DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-19 and 25-26) and Applicant’s election without comment of the below-listed species in the reply filed on 02/09/2026 is acknowledged.
Elected Species:
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Compound 306 as reproduced below:
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It is specifically noted that the individual structural components making up compound 306 are defined as presented below:
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Because Applicant did not distinctly and specifically point out any errors in the species election requirement, the election has been treated as an election without traverse (MPEP 818.03(a)).
Claim Status
Claims 8, 13, 15, 17, and 25 have been amended as requested in the preliminary amendment filed on 11/11/2025. Following the amendment, claims 1-26 are pending in the instant application.
Claims 20-24 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention in the Response filed 02/09/2026, there being no allowable generic or linking claim.
Claims 1-19 and 25-26 are under examination in the instant office action.
Priority
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.
Acknowledgment is made of applicant's claim for foreign priority based on an application filed with the European Patent Office (EPO) on January 13, 2020. It is noted, however, that applicant has not filed a certified copy of the EP20151551.7 application as required by 37 CFR 1.55.
Claims 1-19 and 25-26 have an effective filing date of January 13, 2021 corresponding to PCT/EP2021/050594, because no certified copy of the foreign priority document has been filed and therefore the claim to foreign priority has not been perfected.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/31/2022, 11/11/2025, and 02/09/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
The formatting throughout the specification is inconsistent in terms of line indentations. As an example, see Paragraph 0015. Appropriate correction is required.
There are various structures presented throughout the specification wherein the structures are not properly formatted; bonds are not in the correct places and/or structural elements within a single structure are overlapping. See, for example: structures (23) and (24) on Pages 29-30, respectively; structures (102), (103), and (104) on Page 54; structures (106), (107), (109), (110), and (111) on Page 55, etc. Appropriate correction is required.
The disclosure is further objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see Page 8). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is further objected to for the use of the terms, for example, DARPins, Affibodies, ZORBAX, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 15 and 18-19 are objected to because of the following informalities: claim 15 is drawn to a method of preparing an antibody-payload conjugate, wherein step (a) of the method yields a functionalized antibody. The structure of the functionalized antibody presented in the claim is designated as "(1')", but when referenced in claims 15 and 18-19 (at lines 15, 2, and 2, respectively) the structure is incorrectly referred to as "structure (1)". Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 26 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of a cancer that expresses an antigen with an antibody-payload conjugate comprising an antibody that binds to/targets said antigen expressed by the cancer, does not reasonably provide enablement for the treatment of any and all cancers with an antibody-payload conjugate comprising any antibody. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The Breadth of the Claims
Claim 26 is a method of treating cancer in a subject, comprising administering to the subject a pharmaceutical composition comprising the antibody-payload conjugate of instant claim 1. It is specifically noted that under broadest reasonable interpretation, in view of the instant specification wherein there are no special definitions regarding “cancer” or “antibody”, that the claim is drawn to the treatment of any cancer with an antibody-payload conjugation comprising any antibody. The full scope of this claim is therefore not enabled.
The State of the Prior Art/Level of Predictability in the Art
It is specifically noted that with regard to the current state of the art, and the state of the art as of the effective filing date of the instant application, there are no methods, pharmaceutically relevant compositions, or specific treatments that can effectively treat any and all cancers with any given antibody as instantly claimed.
There is a high level of unpredictability associated with cancer and as pertains to therapeutic approaches. Roy and Saikia (Indian Journal of Cancer, 2017, 53, 441-442) discloses that the transformation of a normal cell into a cancerous cell is probably not such a critical event in the genesis of cancer; rather it is the inability of immune cells of the body to identify and destroy the newly formed cancer cells when they are a few in numbers and the risk of cancer is multiplied in those persons, whose immune system is suppressed due to any factor including chronic stress, old age, chronic debilitating disease, previous use of chemotherapy, and abuse of drugs such as analgesics, antibiotics, and corticosteroids (Page 441, Column 1, Paragraph 3). The difficulty is that different cancers are caused by different things, so there is not one strategy that can prevent them; they also respond to different treatments, so not one kind of treatment can cure them all (Page 442, Column 1, Paragraph 1). Thus, Roy and Saikia highlight the unpredictability in the field regarding cancer; there are many different causes of cancer, and subsequently different cancers respond to different therapies, wherein there is no one universally effective treatment/cure (see entire document).
