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 2, 6, 10, 12, 15-19, 21, and 23 have been cancelled; claims 1, 3-5, 8-9, 11, 13-14, and 24 have been amended; and claims 26-31 have been newly added, as requested in the amendment filed on 07/22/2026. Following the amendment, claims 1, 3-5, 7-9, 11, 13-14, 20, 22, and 24-31 are pending in the instant application.
Claim 22 stands as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention in the Response filed 01/30/2026, there being no allowable generic or linking claim.
Claims 1, 3-5, 7-9, 11, 13-14, 20, 24-31 are under examination in the instant office action.
The elected species, wherein Z comprises an -AA-H corresponding to the side chain of an amino acid that is 2,3-diaminopropionic acid, has been thoroughly searched and is
free of the prior art. As a result, the search was expanded to non-elected species.
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.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. It is further noted that the certified copy of the foreign priority document is in English, and therefore the claim to foreign priority has been perfected.
Claims 1, 3-5, 7-9, 11, 13-14, 20, 24-25, and 27-31 have an effective filing date of May 27, 2020 corresponding to GB2007926.5, as the claim to foreign priority has been perfected.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/05/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections - Withdrawn
Claims 1 and 24 were objected to for minor informalities. Applicant has amended the claims such that the listings of antibody-drug conjugate components/variables and structures are designated by distinct characters. As such, the objection to claims 1 and 24 is withdrawn.
Claim 15 was objected to for a minor informality. Claim 15 has been canceled, rendering its objection moot. As such, the objection to claim 15 is withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 1-5, 7-9, 11, 13-15, 18-20, and 24-25 were rejected on the basis that they contain an improper Markush grouping of alternatives. Claims 15 and 18-19 have been canceled, rendering their rejection moot. Claims 1 and 24 have been amended such that the antibody-drug conjugates (ADCs) or targeting agent-drug conjugates (TDCs) comprise a repeat of Formula (I) which shares the structural features of: (i) a polymer backbone comprising alternating groups -X-Q-Y-; and (ii) amino acid side chain groups joined to a biologically active moiety -B via a linker, wherein said linker is a branched linker that comprises -X’-Q’-Y’-R’. In view of the instant claim amendments, the rejection of claims 1-5, 7-9, 11, 13-15, 18-20, and 24-25 on the basis that they contain an improper Markush grouping of alternatives is withdrawn.
Claims 1-5, 7-9, 11, 13-15, 18-20, and 24-25 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. It is noted that claims 15 and 18-19 have been canceled, rendering their rejection moot. Claims 1 and 24 have been amended such that the antibody-drug conjugates (ADCs) or targeting agent-drug conjugates (TDCs) comprise a repeat of Formula (I) which shares the structural features of: (i) a polymer backbone comprising alternating groups -X-Q-Y-; and (ii) amino acid side chain groups joined to a biologically active moiety -B via a linker, wherein said linker is a branched linker that comprises -X’-Q’-Y’-R’. Applicant argues, generally, on Pages 22-28 of Remarks (filed 07/22/2026) that the specification consistently describes the molecular architecture of the claimed ADCs or TDCs throughout the disclosure, including the structural relationship among the polymer, therapeutic or diagnostic payload, linker, and antibody or targeting agent; the subject matter encompassed by the present claims resides in the disclosed conjugate platform and its defined molecular organization rather than in the discovery of any particular antibody, linker chemistry, or biologically active moiety bound to the polymer, in isolation. Applicant’s arguments, in view of the instant claim amendments, are deemed persuasive and the rejection of claims s 1-5, 7-9, 11, 13-15, 18-20, and 24-25 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 is withdrawn.
