Bifunctional Folate Receptor Binding Compounds

§102 §103 §112 §DP

DETAILED ACTION Notice of Pre-AIA or AIA Status The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Priority The instant application, filed 07/06/2023, is the national stage entry of PCT/US2022/011857, filed 01/10/2022, which claims priority to U.S. Provisional Patent Application Nos. 63/135,510 and 63/214,774, filed on 01/08/2021 and 06/24/2021, respectively. Receipt is acknowledged of certified copies of papers required by 37 CFR § 1.55. Information Disclosure Statement The Information Disclosure Statements filed on 07/06/2023 and 06/05/2026, are acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the Information Disclosure Statements have been considered. Application History Claims 1-118 were originally presented on 07/06/2023. Applicant’s preliminary amendments to the claims also filed on 07/06/2023 were acknowledged and entered. Claims 1, 6, 11, 13, 18, 20-22, 24, 32, 34, 40-41, 51, 53-58, 62, 73-76, 79, 81, 84-85, 88, 94, 99, 105 and 115 were pending and were subject to a Restriction/Election requirement mailed on 03/06/2026. Applicant’s response to the Restriction/Election requirement was received on 06/05/2026. In the response, Applicant amended claims 40, 51, and 84, and cancelled claims 2-5, 7-10, 12, 14-17, 19, 23, 25-31, 33, 35-39, 42-50, 52, 59-61, 63-72, 77-78, 80, 82-83, 86-87, 89-93, 95-98, 100-104, 106-114, and 116-118 without prejudice or disclaimer. Applicant’s amendments to the claims are acknowledged and entered. Accordingly, claims 1, 6, 11, 13, 18, 20-22, 24, 32, 34, 40, 41, 51, 53, 54-58, 62, 73-76, 79, 81, 84-85, 88, 94, 99, 105, and 115 were pending and under consideration. Election/Restriction Claims 1, 6, 11, 13, 18, 20-22, 24, 32, 34, 40, 41, 51, 53, 54-58, 62, 73-76, 79, 81, 84-85, 88, 94, 99, 105, and 115 are subject to the Restriction/Election requirement mailed 03/06/2026. Applicant’s elections to Group I and to the compound species of the invention “without traverse” in the response received 06/05/2026 are acknowledged. See elections below from the Restriction/Election Response received 06/05/2026 at 17: PNG media_image1.png 253 586 media_image1.png Greyscale Restriction/Election Response received 06/05/2026 at 17. Regarding the election of species requirement, discussed in Restriction/Election Response received 06/05/2026 at 17-19, Applicant elected for examination the compound constructed in the manner as Compound I-68, but wherein the Y variable, representing the “moiety of interest”, is specific polypeptide from table A, as well as a slightly different linker L. So that the record is clear, Compound I-68, which appears in the Specification at 78, incorporates a different “moiety of interest” Y, as well as a slightly different “linker” L, as indicated below: PNG media_image2.png 508 921 media_image2.png Greyscale The above compound I-68 is not the elected compound Applicant’s elected compound is instead prepared by assembling the compound by attaching cetuximab at the following location: PNG media_image3.png 292 1049 media_image3.png Greyscale To understand why cetuximab is the elected moiety of interest, see Restriction/Election Response received 06/05/2026 at 18-19, listing as the elected Y variable the polypeptide defined by SEQ ID NOs 1 and 2, and Specification at 64, paragraph [0234] (stating that SEQ ID NOs 1 and 2 correspond to “cetuximab, CAS number 205923-56-4”). Cetuximab, which is marketed as ERBITUX, is a “monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR)”. See, e.g., ERBITUX Label1 at 13. As the examiner understands, Applicant’s elected compound has the following structure: PNG media_image4.png 235 1104 media_image4.png Greyscale However, because this compound was not exemplified in the Specification, its exact chemical structure is unclear. While the Specification provides prophetic examples of measuring EGFR levels in Examples 49 and 50, Specification at 210-211, neither the chemical structure nor data from these compounds were provided. The Specification instead exemplifies constructing a similar compound from a folate receptor ligand linked to an “in house” omalizumab anti-IgE antibody (chemical structure not provided), in Example 57, Specification at 216. As with the omalizumab example, for Applicant’s elected compound, it is not exactly clear if the connection to the antibody is made at the N or C terminus of the antibody, or at some specific residue such as a cysteine or a lysine. Applicant states in its