Cancer treatment is highly unpredictable. Even though the EGFR was identified in some cancers as a drug target, the in vitro (i.e., in a test tube) effectiveness of a drug in inhibiting the EGFR turned out to be a poor proxy for how effective that drug actually was in treating cancer in vivo (i.e., in the body). Numerous EGFR inhibitors that showed promising in vitro activity failed for a variety of reasons. These included poor pharmacokinetics due to poor absorption or rapid metabolism ([**2]or both), undesirable drug-drug interactions, drug toxicity due to drug binding onto healthy cells, drug toxicity due to binding onto other receptors, and metabolite toxicity. Some drug candidates were limited by one or more of these shortcomings, further underscoring the unpredictable nature of cancer treatment. OSI Pharmaceuticals , LLc, v. Apotex Inc, 939 F.3d 1375, 2019. The state of the art at the time of filing was such that the functionality of an anti-tumor antibody was dependent on both its action on the intended target and whether or not the modulation of said target had an effect on any particular cancer cell. Baxevanis (Expert Opinion: Drug Discovery, Vol. 3, No. 4, Pg. 441-452, 2008) teaches that, depending on the epitope against which an antibody is directed, antibody-antigen binding may neutralize circulating targets or cell surface receptors (Pg. 444, Column 1, Paragraph, first full). They teach that presently available monoclonal antibodies (mAbs) are directed against molecular targets that are expressed on tumor cells or play an important role in the tumor microenvironment (Pg. 444, Column 1, Paragraph, first full; Table 1). Table 1 lists currently available antibodies for use in clinical oncology and illustrates that each antibody has a specific target (Table 1, Column 2) and a specific set of cancers for which it has therapeutic utility (Table 1, Column 4). Taken together, the art does not recognize a single antibody that is an effective therapy against all tumors. To further illustrate this point, Baxevanis goes on to explain the functionality of the more commonly used therapeutic antibodies. Trastuzumab targets the receptor HER-2 (HER-2/neu) which is overexpressed in some breast cancers and so is a viable treatment for said breast cancers (Pg. 444, Column 2, Lines 19-24). The basis of this variability in treatment response is due to the fact that the growth inhibitory effect of anti-HER-2 is dependent on the extent of HER-2 overexpression (pg. 443, Column 1, Paragraph, first partial). Because only a portion of breast cancer patients overexpress HER-2 and respond to trastuzumab, the selection of suitable patients is important (Pg. 445, Column 1, Lines 13-15). Rituximab is an antibody against CD20 antigen, which is expressed on most B cells including B-cell lymphomas (Pg. 445, Column 1, Lines 36-38). Therefore, it is used to treat B-cell lymphomas (Pg. 444, Table 1). It has been used to treat patients with relapsed or refractory low-grade non-Hodgkin's lymphoma (a B-cell lymphoma) (Pg. 445, Column 1, Lines 41-50). In contrast to trastuzumab and rituximab, some therapeutic antibodies show efficacy in treating multiple cancers. This stems from the fact that their target antigen is associated with multiple cancers. Cetuximab is an anti-EGFR antibody (Pg. 445, Column 1, Lines 19-20). EGFR is overexpressed in many epithelial cell tumors (Pg. 445, Column 1, Lines 20-21). The association of EGFR overexpression with multiple cell types gives cetuximab a broader therapeutic applicability than trastuzumab (Pg. 444, Table 1) as it is used to treat both renal and head and neck cancers. As a final point, the art also recognizes that the function of the therapeutic antibody must correlate with an effect on its target conducive to tumor growth inhibition or tumor lysis, resulting in patient benefit. Anti-HER-2 antibodies, like Trastuzumab, disrupt HER-2 catalytic activity (Pg. 443, Column 1, Paragraph, first partial, Sentence, ultimate; Table 1, Column 3, (S) referring to decreased protein signaling (activity); and Pg. 444, Column 2, Lines 19-22). Cetuximab also inhibits its target’s activity as it prevents EGFR dimerization and subsequent activation via phosphorylation (Pg. 445, Column 1, Lines 23-25). Since both HER-2 and EGFR activity support growth of cancer cells in which they are overexpressed, their inhibition is therapeutic to patients. Rituximab causes tumor cell lysis by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) (Pg. 445, Column 1, Lines 38-39) and so its therapeutic benefit is provided by specifically inducing cancer cell death. Thus, the teachings of Baxevanis discussed above underline the requirement of a link between a therapeutic (e.g., inhibitory antibody) and its target and specific cancers to make therapy of said cancer predictable to one of ordinary skill in the art.
The Amount of Direction Provided by the Inventor/Existence of Working Examples
It is noted that Applicant lists exemplary antibodies commonly used in cancer therapeutics wherein said antibodies target cancer-related antigens (e.g., trastuzumab, rituximab, etc. at Paragraph 0075), and the Examples provided in the instant specification provide the synthesis and/or structures of various antibody-payload conjugates comprising such antibodies. However, it is noted that there are no working examples of antibody-payload conjugates effective treating cancer wherein the antibody-payload conjugate comprises an antibody specific to an antigen that is not expressed by the cancer.
Considering the factors above and the content of the instant specification, the specification does not reasonably provide enablement for the treatment of . As such, claim 26 is rejected under 35 USC § 112(a) as pertains to scope of enablement.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 11-13 and 15-19 are 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.
Regarding claim 11, the claim recites, with regard to R13, “groups optionally substituted and optionally interrupted by one or more heteroatoms” and “D connected to N, possibly via a spacer moiety”, which renders the claim indefinite because one of ordinary skill in the art could not reasonably ascertain the metes and bounds of the claim. Specifically, it is unclear as to: (i) how many times the group(s) may be substituted and interrupted with heteroatoms, further wherein it is unclear if the substitutions are with heteroatoms or with other structural groups, such that it is unclear how many and which kinds of substitutions and interruptions would still yield a functional antibody-payload conjugate with acceptable/desired properties and (ii) if R13 is D connected to N, whether the connection is required to be connected via a spacer moiety, or if a spacer moiety is merely an exemplary connection. Claim 12 is included in this rejection as it depends from claim 11.