Claims 1-5, 7-9, 11, 13-15, 18, 20, and 24-25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite. Claims 15 and 18 have been canceled, rendering their rejection moot. Claims 1 and 24 have been amended such that the moiety Z is a group of formula (vi), (vii), (viii), or (ix). Claim 4 has been amended to conform to amended claim 1 from which it depends. Claim 5 has amended to remove “sulfone reagents that are Julia-Kocienski like”. Furthermore, claims 8-9, 11, and 13-14 have been amended to remove “preferably”. In view of the instant claim amendments, the rejection(s) of 1-5, 7-9, 11, 13-15, 18, 20, and 24-25 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Claims 2, 8, 11, 13, 15, and 18 were rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim(s) upon which they depend. Claims 15 and 18 have been canceled, rendering their rejection moot. Claims 1 and 24 have been amended such that the moiety Z is a group of formula (vi), (vii), (viii), or (ix). In view of the instant claim amendments, the rejection of claims 2, 8, 11, 13, 15, and 18 were rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 1, 3-5, 7, 9, 14, 19-20, and 24-25 were rejected under 35 U.S.C. 103 as being unpatentable over US 2013/0052130 A1 (previously cited on PTO-892; herein after referred to as "Davis") and WO 2017/089894 A1 (previously cited on PTO-892; herein after referred to as "Kim").
Claim 19 has been canceled, rendering its rejection moot. Independent claim 1 and 24 have also been amended, specifically with regard to the definition and corresponding structure of Z in Formula (I). In view of the instant claim amendments, the rejection of claims 1, 3-5, 7, 9, 14, 19-20, and 24-25 under 35 U.S.C. 103 as being unpatentable over Davis and Kim is withdrawn.
Double Patenting - Withdrawn
Claims 2, 15, and 18-19 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6-7, 9, 11, and 14-22 of copending Application No. 18/687,256 (reference application).
Claims 2, 15, and 18-19 have been canceled, rendering their rejection moot. As such, the rejection of claims 2, 15, and 18-19 on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 18/687,256 is withdrawn.
Claim Objections - New as Necessitated by Amendment
Claim 1 and 24 are objected to because of the following informalities: the claim recites redundant limitations. For claim 1, in the listing of Z groups (i.e., Z groups of formulas (vi)-(ix)), each dashed line is defined as representing a bond which is either present or absent (e.g., see Page 4 of claims) and at Page 5, Line 17 the dashed line is again defined as representing a bond which is either present or absent. For claim 24, in the listing of Z groups (i.e., Z groups of formulas (vi)-(ix)), each dashed line is defined as representing a bond which is either present or absent (e.g., see Pages 11-12 of claims) and at Page 13, Line 5 the dashed line is again defined as representing a bond which is either present or absent. Claim 24 further recites “a polymer comprising from 1 to 50 repeat of Formula (I)” (see Page 9 of claims), but should read “a polymer comprising from 1 to 50 repeats of Formula (I)” or “a polymer comprising from 1 to 50 repeat units of Formula (I)”. Appropriate correction is required.
Claim Rejections - 35 USC § 103 - New as Necessitated by Amendment
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.
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, 3-5, 7-9, 11, 13-14, 20, and 24-31 are rejected under 35 U.S.C. 103 as being unpatentable over US 2013/0052130 A1 (previously cited on PTO-892; herein after referred to as "Davis"), WO 2017/089894 A1 (previously cited on PTO-892; herein after referred to as "Kim"), and WO 2021/151984 A1 (herein after referred to as “Kraiem”).
With regard to claims 1, 3, and 24, Davis teaches general and "substantially pure" branched discrete polyethylene glycol (dPEG) constructs useful in attaching to a variety of biologically active groups, for example, preferential locators, as well as biologics like enzymes, for use in diagnostics, e.g. imaging, therapeutics, theranostics, and moieties specific for other applications (Paragraph 0003). These compositions can be made as part of dPEG containing templates to enhance the functionality and overall utility of the compositions, e.g., by incorporating both diagnostic and therapeutic functionality; also disclosed are methods for preparation of the branched construct intermediates that can be used to attach other compounds, like toxins or other drugs, to effect a certain action in the body, as well as the compositions themselves (Id.). The primary use and application of these conventional polymer PEGylation reagents in therapy or for in vivo imaging/ diagnostics is to increase the blood serum half-life of the protein or peptide or other biologically active agent of interest; as one viewing the art, this seems to be the sole purpose of PEGylation, the additional properties of protection from proteolysis, reduced toxicity and water solubility, are inherent with the PEG construct, polymeric or not (Paragraph 0006). More than one kind of biologically active group could be carried by the disclosed branched dPEG constructs as part of "A" giving multimeric "A" or bis- or higher heterospecificity; optionally more than one branched dPEG construct is attachable to one biologically active group, and this can occur randomly, yet characterizable or site specifically through design of the biologic (Paragraph 0021). Two exemplary alternating lysine-containing dPEG4 units are described, one of includes Fmoc-NH-dPEG4-(Lys)-dPEG4-(Lys)-dPEG4-
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(Lys)-dPEG4-(Lys)-OH (Page 238), which is shown below.