remarks at 19, that “Applicant believes that claims 1, 11, 13, 18, 20, 22, 24, 32, 55, 56, 58, 62, 74, 76, 81, 84, 85, 88, 94, 99, 105, 115 read on the elected species.” The examiner agrees (but see section regarding claim 55 and 112(b)) and thanks Applicant for providing the variables that recite the elected species compound within the various claims. For clarity, in providing the variables on page 18 of the remarks, Applicant states that R1 for formula (1) is OH. This in fact corresponds to the oxo-group on the left side of the above elected compound. Given the extensive lactam-lactim tautomerism of quinazolinones, the variables provided are correct. See, e.g., Mahato 20112 at 2 (showing lactam-lactim tautomerism of 2-methyl-4(3H)-quinazolinone, which is the same quinazolinone of the elected compound): PNG media_image5.png 230 468 media_image5.png Greyscale Mahato 2011 at 2. If the elected species is not anticipated by or obvious over the prior art, the examiner will extend the search and examination to a non-elected species or group of species that falls within the scope of a proper Markush grouping that includes the elected species. The restriction and election of species requirements are deemed proper and are therefore made FINAL. The following page provides a table listing the variables that recite the elected species compound within the various claims, compiled from Restriction/Election Response received 06/05/2026 at 18. Variables that recite elected species compound Variables Assignment Formula I structure PNG media_image6.png 192 338 media_image6.png Greyscale A, R1, R2, A1, A2, R3 PNG media_image7.png 126 137 media_image7.png Greyscale Rl is OH; R2 is CH3 (optionally substituted alkyl); Al is -CH=CH- (-CR3=CR3-, where each R3 is H); A2 is CH (CR3, where R3 is H) T1 T1 is methylene ((C1-C3)alkylene) Z1, R23 Zl is -NR23-, where R23 forms a 5 or 6 membered cycle together with an atom of the B-ring B B is 1,4-phenyl (optionally substituted aryl) Z2 Z2 is -C(=O)NH- (optionally substituted amide) T3 T3 is absent Z3 Z3 is carboxyl T4 T4 is ethylene (optionally substituted (C1-C6)alkylene) Z4 amide PNG media_image8.png 80 83 media_image8.png Greyscale L PNG media_image9.png 81 289 media_image9.png Greyscale n 1 Y cetuximab Status of Claims Claims 1, 6, 11, 13, 18, 20-22, 24, 32, 34, 40, 41, 51, 53, 54-58, 62, 73-76, 79, 81, 84-85, 88, 94, 99, 105, and 115 are pending. Claims 6, 21, 34, 40, 41, 51, 53, 54, 57, 75, 79, 105 and 115 are withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species. Therefore, claims 1, 11, 13, 18, 20, 22, 24, 32, 55, 56, 58, 62, 74, 76, 81, 84, 85, 88, 94, and 99 read on an elected invention and species and are therefore under consideration in the instant application. Claim Objections Claims 74 objected to because of the following informalities: Regarding claim 74, references to figures or tables in the claims are appropriate only in certain circumstances. See MPEP 2173.05(s). In this case, there is no reason for the compounds presently claimed to reside in the Specification and not the claims themselves. The claimed species of the invention should therefore be recited directly within the claims and not incorporated by reference to tables in the Specification. Appropriate correction is required. Claim Rejections - 35 USC § 112(b) 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 22, 55, and 74 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 22, it depends on claim 1 and recites the variable R22 in the configurations of “-Z2CH(-T3-Z3)T4Z4- of formula (I)”. One of ordinary skill in the art would not reasonably understand the metes and the bounds of the claim because the variable R22 is not defined in claim 1 or claim 22. Therefore, claim 22 is rejected as indefinite. Regarding claim 55, it depends on claim 1 and recites the variables A3 and R25. One of ordinary skill in the art would not reasonably understand the metes and the bounds of the claim because the variables A3 and R25 are not defined in claim 1 or claim 55. Therefore, claim 55 is rejected as indefinite. In the interests of compact prosecution, the examiner will assume that the variable A3 is the variable A1 of claim 1, which is consistent with Applicant stating that the elected species compound reads on claim 55. Regarding claim 74, it depends on claim 1 and recites that “the compound comprises a cell surface folate receptor ligand of one of the structures of Tables 1 or 2”. See MPEP 2173.05(s). Where possible, claims are to be complete in