Regarding claim 13, the claim recites, with regard to R4, “groups optionally substituted and optionally interrupted by one or more heteroatoms”, which renders the claim indefinite because one of ordinary skill in the art could not reasonably ascertain the metes and bounds of the claim. Specifically, it is unclear as to how many times the group(s) may be substituted and interrupted with heteroatoms, further wherein it is unclear if the substitutions are with heteroatoms or with other structural groups, such that it is unclear how many and which kinds of substitutions and interruptions would still yield a functional antibody-payload conjugate with acceptable/desired properties.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 17 recites the broad recitation “wherein Q comprises a terminal alkyne or a cyclooctyne moiety”, and the claim also recites “optionally selected from bicyclononyne (BCN), azadibenzocyclooctyne (DIBAC/DBCO), dibenzocyclooctyne (DIBO) or sulfonylated dibenzocyclooctyne (s-DIBO)” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-19 and 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/137456 A1 (herein after referred to as "Verkade") in view of US 8742076 (herein after referred to as "Cohen"), non-patent literature by Remon van Geel et. al. (Bioconjugate Chem., 2015, 26, 2233-2242; herein after referred to as "Geel"), and WO 2019/034764 A1 (herein after referred to as "Dimasi").
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Verkade discloses a method for increasing the therapeutic index of a bioconjugate and the bioconjugates for use in treatment, in particular cancer, wherein the bioconjugates according to the invention have a sulfamide linker comprising a group according to formula (1), reproduced below (Abstract).
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Verkade discloses that bioconjugates comprising a linker that comprises a group of formula (1) exhibits a greater therapeutic index compared to the same bioconjugate, i.e. the same biomolecule, the same target molecule (e.g. active substance) and the same biomolecule drug ratio, containing a linker without the group according to formula (1) present (Page 4, Lines 23-33). Linker-conjugates of the invention may be of formula (4a) or (4b), for example:
wherein a, b, c, d, e, g, and i may independently be 1 or 0; f is an integer in the range of 1 to 150; D is a target molecule (i.e., an active agent); Q1 is a reactive group capable of reacting with a functional group (F1) present on a biomolecule; Sp1, Sp2, Sp3, and Sp4 are all spacer units; and Z1 and Z2 are both connecting groups and may be O, C(O) or N(R1) wherein R1 may be H, alkyl, cycloalkyl, heteroaryalkyl, etc. or may be D, -[(Sp1)b(Z2)e(Sp4)iD], or -[(Sp2)c(Z1)d(Sp3)gQ1], wherein D is a further target molecule and the other structural components are as defined above (Pages 32-33). Thus, Verkade suggests bioconjugates comprising sulfamide linkers, wherein said bioconjugates may comprise two drugs and a single reactive moiety for conjugation to a biomolecule or may comprise a single drug and two reactive moieties for conjugation to a biomolecule(s). Verkade further specifies preferred spacer units of the invention, wherein said spacer units may independently be selected from: (i) Val-Cit-PABC, Val-Cit-PABC, or Fmoc-Val-Cit-PAB (Page 35, Lines 33-38); (ii) linear or branched C1-C200 alkylene groups, C2-C200 alkenylene groups, C2-C200 alkynylene groups, C3-C200 cycloalkylene groups, C5-C200 cycloalkenylene groups, C8-C200 cycloalkynylene groups, C7-C200 alkylarylene groups, C7-C200 arylalkylene groups, C8-C200 arylalkenylene groups and C9-C200 arylalkynylene groups which may be optionally substituted and optionally interrupted by one or more heteroatoms selected from the group of O, S and NR3; and/or (iii) PEG units, for example -(CH2CH2O)nCH2CH2- wherein n is in the range of 1 to 50, more preferably in the range of 1-4 (Page 37, Lines 25-31). Notably, Examples 32-42 disclose the preparation of various linker-conjugates including conjugate 124 (see Pages 73-74):
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In the above example, the N atom is a branching moiety that joins the sulfamide-containing linker and the two OR (i.e., drug-linker) groups. Thus, Verkade discloses bioconjugates with improved therapeutic indices, wherein said bioconjugates comprise a reactive moiety Q1 (a cyclooctyne moiety, corresponding to Z as instantly claimed), a sulfamide linker (corresponding to L1 and/or L2 wherein the linker is of the formula -OC(O)NHS(O)2NH), additional spacer/linker elements including PEG units, alkyl/cycloalkyl groups, and/or cleavable groups (e.g., Val-Cit-PABC), and a N serving as a branding moiety for the attachment of two separate Val-Cit-PAB-MMAE units as shown in conjugate 124 above. It is specifically noted that based on the structure disclosed in formula (4a) above, it would have been within the purview of one having ordinary skill in the art that one of the R groups from conjugate 124 could be replaced with linker/spacer units terminating in an additional reactive moiety (i.e., Q1) for conjugation to a biomolecule.
However, it is noted that Verkade does not teach: (i) DAR1 conjugates wherein a single drug is conjugated to a biomolecule at two separate sites via linkers; (ii) conjugates comprising the instantly claimed linkers/linker components wherein the components are organized as instantly claimed; nor (iii) antibodies suitable for conjugation after glycan trimming as required by instant claim 5. These deficiencies are remedied by Cohen, Geel, and Dimasi.
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Cohen discloses ADCs wherein one or more nemorubicin metabolites or analog drug moieties (D) are covalently attached by a linker (L) to an antibody (Ab) that binds to one or more tumor associated antigens or cell surface receptors wherein said ADCs are useful in the treatment of cancer (Abstract). One specific nemorubicin metabolite disclosed by Cohen includes PNU 159682, reproduced below, which has been shown to be remarkably more cytotoxic than nemorubicin and doxorubicin in vitro, and was effective in vivo tumor models (Columns 2-3).