It is specifically noted that the structure above reads on a polymer of instant Formula (I) wherein Y is C=O, Q is T1O(CH2CH2O)sT2 wherein T1 and T2 are both be divalent ethylene, X is NH, Z comprises -AA-H, wherein the side chain is that of Lysine, x = 1, and s = 4. While it is noted that the dPEG4-(Lys) groups of the structure above are alternating, it is noted that Davis suggests that a linear arrangement of such groups (i.e., dPEG-active amino acid) can have a continuous arrangement as demonstrated by a similar exemplary dPEG-active amino acid composition utilizing tyrosine, shown below, wherein the terminal NH group of Tyr is covalently connected to the C=O that attaches the dPEG units.
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As such, from the exemplary structures of Davis, one of ordinary skill in the art would recognize that a polymeric structure comprising instant Formula (I) is suggested by Davis. It is further noted that Davis teaches that in one final product form of the invention, a chemically reactive moiety can be directly or indirectly attached to a biologically active group-that is, a group that performs a desired function/interaction in vivo, whether as a preferential locator (i.e., a targeting agent; e.g., an antibody or antibody fragment), a nanoparticle, an enzyme, or other substance (Paragraph 0021); wherein a chemically reactable group includes a group that is reactive or can be made reactive, such as a chemically reactive moiety or a chemically reactive moiety with a protective group (Paragraph 0022). “Preferential locator” often can be used largely interchangeably with ligand or "targeting group"; with respect to neoplastic tissue (cancer cells), a "preferential locator" (or "locator") specifically binds a marker produced by or associated with, for example, neoplastic tissue, antibodies and somatostatin congeners being representative such locators wherein, broadly, a "locator" includes a substance that preferentially concentrates at the tumor sites by binding with a marker (the cancer cell or a product of the cancer cell, for example) produced by or associated with neoplastic tissue or neoplasms (Paragraph 0088). As disclosed by Table 2 on Page 19, and as would be recognized by one having ordinary skill in the art, maleimide is an acceptable reactive moiety that can be utilized in the dPEG-containing constructs of Davis (see, for example, Page 206-207), wherein the maleimide may be covalently bound to either the Lysine side chain or any available, reactive amine group (i.e., -NR- group of
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Formula (I) of instant claim 1, wherein R is H) (shown below).
It is specifically noted that the terminal -OH group in the above structure corresponds to R” or E of instant Formulas (III) or (IV), respectively, and the maleimide can be used to covalently attach an antibody to constructs of the invention (i.e., maleimide covalently binds to an active agent and covalently binds to the polymeric structures of the invention (meeting the limitation of L that is a polymer-antibody linker covalently linking the antibody and the polymer of instant claim 1 Formulas (III) or (IV)), and/or each maleimide may conjugate two different active moieties (e.g., two different monoclonal antibody Fab’ fragments; exemplary antibody targets prostate-specific membrane antigen (PSMA) upregulated in prostate cancer) (see Example 5, Pages 238-239).
However, it is noted that while Davis suggests the use of linkers in constructs of the invention (see Paragraph 0047), the exemplary constructs most closely related to the instant invention do not explicitly demonstrate the use of a linker to attach a biologically active agent (i.e., branched linker L4 required to attach B and X’-Q’-Y’-R’ as required by instant claim 1 wherein Z is of formula (vi)). This deficiency is remedied by the combination of Kim and Kraiem.