themselves. Only in exceptional circumstances is incorporation by reference permitted. Here, there are no exceptional circumstances, and failing to recite the claimed “cell surface folate receptor ligand” from Tables 1 or 2 directly within the claim raises uncertainty as to which “cell surface folate receptor ligand” is in fact incorporated into the presently claimed compounds. Accordingly, claim 74 is rejected as indefinite. Improper Markush Grouping Claims 1, 11, 13, 18, 20, 22, 24, 32, 55, 56, 58, 62, 74, 76, 81, 84, 85, 88, 94, and 99 rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117. The Markush grouping of a compound of formula (I) is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: First, formula (I) as defined in claim 1 encompasses at least nine distinct chemical scaffolds due to the options for the A1 and A2 variables. However, in fact, these scaffolds diverge into many more distinct chemical scaffolds represented by the connection of the variables A-T¹-Z¹-B-Z2-C(T3-Z3)-T4-Z4-, which the Specification appears to define as a “cell surface folate receptor ligand”. For the multiple distinct chemical scaffolds, the only fixed portion embraced by all the alternatives is a fused pyrimidine-derivative (left side of the A variable), and T1, which represents “an optionally substituted (C1-C3)alkylene”. Even if the permitted, completely unbounded optional substitution is set aside, these fixed portions represent just a small portion of the chemical structures of the many, if not infinite number of compounds embraced by the claims. Taken as a whole, when the compounds are assembled by connecting a “cell surface folate receptor ligand”, to a linker L, which has infinite breadth, to any moiety of interest, the compounds do not represent chemicals from the same recognized physical or chemical class or to the same art-recognized class. MPEP 2117 gives a simple example where single structural similarity is established with analogy to a fastener mechanism, which may include a buckle, or a loop. In that case, “a review of the prior art would establish that it was well known that each member could be substituted for each other with the expectation that the intended result (repositionable and refastenable) would occur.” In this case, a review of the prior art did not establish that all members of this expansive Markush grouping were “well known” to be interchangeable. For example, considering just the “cell surface folate receptor ligand”, based upon its name alone, it functions like folate, which binds to folate receptors in cells. Folate has the following chemical structure: PNG media_image10.png 243 709 media_image10.png Greyscale Folate Folate receptors are known to be highly expressed in some biological targets, such as cancer cells. As such, certain variants of folate were known and used in chemotherapies, like compounds 75 - 76 of Marsham 19993, shown below. However, a review of the prior art fails to establish that the immense variety of “cell surface folate receptor ligand[s]” permitted by the claimed structures, were known and functionally equivalent interchangeable folate receptor ligands: PNG media_image11.png 373 454 media_image11.png Greyscale PNG media_image12.png 238 1207 media_image12.png Greyscale See Marsham 1999 at 2122 and 2114 for the above structures and table. Moreover, “single structural similarity” and a common use require assessing the compounds as a whole. The use of these compounds is dictated by the “moiety of interest”, Y. However, because the moiety of interest is never fully defined in the Specification, see Specification at 55, its plain and ordinary meaning means that these compounds can anything “of interest”. Some of the compounds represent active pharmaceutical ingredients (APIs), and their “use” would be the indication listed on a drug label. Other compounds represent simple synthetic intermediates. Others represent probes used to tag targets that have folate receptors, such as those wherein the moiety of interest is a fluorophore. Therefore, a review of the prior art fails to establish “single structural similarity”, and the Specification itself fails to establish a common use for all of the alternatives. For the second prong of the analysis, “single structural similarity” and a common use can be established from a substantial structural feature and a common use that flows from the substantial structural feature. As discussed above, for the multiple distinct chemical scaffolds, the only fixed portion