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Exemplary ADCs of the invention are shown below (Pages 47 and 58, respectively):
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wherein it is noted that Yy of the first structure is defined as a divalent unit, such as PAB (para-aminobenzyloxycarbonyl) which links an amino acid unit to the drug moiety (D) when an amino acid unit is present and the group connecting the linker to the antibody comprises MEG units before the maleimide group (Column 91). Thus, Cohen discloses ADCs comp rising a Drug-Linker moiety corresponding to instantly claimed (L3)c-D wherein D is PNU 159682 and wherein c = 1 and L3 corresponds to -(L4)n-(L5)o-(L6)p-(L7)q-, further wherein: (i) n, o, p and q are individually 1; (ii) L4 is represented by -(W)k1-(A)d1-(B)e1-(A)f1-(B)g1-C(O)- wherein k1, d1, and f1 are each 0, B is -CH2CH2O-, and together the total of e1 and g1 is 2 (e.g., e1 =2/g1 = 0; e1 = 0/g1 = 2; or e1 = 1/g1 = 1); (iii) L5 is peptide linker Val-Cit; (iv) L6 is self-immolative linker PABC; and (v) L7 is aminoalkanoic acid spacer unit corresponding to
-N(Me)CH2CH2N(Me)C(O)-.
Geel teaches that the vast majority of ADCs in the clinic are based on conjugation of payload to naturally available amino acid side-chains (lysine, cysteine), leading to a stochastic distribution of drug-antibody ratio (DAR) between 0 and 8 (or even higher), and that it has been demonstrated that random conjugation has a negative impact on efficacy, and as a consequence the therapeutic index remains low (Page 2233, Column 1, First Paragraph). Two main strategies can enhance the therapeutic index of a given mAb-payload combination: (a) site-specific conjugation and (b) enhancing stability; site-specific conjugation is typically achieved by engineering of a specific amino acid (or sequence) into an antibody, serving as the anchor point for payload attachment (Page 2233). However, re-engineering of protein sequence and site optimization is a laborious exercise and expression yields may be compromised (typically ∼50% yield reduction for a cysteine-engineered mAb, while expression yields for genetic encoding of an unnatural amino acid typically reach 1 g/L maximally), which has a significant impact on the cost of goods of the ADC (Page 2233, Column 2, First Partial Paragraph). Additionally, it has been amply demonstrated that ADCs obtained by conjugation to cysteine side chains often display limited stability in circulation, leading to premature disconnection of the cytotoxic payload before the tumor site is reached (Id.). The authors report a unique and robust chemoenzymatic technology for efficient mAb-to-ADC conversion by anchoring a payload to the antibody’s glycan at precisely one azide, a unique anchor point is introduced for copper-free click conjugation with a payload wherein the versatility of this technology, termed GlycoConnect, is demonstrated across a range of different mAb isotypes and linker-payload combinations both in vitro and in vivo; seamless upscaling of GlycoConnect corroborated manufacturability, whereas the superiority of the native glycosylation site for conjugation was demonstrated through in vivo efficacy assessment of a series of ADCs based on glycosylation mutants (Pages 2233-2234). The authors disclose a chemoenzymatic ligation strategy to generate DAR2 ADCs, based on the strategy depicted in Figure 1 (Fig. 1A reproduced below): (1) trimming of all glycan isoforms (complex, hybrid, high-mannose) with an endoglycosidase, thereby liberating the core GlcNAc; (2) enzymatic transfer of a galactose residue harboring a reactivity-enhanced azide to reduce conjugation stoichiometry and incubation time; and (3)
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copper-free click conjugation with bicyclononyne (BCN), a cyclooctyne with minimal lipophilicity to reduce aggregation.
The advantage of glycan-remodeled ADCs versus randomly labeled ADCs becomes apparent in vivo; PDX mice with an average tumor size of 100 mm3 were intravenously injected with one of three different GlycoConnect ADCs (cleavable/noncleavable with maytansine or cleavable with MMAF) and compared to Kadcyla at 9 mg/kg (single dose bolus injection), followed by twice weekly tumor sizes measurements (Figure 5) (Page 2237, Column 1, First Full Paragraph). The results were as follows: (i) during the first week, all groups showed significant tumor shrinkage or even complete regression; (ii) after 1 week, tumor sizes gradually increased for mice treated with Kadcyla but not for any of the GlycoConnect ADCs; (iii) only after approximately 3 weeks, reappearance and regrowth of tumors became apparent for mice treated with trastuzumab-vc-PABA-MMAF, while both ADCs based on maytansine (cleavable or noncleavable) showed complete tumor regression for the whole length of the study (60 days) (Id.). This study thus clearly demonstrates the superiority of GlycoConnect conjugation technology versus a randomly
conjugated ADC based on the same components, wherein the latter observation becomes particularly interesting in view of the higher drug loading of Kadcyla (average DAR3.5) versus
GlycoConnect ADCs (DAR2; the modified N297 site of each heavy chain in the antibody is conjugated to a drug-linker) (Id.). The authors also note that no difference in blood clearance was observed (Page 2237, Column 1, Second Full Paragraph). Thus, the resulting ADCs were found to be homogeneous and highly hydrolytically stable, while displaying negligible aggregation, and benchmark in vitro and in vivo efficacy studies against the marketed product Kadcyla, based on the same antibody and payload components, generated strong biological data in favor of the GlycoConnect ADCs, despite the lower DAR (Page 2238, Column 2). The authors also highlight current efforts in their laboratory focusing on the development of linkers with increased potential to accommodate highly lipophilic payloads (duocarmycins, PBD dimers) versus the commonly employed ethylene glycol linkers, which show only limited usefulness in this regard (Id.) GlycoConnect technology is readily applicable to any off-the-shelf monoclonal antibody (turnaround in <1 week), while delivering site-specific, stable, and highly efficacious ADCs, and therefore GlycoConnect shows high promise as the next generation ADC generation technology for targeted therapy with improved therapeutic index (Id.). Thus, Geel discloses antibody modification at N297 such that each antibody heavy chain is modified to comprise, generally, GlcNAc(Fuc)GalNAc-Azide which may be reacted with a cyclooctyne group (e.g., BCN) to yield a Z group obtainable by a [4+2] cycloaddition or a 1,3-dipolar cycloaddition wherein Z further comprises a triazole; and linkers comprising cleavable dipeptide Val-Cit (corresponding to general structure (27) of instant claim 12 wherein R17 corresponds to CH2CH2CH2NHC(O)NH2), a PAB moiety, and/or PEG polymers.