Kim teaches antibody-drug conjugates comprising an antibody, a linker, and at least two active agents wherein the linker comprises a peptide sequence of a plurality of amino acids where at least two active agents are covalently coupled to the side chains of the amino acids (Abstract). At least two of the active agents may be coupled to the side chains of lysine (Page 2). Each active agent can be independently selected from chemotherapeutic agents and toxins (Page 11). An active agent may be covalently coupled to the side chain of an amino acid, termed a “linking amino acid”, wherein in certain preferred embodiments a linking amino acid may be selected from, for example, lysine, 5-hydroxylysine, 4-oxalysine, 4-thialysine, 4-selenalysine, 4-thiahomolysine, 5,5-dimethyllysine, 5,5-difluorolysine, trans-4-dehydrolysine, 2,6-diamino-4-hexynoic acid, cis-4-dehydrolysine, 6-N-methyllysine, diaminopimelic acid, ornithine, 3-methylornithine, α-methylornithine, citrulline, and homocitrulline (Pages 27-28). In some embodiments, the active agents may be coupled to the side chains of amino acids through one or more linkers, optionally including a cleavage group, wherein any or all of the linkers according to the invention may be branched linkers wherein (i) each branch of the linker terminates in an active agent (e.g., linked through a cleavage group), or (ii) wherein one or more branches of the linker terminate in an active agent (e.g., linked through a cleavage group) and one or more others comprise a polyethylene glycol moiety and do not include an active agent; a branched linker may comprise a branching unit, such that each active agent is coupled to the branching unit through a secondary linker and the branching unit is coupled to the peptide by a primary linker (see Page 39). Kim further provides an exemplary embodiment wherein biologically active agents (B) are attached via the Lysine side chain (see, for example, Page 44):
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It is noted that while the cleavable portion of linker corresponds to the formula below as defined at Pages 15-16 (wherein the cleavage group is covalently attached via -C(O)-NH-, wherein the NH group is the nitrogen atom of the side chain of a linking amino acid (e.g., lysine or ornithine)), Kim further teaches that alternative cleavage groups include valine-citrulline-p-aminobenzylcarbamate (VC-PABC) (Page 16).
Kraiem teaches, for example, an immunoconjugate represented by Formula (II), corresponding to Ab-(X-(Z)n)m wherein, Ab is an anti-Nectin4 antigen binding protein (e.g. an antibody); X is a linker which connects Ab and Z, e.g., the residue of a linker following covalent linkage to one or both of Ab and Z; and Z is a camptothecin analogue, optionally Z comprises a structure of Compounds 1 or 2 (exatecan or a SN-38 molecule); n is 1 or 2; and when n is 1, m is from among 1 to 8 (Page 43, Lines 3-20). In one embodiment, the linker moiety (X-Z) is or comprises the structure shown in Formula VIII (reproduced below), wherein (Y) is a spacer comprising (e.g., at its terminus) the residue of the reaction of a reactive group (R) with an amino acid residue, for example a free amino, hydroxyl, sulfhydryl or carboxyl group on the antibody (e.g., on the epsilon amino group of one or more lysine residues (i.e., the amine of the lysine side chain), the free carboxylic acid group of one or more glutamic acid or aspartic acid residues, or to the S atom of one or more cysteinyl residues) (Pages 62-63):
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Exemplary linkers, wherein the R group is maleimide, are further provided at Pages 63-64; notably one exemplary linker is that of Compound 7, reproduced below (see Page 64):
It is specifically noted that the linker structure above reads on a branched linker, said branched linker comprising, corresponding to instant formula (vi): L4 corresponding to Mal-Glu-(Val-Cit-PAB); a biologically active moiety B that is a exatecan; an A that is a direct bond; an X’ that is an NH; a Q’ that comprises T’2(OCH2CH2)7OT’1 wherein each of T’1 and T’2 are divalent ethylene (i.e., CH2CH2); a Y’ that is -O-; and a R’ that is CH3 (i.e., C1 hydrocarbyl). Furthermore, it is noted that, as presented above, Mal is an R group capable of reacting with an amino acid residue, for example a free amino, hydroxyl, sulfhydryl or carboxyl group on the antibody (e.g., on the epsilon amino group of one or more lysine residues (i.e., the amine of the lysine side chain, which corresponds to -AA-H of instant formula (vi)), the free carboxylic acid group of one or more glutamic acid or aspartic acid residues, or to the S atom of one or more cysteinyl residues).