embraced by all the alternatives is a fused pyrimidine-derivative (left side of the A variable), and T1, which represents “an optionally substituted (C1-C3)alkylene”. Even if the permitted optional substitution is set aside, these fixed portions represent just a small portion of the chemical structures of the many, if not infinite number of compounds embraced by the claims. For this prong to be satisfied, the examiner has to find that these small, fixed portions shared by all the alternatives is “substantial”, and that common use flows from that feature. Looking at the data applicant proffered, a single folate binding assay was reported. The compound utilized was compound I-21, structure shown in specification at 174, assay at 212. PNG media_image13.png 238 722 media_image13.png Greyscale Compound I-21 incorporates folate (see structure provided on the prior page), and as a result, it binds folate receptors. Folate has a fused pyrimidine-derivative, and a T1 variable as CH2. From this single data point, the examiner has to consider whether all alternative compounds constructed in the manner explicitly permitted by the claims even bind folate receptors, before assessing whether the moiety of interest Y establishes some sort of common use. Nothing in the Specification suggests that they do. Some of the A-T1 linkers explicitly encompassed by the claims are provided here: PNG media_image14.png 218 325 media_image14.png Greyscale , PNG media_image15.png 223 321 media_image15.png Greyscale , and PNG media_image16.png 221 324 media_image16.png Greyscale . Therefore, nowhere in the record has it been established that the variety of compounds included within the explicit scope of the claims are recognized by the art as being functionally equivalent, nor that common use flows from the relatively small, fused pyrimidine-derivative, and T1 variable. Accordingly, the Markush grouping instantly recited lacks a “single structural similarity” and a common use. To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use. The examiner recommends amending the claims and basing the Markush grouping upon the structure of the elected species compound with alternatives that share a single structural similarity as well as a common use. PNG media_image4.png 235 1104 media_image4.png Greyscale Elected species compound Claim Rejections - 35 USC § 102 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. Claims 1, 11, 13, 18, 20, 22, 24, 32, 55, 56, 58, 62, 74, 76, 81, 84, 85, 88, 94, and 99 Anticipated by US’902 Claim(s) 1, 11, 13, 18, 20, 22, 24, 32, 55, 56, 58, 62, 74, 76, 81, 84, 85, 88, 94, and 99 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US’343.4 US’343 discloses compounds L-8 and L-9 at col. 59, shown below: PNG media_image17.png 248 880 media_image17.png Greyscale Compounds L-8 and L-9 correspond to a compound of the instant formula (I) wherein the moiety of interest Y is “a chemoselective ligation group or a precursor thereof”. To confirm, see Specification at 55, paragraph 0185, and at 59 (listing azide); see also, Specification at 41 (discussing that the claimed linkers can be anything “that covalently connects two or more moieties or compounds, such as ligands and other moieties of interest.”). See also, US’343 at cols. 162-164 (preparation of Ligand-Fluorescent Substance FA-Cy5, disclosing the compound designated FA-Cy5): PNG media_image18.png 407 636 media_image18.png Greyscale In above compound designated FA-Cy5, the “moiety of interest” is a fluorophore. See also, US’343 at col 148, compound 6, wherein the “moiety of interest” is the chemotherapy agent monomethyl auristatin F (“MMAF”): PNG media_image19.png 269 1106 media_image19.png Greyscale Accordingly, claims 1, 11, 13, 18, 20, 22, 24, 32, 55, 56, 58, 62, and 74 (see 3rd ligand of Table 1, Specification at 36) are anticipated by at least compounds L-8, L-9, FA-Cy5, and 6 of US’343. To the extent that Applicant may argue that these compounds do not anticipate the claims because of its provisos recited in claim 1, that position would be incorrect for at least four reasons: 1) Applicant chose to recite provisos in claim 1 that are optional due to the “at least one of the following applies” qualifier. To explain, under one reasonable interpretation of the claims, proviso 1 applies, and the others do not. Under another reasonable interpretation of the claims, proviso 2 applies, and the others do not. The same applies to the remaining provisos. So long as only one proviso applies, they are optional within the context of the claims. 