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Dimasi teaches conjugates of formula (I), reproduced below, wherein Ab is a modified antibody having at least one free conjugation site on each heavy chain (Abstract; emphasis added).
Dimasi further discloses that it is thought that such ADCs which effectively have a drug antibody ratio (DAR) of 1 could offer significant advantages, including off-target toxicity and an enhanced therapeutic window by reducing the maximal effective dose requirement over ADCs consisting of heterogeneous mixtures with higher DARs (Pages 8-9). Examples 12-13 of Dimasi evaluate various ADCs (Pages 98-101) wherein the Examples compare: (i) HerC239i-10 ADC (DAR = 1.00; only singly conjugated compound 10 species) and HerC239i-11 ADC (DAR = 1.10; mix of unconjugated antibody, singly conjugated compound 11 species, and doubly conjugated compound 11 species) wherein the EC50 of HerC239i-10 ADC in HER2-expressing NCI-N87 cells was almost 50% lower than that of HerC239i-11 ADC whereas in HER2-negative MDA-MB-468 cells the EC50 of HerC239i-10 ADC was higher than that of HerC239i-11 ADC (see Page 100); and (ii) HerC239i-10 ADC and HerC239i-SG3249 (DAR = 2) wherein at the same dose of 0.3 mg/kg the activity of both ADCs was similar, with the HerC239i-10 ADC demonstrating slightly better activity, despite HerC239i-SG3249 having twice as many PBD warheads conjugated to the antibody (see Page 101, Figure 6). The invention provides pyrrolobenzodiazapines (PBDs, anti-tumor agents) and related PBD dimer conjugates wherein the PBDs are conjugated to antibodies that are modified so as to have at least one free conjugation site on each heavy chain and wherein the conjugation is via each N10 group of the PBD via a linker (Page 4, Lines 14-17). In formula (I) above, RLL2 and RLL1 are linkers connected to the antibody at different sites, wherein the linkers are independently selected from
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formula (IIIa’) and (IIIb’) (Page 8):
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It is further noted that GLL may include the structure of GL10 (i.e., BCN) shown below (see Page 55), which is derived from the GL structure below (see Page 53) wherein CBA is, for example, an antibody:
Additionally, QX may be selected from various dipeptide sequences recognized by cathepsin, including the CO-Val-Cit-NH dipeptide (see Pages 56-57). Thus, Dimasi discloses ADC structures wherein DAR = 1 (i.e., a single antibody wherein each heavy chain is conjugated via linker to a single anti-tumor agent), comprising the instantly claimed structural elements of: (i) a Z group obtainable by a 1,3-dipolar cycloaddition wherein Z further comprises a triazole (see GLL, i.e., BCN, shown above); and linkers comprising cleavable dipeptide Val-Cit (corresponding to general structure (27) of instant claim 12 wherein R17 corresponds to CH2CH2CH2NHC(O)NH2), a PABC derivative (corresponding to general structure (25) of instant claim 13 wherein R3 is hydrogen), and PEG polymers.