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It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed that the invention of Davis could be modified based on the teachings of Kim and Kraiem. The invention of Davis reads on antibody-drug conjugates comprising a dPEG-reactive amino acid polymer (exemplary polymer shown below):
wherein the lysine repeats may be contiguous instead of alternating (as taught by Davis), which reads on the instantly claimed continuous repeats of instant Formula (I), wherein Y is C=O, Q is T1O(CH2CH2O)sT2 wherein T1 and T2 can both be divalent ethylene, X is NH, x = 1, s = 4, Z comprises the side chain of the amino acid Lysine (i.e., -AA-H), wherein the dPEG-reactive amino acid polymer can be linked directly to a biologically active agent B (e.g., an antibody, enzyme, nanoparticle, etc.) and additional agents (e.g., drugs that effect certain actions in the body) as suggested by Davis, wherein reactive amines may be used to attach maleimide groups that are covalently bound to the polymer and an antibody (i.e., is a polymer-antibody linker corresponding to L and used to attach Ab of instant Formulas (III) and (IV)) and wherein the dPEG-reactive amino acid polymer terminates in an -OH group (i.e., R” or E of instant Formula (III) or (IV), respectively, is -OH). One of ordinary skill in the art would recognize that a dPEG-reactive amino acid polymer core may be modified based on the teachings of Kim and Kraiem such that: a drug (e.g., chemotherapeutic agent or toxin) may be attached directly to an amino acid side chain (using, for example, an accessible amine on the side chain) via a branched linker (e.g., a branched linker terminating in a PEG group and a drug) as suggested by Kim, wherein such a branched linker can comprise the structure of Compound 7 of Kraiem (shown above) which reads on instant formula (vi) wherein L4 corresponds to Mal-Glu-(Val-Cit-PAB); the biologically active moiety B is a exatecan; A is a direct bond; X’ is an NH; Q’ comprises T’2(OCH2CH2)7OT’1 wherein each of T’1 and T’2 are divalent ethylene (i.e., CH2CH2); Y’ is -O-; and R’ is CH3 (i.e., C1 hydrocarbyl). It would have been obvious to combine the teachings of Davis, Kim, and Kraiem to arrive at the instantly claimed antibody-drug conjugate structure because Davis, Kim, and Kraiem all read on generally on conjugate constructs/platforms, including antibody-drug constructs, wherein Davis teaches dPEG-reactive amino acid polymers as the foundation for such conjugates wherein the dPEG constructs have increasing serum half-lives as the size and MW increase (Davis Paragraph 0009) and Davis suggests the attachment of antibodies and other active agents, wherein one of ordinary skill in the art would recognize that antibodies and drugs could both be conjugated to the platform of Davis, wherein the drugs (e.g., chemotherapeutic agents/toxins) can be attached to the reactive amino acid side chains with a branched linker terminating in a PEG group and a drug, as suggested by Kim, wherein such a branched linker could comprise the structure of Compound 7 of Kraiem wherein the resultant conjugate would reasonably be expected to be functional (i.e., therapeutic by way of biologically active antibodies, enzymes, nanoparticles, and/or therapeutic agents) and targetable via an antibody, wherein such conjugates would also reasonably be expected to have improved serum half-life, protection from proteolysis, reduced toxicity, and water solubility, as suggested by Davis owing to the dPEG-reactive amino acid core structure.
Response to Arguments - 35 USC § 103
Applicant’s arguments filed 07/22/2026 with respect to the rejection of claims 1, 3-5, 7-9, 11, 13-14, 20, and 24-25 under 35 USC § 103 have been considered, but are deemed not persuasive in view of the new grounds of rejection presented above.