2) The linkers in US’343 are “non-cleavable” in the blood. See US’343 at col. 4, lines 40-50 (“Accordingly, the present invention provides a compound comprising a β-galactoside introduced self-immolative linker which is very stable in the blood and releases the drug only to the target cancer cell. This self-immolative group improves physicochemical properties of the conjugates, provided easier preparation, and overcomes limitations of existing β-glucuronide and β-galactoside as described up to now, and in particular, provides a compound comprising a self-immolative linker having an excellent universal use which can be applied to the drug which was difficult with β-glucuronide.”). Further, the compounds permit Y as an “Extracellular target-binding moiety”, such as MMAF, or antibodies, as discussed below. 3) Provisos 3 and 4 still permit Z1 to be -NR23-. 4) Applicant chose to permit endless “optional substitution” for all of its compound claims. This endless optional substitution is particularly relevant to the discussion below of folate receptor ligand-antibody-drug conjugates, which in fact anticipate the instant claims because the instant linkers may be optionally substituted with another linker to a drug. Regarding claims 76, 81, 84, 85, 88, 94, and 99, first, see US’343 at col. 1 et seq, BACKGROUND ART section. The second paragraph of the background discusses antibody drug conjugates, which were commonly referred to as ADCs. The second paragraph of the background states that ordinary chemists commonly prepared these drugs by linking a thiol of cystine or amino group of lysine of the antibody to the drug. See also, US’343 at FIG. 9, providing an example of such a connection. Now, see US’343 at col. 25, stating that for the compound of the invention, “[i]t is preferable that the antibody is selected from the group consisting of the following, but is not limited thereto: … Cetuximab….”. See also, US’343 at cols. 185-186 (discussing Test Example 3, and the Ligand-Drug conjugate to a folate receptor, and cols. 186-187 (discussing Preparation of Protein-drug Conjugates), wherein the monoclonal antibody “Herceptin substituted with thiol group at a particular position … to prepare [the drug conjugate]”. See also, US’343 at col. 194, claim 11, which depends upon claims 10, 9, and 1, and recites that the “antibody is selected from the group consisting of … Cetuximab”. Claim 9 explains that the claim term “an antibody” is “the proteins” of claim 1. Claim 1 appears at cols. 188-190. Col. 190 states that the variables “B and B’ are each independently a ligand or a protein …”. The key phrase is that B and B’ are each independently a ligand or a protein. It follows from claims 9-11, that the protein is an antibody is selected from the group consisting of … Cetuximab. The “ligand” exemplified throughout US’343 was a folate receptor ligand. Accordingly, claim 1 teaches a folate receptor ligand-antibody-drug conjugate: PNG media_image20.png 338 715 media_image20.png Greyscale Reviewing the Specification of US’343, it teaches how to make such compounds as well. First, see US’343 at col. 187, which discusses how to prepare Protein-Drug conjugates, or ADCs. The ADCs exemplified were prepared from compounds 17 and 18. Reviewing, for example, how compound 17 was prepared, see US’343 at col. 173, wherein the “drug” is clicked at azide (standard click reaction) to a ligand with a free butylamine ligand. Subsequently, the remaining linker and U1 groups are added at the free butylamine ligand, as shown below: PNG media_image21.png 163 233 media_image21.png Greyscale PNG media_image22.png 170 430 media_image22.png Greyscale PNG media_image23.png 310 476 media_image23.png Greyscale US’343 at col. 173. Reviewing the folate ligand-drug conjugates like compound 6 discussed above, these compounds also have a free butylamine ligand. See, e.g., preparation of compound 6, col. 148, annotated below: PNG media_image24.png 273 1130 media_image24.png Greyscale The free butylamine is amenable to the same reaction used to prepare compound 17 and then the ADC discussed in US’343 at col. 187. Following the process results in a folate ligand-antibody-drug conjugate linked to a thiol of cystine or amino group of lysine of the antibody which reads on claims 76, 81, 84, 85 (X is not folic acid, because if it were, it would require ester linkage), 88, 94, and 99. Accordingly, claims 76, 81, 84, 85, 88, 94, and 99 are also anticipated by US’343. Claims 1, 11, 