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the instant invention was filed to make an antibody-payload conjugate, wherein the antibody-payload conjugate generally comprises an antibody wherein two separate sites of the antibody are bound, via two reactive moieties of a single branched linker, to a single payload moiety (e.g., PNU 159682). One of ordinary skill in the art would have been motivated to modify the bioconjugates taught by Verkade wherein the biomolecule (e.g., antibody) is bound at two separate sites (as suggested by Dimasi) via a branched linker having two reactive moieties and a single drug moiety (as suggested by Cohen) wherein said sites for conjugation of the antibody are made available by glycan trimming at N297 of each heavy chain (as suggested by Geel) because such an antibody-payload conjugate would be expected to be useful in treating cancer, be serum stable, and be a DAR1 conjugate, therefore having an improved therapeutic index, as suggested by Verkade, Cohen, Dimasi, and Geel.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) Verkade discloses bioconjugates with improved therapeutic indices, wherein said bioconjugates comprise a branched linker wherein said branched linker comprises: (i) one or two reactive moieties Q1 (e.g., a cyclooctyne moiety, corresponding to Z as instantly claimed), a sulfamide linker (corresponding to L1 and/or L2 wherein the linker is of the formula -OC(O)NHS(O)2NH), additional spacer/linker elements required by instant L1, L2, and/or L3 including PEG units, alkyl/cycloalkyl groups, and/or cleavable groups (e.g., Val-Cit-PABC; corresponding to instant L5 and L6 portions of L3 in instant claims 12-13 wherein R17 corresponds to CH2CH2CH2NHC(O)NH2 and R3 is H), and a N serving as a branding moiety for the attachment of, for example, two separate Val-Cit-PAB-MMAE units, wherein one of said Val-Cit-PAB-MMAE may be replaced by a linker moiety terminating in a reactive moiety instead of a payload. It is specifically noted that based on the structure disclosed in formula (4a) above, it would have been within the purview of one having ordinary skill in the art that one of the R groups from conjugate 124 could be replaced with linker/spacer units terminating in an additional reactive moiety (i.e., Q1) for conjugation to a biomolecule.
(2) Cohen discloses Cohen discloses ADCs comprising a Drug-Linker moiety corresponding to instantly claimed (L3)c-D wherein D is PNU 159682 (a highly cytotoxic anti-tumor compound) and wherein c = 1 and L3 corresponds to -(L4)n-(L5)o-(L6)p-(L7)q-, further wherein: (i) n, o, p and q are individually 1; (ii) L4 is represented by -(W)k1-(A)d1-(B)e1-(A)f1-(B)g1-C(O)- wherein k1, d1, and f1 are each 0, B is -CH2CH2O-, and together the total of e1 and g1 is 2 (e.g., e1 =2/g1 = 0; e1 = 0/g1 = 2; or e1 = 1/g1 = 1); (iii) L5 is peptide linker Val-Cit; (iv) L6 is self-immolative linker PABC; and (v) L7 is aminoalkanoic acid spacer unit corresponding to -N(Me)CH2CH2N(Me)C(O)-.
(3) Geel discloses antibody modification at N297 such that each antibody heavy chain is modified to comprise, generally, GlcNAc(Fuc)GalNAc-Azide which may be reacted with a cyclooctyne group (e.g., BCN) to yield a Z group obtainable by a 1,3-dipolar cycloaddition wherein Z further comprises a triazole, and subsequent ADCs comprising linkers that include cleavable dipeptide Val-Cit (corresponding to instant L5 portion of L3 of instant claim 12 wherein R17 corresponds to CH2CH2CH2NHC(O)NH2), a PAB moiety, and/or PEG polymers.
(4) Dimasi discloses ADC structures wherein DAR = 1 (i.e., a single antibody wherein each heavy chain is conjugated via linker to a single anti-tumor agent), comprising the instantly claimed structural elements of: (i) a Z group obtainable by a [4+2] cycloaddition or a 1,3-dipolar cycloaddition wherein Z further comprises a triazole (see GLL, i.e., BCN, shown above); and linkers comprising cleavable dipeptide Val-Cit (corresponding to instant L5 portion of L3 of instant claim 12 wherein R17 corresponds to CH2CH2CH2NHC(O)NH2), a PABC derivative (corresponding to corresponding to instant L6 portion of L3 of instant claim 13 wherein R3 is H), and PEG polymers.
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Thus, to one of ordinary skill in the art, it would have been obvious to try and modify the bioconjugates taught by Verkade of structure (4a) reproduced below:
wherein Q1 is a cyclooctyne moiety (e.g., BCN, reactive with an azide to further comprise a triazole, corresponding to instant reactive moiety Z), g/d/c are each zero, a is 1, R1 is H, b/e are each 1, Sp1 is a PEG spacer having the formula -(CH2CH2O)nCH2CH2- wherein n is 2, Z2 corresponding to N(R1) and R1 is the formula -[(Sp2)c(Z1)d(Sp3)gQ1] (i.e., N of N(R1) serves as a branching moiety (BM)). Verkade indicates that the sulfamide linker component improves the therapeutic index of bioconjugates and suggests using more than one sulfamide component in a given linker (i.e., f > 1), and Dimasi suggests that the linker components used to conjugate a single payload to a single site on each of the heavy chains of an antibody may be the same (i.e., symmetrical/identical linkers for conjugation). Thus, it would be within the purview of one having ordinary skill in the art that the (Sp2)c(Z1)d(Sp3)gQ1 branch of the linker could correspond to the portion of structure (4a) above comprising the structural elements of Q1(Sp3)g(Z1)d(Sp2)c(O)aC(O)NHS(O)2N(R1)(Sp1)b wherein the components are as defined above. With regard to the (Sp4)i(D) portion of structure (4a), it is noted that Verdeke indicates that each spacer unit may individually be selected from, for example, PEG units, C1-C100 alkyl groups (optionally substituted and optionally interrupted by one or more heteroatoms, including O), and/or cleavable groups. Thus, in view of the possible Sp4 definitions of Verkade, and in view of
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the drug-linker structure(s) of Cohen reproduced below:
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it would have been within the purview of one having ordinary skill in the art to arrive at a linker-drug component (i.e., (Sp4)i(D)) corresponding to C(O)OCH2CH2OCH2CH2OC(O)-Val-Cit-PABC-N(Me)CH2CH2N(Me)C(O)-PNU 159682. Furthermore, the biomolecule (e.g., antibody) may be bound at two separate sites on a single antibody (as suggested by Dimasi) via such a linker-payload structure wherein said sites for conjugation of the antibody are made available by glycan trimming at N297 of each heavy chain according to the methods of Geel wherein the conjugation site at N297 of each heavy chain comprises GlcNAc(Fuc)GalNAc-Azide, wherein the azide may be reacted with a cyclooctyne group (e.g., BCN) to yield a Z group obtainable by a 1,3-dipolar cycloaddition, wherein Z further comprises a triazole, and the payload-antibody conjugate corresponds to structure (5) of instant claim 5. Thus, one of ordinary skill in the art could have arrived at the general antibody-payload structure corresponding to instant structure
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(1) wherein the structure of the linker-payload is:
and wherein the individual structural elements are defined as follows:
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One of ordinary skill in the art would be motivated, and would have a reasonable expectation of success, to try the combination of linkers, reactive groups, and drug in a branched linker format, to produce an antibody-payload conjugate useful in treating cancer that is serum stable and a DAR1 conjugate, wherein a DAR of 1 and the use of the cleavable, PEG, and sulfamide linker components would impart an improved therapeutic index, as suggested by Verkade, Cohen, Dimasi, and Geel. The rejection above reads on instant claims 1-14.
