary), imine, cycloheteroalkyane, heteroaromatic, alkoxime or amide bond and a list of possible functional groups from which X and Y can be selected are provided (Pages 4-5).
It is further noted that Zhao discloses that in the exemplary Formulas I-p and I-r, reproduced below, structures X7 and Y7 can be, for example, an NH group which satisfies one of various possible structures for X1/X2 of instant claim 48 and is not “S” or “S-S”; specifically X/Y of Zhao are defined the same as Y1/Y2 of instant claim 48. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to the claim rejections under 35 U.S.C. 103 above, Applicant argues the following on Pages 192-197 of Remarks:
Zhao relates to the conjugation of a cytotoxic agent to a cell-binding molecule with a bis-linker (dual-linker) where the cytotoxic agent has dual functional groups wherein the cytotoxic agent molecule has two connecting sites each connected to one branch of the dual linker, whereas the present application, for example, as shown in formulae (IIa)-(IIc), when the bond between Y2 and Drug2 is absent, the conjugation contains only one cytotoxic drug/molecule, Drug1, which has only one connecting site connected to a branch of the linker. Thus, the instant formulas are different than those of Zhao.
Zhao teaches that readily reactive bis-linkers of the invention can sequentially or simultaneously react with two or more functional groups of a cytotoxic molecule. That is, the bis-linker reacts, sequentially or simultaneously, with the functional groups of the same cytotoxic drug molecule to form the desired conjugate. For example, Zhao describes a readily-reactive bis-linker of Formula (III), with which two or more function groups of a cytotoxic molecule can react simultaneously or sequentially to form Formula (I), which contains one cytotoxic molecule. The Office Action's statement that "X and Y could be used to link two separate cytotoxic drugs to the bis-linker" is not taught or suggested by Zhao and Applicant argues the assertion that “if X or Y of Zhao are absent there is also only a single connection to the cytotoxic agent” is improper; Zhao is Applicant's own application and contains some same definitions as the present application wherein, for example, in formula (I) of Zhao, when X (or Y) is absent, the cytotoxic agent is still linked to the bis-linker via two bonds: one to L1 and the other to Y (or X and L2, respectively).
Zhao describes that the conjugate having the bis-linkage obtained from the cytotoxic agent has dual groups is more stable than the regular mono-linked conjugates in the mouse serum. Therefore, one of ordinary skill in the art would not have been motivated to modify Zhao by adopting mono-linked conjugates such as that described in Levengood et al. because the proposed modification would render Zhao unsatisfactory for its intended purpose of achieving improved stability.
Applicant’s arguments have been fully considered, but are deemed not persuasive.
With regard to Applicant’s arguments regarding the interpretation of terms, notably the term “absent”, it is noted that such arguments are addressed above and said response is also applicable to the Zhao reference, which utilizes the same definitions as the instant application and does not provide a special definition of “absent”. With regard to the arguments against the cited references individually, it is noted that it has been held that one cannot show non-obviousness by attacking references individually where, as here, the rejections are based on combinations of references. In re Keller, 208 USPQ 871 (CCPA 1981). Furthermore, regarding the argument against combining the prior art references to render the instant claims obvious, it is noted that the rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992); see also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP 2144. Specifically, it is noted that Zhao suggests that the bis-linker of the invention comprises two functional groups, which may be the same or different, capable of reacting with a cytotoxic molecule (simultaneously or sequentially). Levengood teaches conjugating more than one cytotoxic agent to an antibody wherein dual-drug ADCs demonstrated how delivery of multiple cytotoxic warheads can lead to improved ADC activities; the multi-drug ADCs of the study are active on cell types that are refractory to either of the individual component drugs, and highlights the potential for a new class of targeted therapeutics where multiple drugs with complementary or synergistic activities are simultaneously delivered. Thus, it would have been within the purview of one of ordinary skill in the art that for an ADC, one could select different, independently reactive groups for X and Y of Zhao wherein each could be sequentially reacted with a cytotoxic agent (sequential reactions with cytotoxic agents, i.e., single or multiple agents, are suggested by Zhao and Levengood, respectively) in order to (i) improve/increase drug loading and improve potency and/or (ii) load more than one kind of cytotoxic agent wherein complementary/synergistic cytotoxic agents in the same ADC molecule would further be expected to have improved activities (as supported by Levengood) because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success.
Double Patenting - Maintained/Updated
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.