More specifically, Applicant argues the following:
Davis does not address the production of ADCs at all, but rather Davis is directed to developing branched discrete PEG constructs (i.e., dPEG reagents) that can be attached to compounds of therapeutic or diagnostic significance to effect and control biodistribution and pharmacokinetics of those compounds; there is no indication in Davis that the disclosed dPEG reagents might be used as linkers between antibodies and drugs in the preparation of ADCs. Additionally, Davis does not contain all of the structural features of Formula (I) required by the instant claims.
Kim describes a laundry list of polymer cores for a variety of uses with no guidance for a person of ordinary skill in the art as to which particular polymer cores may be useful specifically as a linker group in an ADC. The only working example of Kim drawn to ADCs is that of example 21, wherein an anti-CD3 scFv is conjugated via polymeric linker to four octapeptide CCK8 moieties, wherein the polymer core “C” comprises a linear peptide chain comprising glycine, serine, and lysine residues wherein the CCK8 peptides are attached via lysine side chain residues; this structure differs from Formula (I) of the instant claims.
The combination of a backbone as instantly claimed (comprising alternating X-Q-Y moieties and amino acid moieties) and amino acid side chain Z of one of formulas (vi)-(ix) contributes to improved solubility and stability of the instantly claimed ADCs and allows for high drug-antibody ratios (DAR).
A person of ordinary skill in the art would not have known from the teachings of Davis and/or Kim that the polymer structures of instant Formula (I) would lead to an ADC having desirable physical and pharmacological properties, let alone an ADC with improved properties over the prior art of Kim.
In response to applicant's arguments against the references individually, 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). In the instant case, in view of the instant claim amendments, the new grounds of rejection above rely on the combination of Davis, Kim, and Kraiem to render obvious the instant ADCs and TDCs. Particularly, Davis is relied upon for its teaching of a dPEG-reactive amino acid polymer backbone/core structure, wherein Davis suggests that such structures may be conjugated to, for example, antibodies and/or other agents such as drugs in order to effect a specific action in the body, further wherein the dPEG-reactive amino acid polymers of the invention (alternating linear, contiguous linear, and/or branched constructs) improve serum half-life, protect against proteolysis, reduce toxicity, and are water soluble. Kim is relied upon for the teaching that active agents, such as chemotherapeutic agents/toxins, can be conjugated (e.g., via linkers including branched linkers terminating in the chemotherapeutic agent/toxin and a PEG moiety) using reactive amines of amino acid side chains (e.g., lysine, ornithine, citrulline, etc.). Newly added reference Kraiem is relied upon for an exemplary branched linker structure that terminates in a drug (i.e., camptothecin derivatives such as SN38 and/or exatecan) which can be conjugated to amino acid side chains via, for example, reactive amines. One of ordinary skill in the art would recognize that a dPEG-reactive amino acid polymer core may be modified based on the teachings of Kim and Kraiem such that: a drug (e.g., chemotherapeutic agent or toxin) may be attached directly to an amino acid side chain (using, for example, an accessible amine on the side chain) via a branched linker (e.g., a branched linker terminating in a PEG group and a drug) as suggested by Kim, wherein such a branched linker can comprise the structure of Compound 7 of Kraiem (shown above) which reads on instant formula (vi) wherein L4 corresponds to Mal-Glu-(Val-Cit-PAB); the biologically active moiety B is a exatecan; A is a direct bond; X’ is an NH; Q’ comprises T’2(OCH2CH2)7OT’1 wherein each of T’1 and T’2 are divalent ethylene (i.e., CH2CH2); Y’ is -O-; and R’ is CH3 (i.e., C1 hydrocarbyl). It would have been obvious to combine the teachings of Davis, Kim, and Kraiem to arrive at the instantly claimed antibody-drug conjugate structure because Davis, Kim, and Kraiem all read on generally on conjugate constructs/platforms, including antibody-drug constructs, wherein Davis teaches dPEG-reactive amino acid polymers as the foundation for such conjugates wherein the dPEG constructs have increasing serum half-lives as the size and MW increase (Davis Paragraph 0009) and