With regard to claims 15-19, it is noted that an antibody-payload conjugate according to structure (1’), wherein as defined by claim 15 the element V is a payload (e.g., PNU 159682), is rendered obvious by the combination of Verkade, Cohen, Geel, and Dimasi. Furthermore, it is specifically noted that Geel discloses the methods of producing ADCs using glycan trimming, wherein an antibody is modified at each of the N297 sites in the heavy chains, wherein the antibody is functionalized such that at the N297 site there is GlcNAc(Fuc)GalNAc-Azide which, via the azide group (corresponding to instant reactive group F), may be reacted with a linker-payload comprising a reactive cyclooctyne group (e.g., BCN; corresponding to instant reactive group Q) by a 1,3-dipolar cycloaddition (see entire document). Thus, it would have been prima facie obvious to one of ordinary skill in the art that the instantly claimed payload-linker structure of claim 15 (corresponding to structure (2), which is rendered obvious by the combination of references as cited above) could be reacted with a glycan-modified antibody of Geel according to the methods of Geel to achieve an antibody-payload conjugate of structure (1’) wherein V corresponds to a payload (D), ultimately yielding the instantly claimed structures (1) and (5) of instant claims 1 and 5. Furthermore, it is noted that methods and routed of ADC preparation were well understood and routine in the art at the time the invention was filed, as supported by Cohen. Specifically, Cohen indicates that ADCs may be prepared by several routes, employing organic chemistry reactions, conditions, and reagents known to those skilled in the art, including: (1) reaction of a nucleophilic group or an electrophilic group of an antibody with a bivalent linker reagent, to form antibody-linker intermediate (Ab-L), via a covalent bond, followed by reaction with an activated drug moiety reagent; and (2) reaction of a nucleophilic group or an electrophilic group of a drug moiety reagent with a linker reagent, to form drug-linker
reagent (D-L), via a covalent bond, followed by reaction with the nucleophilic group or an electrophilic group of an antibody; conjugation methods (1) and (2) may be employed
with a variety of antibodies, drug moieties, and linkers to prepare antibody-drug conjugates (Column 145, Lines 12-26). Thus, it would have also been within the purview of one having ordinary skill in the art that instead of reacting the antibody with a payload-linker (i.e., wherein instantly claimed group V is a payload) as detailed above, the antibody could first be reacted with the linker to yield an antibody-linker structure (i.e., wherein instantly claimed group V is a reactive group Q’) which can then be reacted with a payload. 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 claim 25, the antibody-payload conjugate of claim 1 is rendered obvious by Verkade, Cohen, and Dimasi. It is further noted that: (i) Cohen teaches pharmaceutical formulations of therapeutic antibody-drug conjugates (ADC)s are typically prepared for parenteral administration with a pharmaceutically acceptable parenteral vehicle and in a unit dosage injectable form wherein an ADC having the desired degree of purity is optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers, in the form of a lyophilized formulation or an aqueous solution (Column 148, Lines 40-56); and (ii) Dimasi teaches pharmaceutical compositions comprising an active ingredient (i.e., an ADC) and a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art (Page 31, Lines 24-27). 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 claim 26, the pharmaceutical composition of claim 25 is rendered obvious by Verkade, Cohen, Geel, and Dimasi. It is further noted that It is further noted that: (i) Verkade discloses that in one embodiment, the method, use, or linker for use according to the first aspect of the invention further comprises the administration of the bioconjugate according to the invention to a subject in need thereof, most suitably a cancer patient wherein the use of bioconjugates such as antibody-drug conjugates, is well-known in the field of cancer treatment, and the bioconjugates according to the invention are especially suited in this respect (Page 59, Lines 28-32); (ii) Cohen teaches that ADCs of the invention may be used to treat various diseases or disorders in a patient, such as cancer and autoimmune conditions including those characterized by the over-expression of a tumor-associated antigen, wherein exemplary conditions or disorders include benign or malignant tumors; leukemia and lymphoid malignancies, other disorders such as neuronal, glial, astrocytal, hypothalamic, glandular, macrophagal, epithelial, stromal, blastocoelic, inflammatory, angiogenic and immunologic disorders, wherein cancer types susceptible to ADC treatment include those which are characterized by the over-expression of certain tumor associated antigens or cell surface receptors (e.g., HER2) (Column 151, Lines 29-42); and (iii) Dimasi teaches that pharmaceutical compositions of the invention and for use in accordance with the invention comprising the conjugates and a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art (the precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous, or intravenous) (Page 31, Lines 24-30) wherein one such use of the conjugates of the invention is to treat proliferative disease and autoimmune disease wherein examples of proliferative conditions include, but are not limited to, benign, pre-malignant, and malignant cellular proliferation, including but not limited to, neoplasms and tumours (e.g., histocytoma, glioma, astrocyoma, osteoma), cancers (e.g. lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g. of connective tissues), and atherosclerosis. (Page 32, Lines 11-26). 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.