18, 20, 24, 32, 55, 56, 62, 76, 81, 84, 88, 94, and 99 Anticipated by CN’676 Claim(s) 1, 11, 18, 20, 24, 32, 55, 56, 62, 76, 81, 84, 88, 94, and 99 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by CN’676.5 CN’676 Translation at pdf page 2, claim 1, teaches a “bispecific dimer” of the following formula PNG media_image25.png 60 563 media_image25.png Greyscale wherein A1 is an antibody and A2 targets folate receptors. L1 and L2 variables corresponded to linkers known in the art. Alkyl and oxyethylene linkers were exemplified throughout the claims and structures of CN’676. See, e.g., CN’676 Translation at pdf page 2, claim 4, teaching simple alkyl linkers like PNG media_image26.png 94 161 media_image26.png Greyscale for L1 and oxyethylene linkers like PNG media_image27.png 124 495 media_image27.png Greyscale for L2. In particular, CN’676 Translation at pdf page 28 reports the following folate receptor-anti-EGFR antibody conjugate that showed a 32-fold increase in cancer cell binding compared the anti-EGFR antibody alone. This compound was of the exact same class of compounds as the elected species compound. Data were reported by EC50 (μg/ml): PNG media_image28.png 121 982 media_image28.png Greyscale CN’676 Translation at pdf page 28. “The results showed that Anti-EGFR-Mc-Ser-MTX exhibited good binding activity compared with Anti-EGFR.” CN’676 Translation at pdf page 28. The exemplified compound has the following chemical structure, shown in CN’676 Translation at pdf page 26: PNG media_image29.png 348 616 media_image29.png Greyscale CN’676 Translation at pdf page 26. The compound has a Z3 variable as a serine methyl ester prodrug of the carboxylate of methotrexate. There is no indication that L is cleavable, and Y is an extracellular target-binding moiety that binds EGFR (being a maleimide consistent with linkage to a thiol of cystine of the anti-EGFR antibody). The exemplified compound reads on claims 1, 11, 18, 20, 24, 32, 55, 56 (see CN’676 Translation at pdf page 2, “m is selected from 1, 2, 3, 4, 5, 6, 7, and 8”), 62, 76, 81, 84 (see Table 4, instant Specification 58, listing maleimide), 85 (X is not methotrexate, it is a serine methyl ester prodrug of methotrexate), 88 (see CN’676 Translation at pdf page 2, “m is selected from 1, 2, 3, 4, 5, 6, 7, and 8”), 94 (see CN’676 Translation at pdf page 2, “m is selected from 1, 2, 3, 4, 5, 6, 7, and 8”), and 99 (linkage is consistent with linkage to a thiol of cystine). Accordingly, claims 1, 11, 18, 20, 24, 32, 55, 56, 62, 76, 81, 84, 88, 94, and 99 are anticipated by CN’676. Claim Rejections - 35 USC § 103 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, 11, 13, 18, 20, 22, 24, 32, 55, 56, 58, 62, 74, 76, 81, 84, 85, 88, 94, and 99 Obvious over US’343 in view of CN’676, Marsham 1999, Patani 1996, ERBITUX Label, Abdel-Aziz 2013, and US’630 Claim(s) 1, 11, 13, 18, 20, 22, 24, 32, 55, 56, 58, 62, 74, 76, 81, 84, 85, 88, 94, and 99 is/are rejected under 35 U.S.C. 103 as being unpatentable over US’3436 in view of CN’676,7 Marsham 1999,8 Patani 1996,9 ERBITUX Label,10 Abdel-Aziz 2013,11 and US’630.12 The discussions of US’343 and CN’676 in the anticipation sections are incorporated herein. As discussed, US’343 teaches a folate receptor ligand-antibody-drug conjugate with cetuximab as the antibody. It does not appear to expressly teach the chemical structure of the elected folate receptor-antibody conjugate: PNG media_image4.png 235 1104 media_image4.png Greyscale Elected species compound However, one of ordinary skill in the art would have a reasonable expectation of success in preparing a folate receptor ligand-antibody conjugate in the form of the elected species compound because: CN’676 teaches that in cancer treatments, folate-receptor-anti-EGFR antibody conjugates (like the elected species compound) surpass the activity of the antibody alone; Marsham 1999 teaches preferrable forms of folate receptor ligands for use in cancer treatments, including a folic acid indole derivative that is a bioisostere of the elected cell surface folate receptor binding moiety. Marsham 1999 further indicates its potential use in leukemias; Patani 1996 teaches the well-known principles of bioisosterism; ERBITUX Label teaches the anti-EGFR antibody cetuximab, which was known to target EGFR expressed in normal and cancer cells; Abdel-Aziz 2013 teaches that EGFR is elevated in certain patients with acute leukemias; and US’295 teaches simple linkers, including the oxyethylene – triazole – alkyl linker utilized in