Davis suggests the attachment of antibodies and other active agents, wherein one of ordinary skill in the art would recognize that antibodies and drugs could both be conjugated to the platform of Davis, wherein the drugs (e.g., chemotherapeutic agents/toxins) can be attached to the reactive amino acid side chains with a branched linker terminating in a PEG group and a drug, as suggested by Kim, wherein such a branched linker could comprise the structure of Compound 7 of Kraiem wherein the resultant conjugate would reasonably be expected to be functional (i.e., therapeutic by way of biologically active antibodies, enzymes, nanoparticles, and/or therapeutic agents) and targetable via an antibody, wherein such conjugates would also reasonably be expected to have improved serum half-life, protection from proteolysis, reduced toxicity, and water solubility, as suggested by Davis owing to the dPEG-reactive amino acid core structure. Furthermore, one of ordinary skill in the art would recognize that in a dPEG-reactive amino acid polymer of Davis, which can comprise multiple reactive amino acids, each reactive amino acid can subsequently be conjugated to an active agent/drug, and multiple dPEG-reactive amino acid polymers can be conjugated per antibody, which would reasonably be expected to drastically increase the DAR of resulting conjugates while preserving desirable properties attributable to the dPEG-active amino acid polymer core itself.
As such, the new grounds of rejection above are deemed proper and Applicant’s arguments are deemed not persuasive.
Double Patenting - Updated as Necessitated by Amendment
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 1, 3-5, 7-9, 11, 13-14, 20, and 24-25 stand as provisionally rejected, and new claims 26-31 are newly rejected, on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6-7, 9, 11, and 14-22 of copending Application No. 18/687,256 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
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Claim 1 of the reference application is drawn to an antibody-drug conjugate comprising: (i) an antibody or antigen-binding fragment thereof; (ii) a polymer comprising a repeat of Formula (II) or Formula (II’), both reproduced below, wherein the structural components are defined by the claim; and (iii) a polymer-antibody linker which is covalently bonded to both the antibody and the polymer.
It is specifically noted that from the structural definitions provided by claim 1: pS may be 0; QA may be a polymer -Y-Q-X- wherein Y is selected from C=O, C=NH, C=NRA and C=S, X is selected from O, NH, NRA and S, RA is C1-20 hydrocarbyl, and each Q is independently selected from -CH2(NMe(C=O)CH2)o-, -T1O(CH2CH2O)sT2- and -T1O(CH2CH2CH2O)sT2-, wherein T1 is selected from a divalent methylene, ethylene, propylene or butylene radical, T2 is selected from a divalent methylene, ethylene, propylene or butylene, o is an integer from 0 to 100, and s is an integer from 0 to 150; R is hydrogen or C1-20 hydrocarbyl; x is an integer from 1 to 6; and Z is independently selected from, for example, formulas (i)-(v) reproduced below, wherein the structural components of formulas (i)-(v) are defined by claim 1.
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Thus, when pS = 0, QA is a polymer -Y-Q-X-, and Z is a group of formulas (i)-(v), it is noted that both Formula (II) and (II’) of the reference application read directly on instant claim 1 Formula (I). Reference application claim 3 further limits claim 1 wherein pS = 0. Claims 6-7 each further limit claim 1 wherein, respectively, (i) each QA is a polymer of -Y-Q-X- and (ii) each Z is independently selected from a group of formulas (i)-(v), or a group of formulas (xvi)-(xviii), or a group of formulas (xxiv)-(xxx). Claim 9 further limits claim 1 regarding, for example, Z of formulas (ii)-(v) as shown below:
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It is noted that reference application formulas (xxvi)-(xxix) read directly on instant claim 1 formulas (vi)-(ix). Claim 11 further limits claim 9, wherein:
(I) each QA’ is a polymer -Y'-Q'-X'-, optionally wherein:
(a) Q' is selected from -T1’O(CH2CH2O)s’T2'- and -T1’O(CH2CH2CH2O)s’T2'-, X' is selected from O, NH, NRA' and S, and Y' is selected from O, NH, NRA' and S: or
(b) Q' is -CH2(NMe(C=O)CH2)o'-, X' is selected from -(C=O)-O-, -(C=O)-NH-,- (C=O)-NRA'-, and -(C=O)-S, and Y' is selected from O, NH, NRA' and S; and/or
(II) R' is selected from hydrogen and C1-6 alkyl, preferably wherein R' is hydrogen, methyl, ethyl or n-propyl.