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.
Claims 14-19 and 25-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16, 19-20, and 27-28 of copending Application No. 17/812,153 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
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Reference application claim 1 is drawn to an antibody-payload conjugate having structure (1), reproduced below.
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Claims 2-5 of the reference application further limit the antibody-payload conjugate of claim 1 wherein, respectively: (i) Z can be obtained by a cycloaddition or a nucleophilic reaction, wherein the cycloaddition is a [4+2] cycloaddition or a 1,3-dipolar cycloaddition and the nucleophilic reaction is a Michael addition or a nucleophilic substitution; (ii) Z contains a triazole, a cyclohexene, a cyclohexadiene, an isoxazoline, an isoxazolidine, a pyrazoline, a piperazine, a thioether, an amide or an imide group; (iii) each of L1, L2 and L3, if present, are a chain of at least 2 atoms selected from C, N, O, S and P; and/or (iv) a and b are 1. Reference application claims 6-7 further limit the antibody-payload conjugate of claim 5 wherein, respectively: (i) L1 and L2 are the same; and/or (ii) each occurrence of Su is the same, each occurrence of Z is the same, each occurrence of G is the same, and each occurrence of e is the same. Claims 8-9 pf the reference application further limit the antibody-payload conjugate of claim 1 wherein, respectively: (i) branching moiety BM is selected from a carbon atom, a nitrogen atom, a phosphorus atom, a (hetero)aromatic ring, a (hetero)cycle or a polycyclic moiety; and/or (ii) L3 is -(L4)n(L5)o(L6)p(L7)q-, wherein L4, L5, L6 and L7 are linkers that together form linker L3 and n, o, p and q are individually 0 or 1. Reference application claim 10 further limits claim 9 wherein:
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Claims 11-12 of the reference application further limit claim 10 wherein, respectively, L5 is represented by general structure (27):
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and/or L6 is a PABC derivative according to structure (25):
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Reference application claim 13 further limits claim 1 wherein D is a cytotoxin selected from PBD dimers, indolinobenzodiazepine dimers (IGN), enediynes, PNU159,682, duocarmycin dimers, amanitin, and auristatins. Claim 14of the reference application is drawn to a method of preparing an antibody-payload conjugate, comprising the steps of (a) reacting a compound having structure (2) containing at least two reactive groups Q with an antibody having structure (3), which is symmetrically functionalized with two reactive groups F:
to obtain a functionalized antibody according to structure (1):
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and (b) in the case V = Q’, reacting reactive group Q’ with a payload containing a reactive group F’ to obtain the antibody-payload conjugate wherein V is the payload D. Reference application claims 15-16 and 19-20 further limit the method of claim 14 wherein, respectively: (i) the reaction is a cycloaddition or a nucleophilic reaction, wherein the cycloaddition is a [4+2] cycloaddition or a 1,3-dipolar cycloaddition and the nucleophilic reaction is a Michael addition or a nucleophilic substitution; (ii) Q comprises a terminal alkyne or a cyclooctyne moiety selected from bicyclononyne (BCN), azadibenzocyclooctyne (DIBAC/DBCO), dibenzocyclooctyne (DIBO), and sulfonylated dibenzocyclooctyne (s-DIBO); (iii) in step (a) a functionalized antibody according to structure (1) is obtained wherein D is the payload, and step (b) is not performed; and/or (iv) in step (a) a functionalized antibody according to structure (1) is obtained wherein D is a reactive group Q, and step (b) is performed. Claim 27 of the reference application is drawn to a pharmaceutical composition comprising the antibody-payload conjugate according to claim 1 and a pharmaceutically acceptable carrier. Reference application claim 28 is drawn to a method of treating cancer in a subject, comprising administering to the subject the pharmaceutical composition according to claim 27, wherein the cancer is an antigen expressing cancer, and the antibody-payload conjugate specifically binds to a cancer antigen expressed by the antigen expressing cancer. Thus, claims 1-16, 19-20, and 27-28 read directly on instant claims 1-19 and 25-26, wherein the antibody-payload conjugate, pharmaceutical composition, method of preparing, and method of treatment thereof of the reference application are species of the instantly claimed antibody-payload conjugate, pharmaceutical composition, method of preparing, and method of treatment thereof.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1-26 are pending. Claims 20-24 are withdrawn. Claims 1-19 and 25-26 are rejected. No claims are allowed.
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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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