Claims 48-54, 59-63, 71, and 83-92 stand as provisionally rejected, and new claim 93 is newly rejected, on the ground of nonstatutory double patenting as being unpatentable over the below listed copending Applications in view of WO 2018/185526 A1 (previously cited on PTO-892; herein after referred to as "Zhao") in view of non-patent literature by Levengood et. al. (Angew. Chem. Intl. Ed., 2017, 56, 733-737; previously cited on PTO-892; herein after referred to as “Levengood”):
Claims 1, 5, 9, 11-13, 17-33, 36-42, 44, 46-51, 53, 55-59, and 63 of Application No. 16/488,764;
Claims 1-2, 4-20, and 22 of Application No. 17/389,922;
Claims 1-3, 5-12, 16, and 20-22 of Application No. 17/390,064.
This is a provisional nonstatutory double patenting rejection.
Claims 48-54, 59-63, 71, 83, and 85-92 stand as provisionally rejected, and new claim 93 is newly rejected, on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 11-15, 17-18, and 20-27 of copending Application No. 17/387,205 in view of WO 2018/185526 A1 (previously cited on PTO-892; herein after referred to as "Zhao") in view of non-patent literature by Levengood et. al. (Angew. Chem. Intl. Ed., 2017, 56, 733-737; previously cited on PTO-892; herein after referred to as “Levengood”).
Claims 48-49, 59-63, 71, and 83-92 stand as provisionally rejected, and new claim 93 is newly rejected, on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 9, 11-13, 17-33, 36-42, 44, 46-51, 53, 55-59, and 63 of copending Application 16/488,764 in view of WO 2018/185526 A1 (previously cited on PTO-892; herein after referred to as "Zhao") in view of non-patent literature by Levengood et. al. (Angew. Chem. Intl. Ed., 2017, 56, 733-737; previously cited on PTO-892; herein after referred to as “Levengood”).
Claims 48-49, 53-63, 71, 83-84, and 88 stand as provisionally rejected, and new claim 93 is newly rejected, on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-20, and 22 of copending Application 17/389,922 in view of WO 2018/185526 A1 (previously cited on PTO-892; herein after referred to as "Zhao") in view of non-patent literature by Levengood et. al. (Angew. Chem. Intl. Ed., 2017, 56, 733-737; previously cited on PTO-892; herein after referred to as “Levengood”).
Claims 48-53, 59-63, 71, 83-84, and 88 stand as provisionally rejected, and new claim 93 is newly rejected, on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-12, 16, and 20-22 of copending Application 17/390,064 in view of WO 2018/185526 A1 (previously cited on PTO-892; herein after referred to as "Zhao") in view of non-patent literature by Levengood et. al. (Angew. Chem. Intl. Ed., 2017, 56, 733-737; previously cited on PTO-892; herein after referred to as “Levengood”).
Claims 48-53, 59-63, 71, 83-84, and 88 stand as provisionally rejected, and new claim 93 is newly rejected, on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-12, 16, and 20-22 of copending Application 17/387,205 in view of WO 2018/185526 A1 (previously cited on PTO-892; herein after referred to as "Zhao") in view of non-patent literature by Levengood et. al. (Angew. Chem. Intl. Ed., 2017, 56, 733-737; previously cited on PTO-892; herein after referred to as “Levengood”).
It is noted that new claim 93 has been added to each provisional nonstatutory double patenting rejection above. This is supported by the overlapping subject matter between the instant claims and the reference application claims indicated in the previous Office Action (08/27/2025) and the disclosure of Zhao specifically. With regard to new claim 93, claim 48 is rendered obvious by the reference applications, Zhao, and Levengood as detailed in the previous Office Action. With regard to new claim 93, it is noted that in Formula I of Zhao, reproduced below, X and Y are defined as representing the same or different, and independently, a functional group that links a cytotoxic drug via a disulfide, thioether, thioester, peptide, hydrazone, ether, ester, carbamate, carbonate, amine (secondary, tertiary, or quartary), imine, cycloheteroalkyane, heteroaromatic, alkoxime or amide bond and a list of possible functional groups from which X
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and Y can be selected are provided (Pages 4-5).
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It is further noted that Zhao discloses that in the exemplary Formulas I-p and I-r, reproduced below, structures X7 and Y7 can be, for example, an NH group which satisfies one of various possible structures for X1/X2 of instant claim 48 and is not “S” or “S-S”; specifically X/Y of Zhao are defined the same as Y1/Y2 of instant claim 48.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Furthermore, it is noted that no additional arguments against the above-listed double patenting rejections have been provided. As such, the above-listed double patenting rejections are maintained.
Conclusion
Claims 48-93 are pending. Claims 55-58, 64-70, and 72-82 are withdrawn. Claims 48-54, 59-63, 71, and 83-93 are rejected. No claims are allowed.
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.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642