Claim 14 further limits claim 1 wherein the -AA- groups comprised within the Z groups are further limited to specific amino acid side chains (e.g., 2,3-diaminopropionic acid, lysine, etc.). Claim 15 further limits claim 1 wherein the polymer-antibody linker is derived from maleimide, monobromomaleimide, vinyl sulfones, bis(sulfone)s, allenamides, dehydroalanine, alkenes, perfluoroaromatic species, sulfone reagents that are Julia-Kocienski like, N- hydroxysuccinamide-ester activated carboxylate species, aldehydes, ketones,hydroxylamines, alkynes and azides. Claim 16 further limits claim 1 wherein: (a) X is O or NH and Y is C=O; and/or (b) X' is O or NH and Y' is O or NH; and/or (c) XS is O or NH and YS is C=O; and/or (d) XS’ is O or NH and YS’ is O or NH. Claim 17 further limits claim 1 wherein:
(a) Q is -CH2CH2O(CH2CH2O)sCH2CH2- or -CH2CH2CH2O(CH2CH2O)sCH2CH2CH2-, preferably wherein s is from 1 to 100, more preferably wherein Q is
-CH2CH2O(CH2CH2O)sCH2CH2- and s is 3, 7, 11, 23 or 35; and/or
(b) Q' is -CH2CH2O(CH2CH2O)sCH2CH2- or -CH2CH2CH2O(CH2CH2O)sCH2CH2CH2-, preferably wherein s is from 1 to 100, more preferably wherein Q is
-CH2CH2O(CH2CH2O)sCH2CH2- and s is 3, 7, 11, 23 or 35.
Claim 18 further limits claim 1 wherein each biologically active moiety -B is the same or different, such that each B- H or B-OH is independently selected from small molecule drugs, peptides, proteins, peptide mimetics, antibodies, antigens, DNA, mRNA, small interfering RNA, small hairpin RNA, microRNA, PNA, foldamers, carbohydrates, carbohydrate derivatives, non- Lipinski molecules, synthetic peptides and synthetic oligonucleotides, preferably small molecule drugs. Claim 19 further limits claim 1, such that for each Z group of the recited formulas, the linker moieties (e.g., L1 of formula (ii)) are further defined. Claim 20 further limits claim 19 wherein Xl is NH, X2 is 0,X3 is 0, preferably wherein one of m and p is either 2 or 3, and the other is 0. Claim 21 further limits claim 1 such that the antibody-drug conjugate has a structure
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according to one of Formulas (III), (III’), (IV), or (IV’):
Claim 22 is drawn to a pharmaceutical composition comprising an antibody-drug conjugate according to claim 1 and a pharmaceutically acceptable excipient. Thus, the reference application, in view of the structural definitions provided in the claims, reads directly on instant claims 1, 3-5, 7-9, 11, 13-14, 20, and 24-31; specifically with regard to instant claims 24-25, it is noted that an antibody meets the instant limitation of a “targeting agent”.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments - Double Patenting
It is noted that no specific arguments have been presented regarding the above-listed rejection on the ground of nonstatutory double patenting; Applicant has requested that the double patenting rejection be held in abeyance until the claims of the present application are otherwise deemed to be in condition for allowance. As such, the above-listed rejection on the ground of nonstatutory double patenting is maintained.
Conclusion
Claims 1, 3-5, 7-9, 11, 13-14, 20, 22, and 24-31 are pending. Claim 22 is withdrawn. Claims 1, 3-5, 7-9, 11, 13-14, 20, 24-31 are rejected. 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 ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
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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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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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