the elected species compound, and their incorporation into related conjugates. CN’676 For example, CN’676 Translation at pdf page 2, claim 1, teaches a “bispecific dimer” of the following formula PNG media_image25.png 60 563 media_image25.png Greyscale wherein A1 is an antibody and A2 targets folate receptors. L1 and L2 variables corresponded to linkers known in the art. Alkyl and oxyethylene linkers were exemplified throughout the claims and structures of CN’676. See, e.g., CN’676 Translation at pdf page 2, claim 4, teaching simple alkyl linkers like PNG media_image26.png 94 161 media_image26.png Greyscale for L1 and oxyethylene linkers like PNG media_image27.png 124 495 media_image27.png Greyscale for L2. In particular, CN’676 Translation at pdf page 28 reports the following folate receptor-anti-EGFR antibody conjugate that showed a 32-fold increase in cancer cell binding compared the anti-EGFR antibody alone. This compound was of the exact same class of compounds as the elected species compound. Data were reported by EC50 (μg/ml): PNG media_image28.png 121 982 media_image28.png Greyscale CN’676 Translation at pdf page 28. “The results showed that Anti-EGFR-Mc-Ser-MTX exhibited good binding activity compared with Anti-EGFR.” CN’676 Translation at pdf page 28. CN’676 explains that these conjugates were effective for treating tumors because they target the known phenomenon that “folic acid receptors are overexpressed in the cell membranes of most malignant tumor cells”. CN’676 Translation at pdf page 10, paragraph [0004]. CN’676 explains that these compounds were in need because the “global cancer incidence rate” continues to increase, CN’676 Translation at pdf page 10, paragraph [0002], and that systemic chemotherapy lacks the ability to specifically target tumor cells. To address these problems, the solution provided by the inventors of CN’676 was to prepare “antibody-mediated and receptor-mediated active targeted drug delivery systems”. CN’676 Translation at pdf page 10, paragraph [0003]. CN’676 teaches that for these compounds, the A2 variable is simply a moiety that specifically targets folate receptors. CN’676 utilizes “methotrexate and its derivatives” in its examples to target folate receptors. CN’676 Translation at pdf page 10-11, paragraphs [0006]-[0008], quotation appearing in paragraph [0008]. “Methotrexate (MTX) [itself] is an anti-folate anti-tumor drug…” indicated for cancer treatments including “acute leukemia” and “breast cancer”. CN’676 Translation at pdf page 10, paragraph [0004]. The chemical structure of methotrexate appears on page 18: PNG media_image30.png 135 305 media_image30.png Greyscale CN’676 Translation at pdf page 18 (showing the chemical structure of Methotrexate). CN’676 Translation at pdf page 24-27, Examples 2 and 3 teach how to link the folate receptor to known antibodies. CN’676 Translation at 27-31, Examples 4 and Figures, teach exemplary biological data of these conjugates. Marsham 1999 Marsham 1999 teaches a structural activity relationship study (a “SAR”) about folate receptors. It explains in the introduction that “structural modifications to the folic acid molecule can produce potent antitumor agents that act through inhibition of thymidylate synthase”. Marsham 1999 at 2209. An indole derivative discovered during the SAR was designated compound 75, structure shown on page 2212 and below. The folic acid indole derivative designated compound 75 is a bioisostere of the amide utilized in the elected species compound (in the elected species compound, the CH2CH2CO2H group becomes CH2CH2C(O)NH): PNG media_image31.png 140 468 media_image31.png Greyscale Marsham 1999 at 2212. Its activity is shown on page 2214, Table III, first row: PNG media_image32.png 228 1217 media_image32.png Greyscale Marsham 1999 at 2214. While Marsham 1999 discovered that its compound 75 had a decrease in activity against thymidylate synthase (“TS”), compound 75 was believed to be highly effective as a substrate for folylpolyglutamate synthetase (“FPGS”) as evidenced by the inhibition of L1210 cell growth. Indeed, Marsham 1999 states that “the compound is transported and/or polyglutamylated very efficiently by the cells”. Id. at 2215. For clarity, L1210 cells are mouse leukemia cells used in standard models for cancer research. See, e.g., citation 21 of Marsham 1999 to Hynes 1989,13 attached hereto. Patani 1996 The exchange of the carboxylic acid group C(O)-O-H to an amide group C(O)-NH-R represents a classical bioisosteric exchange of O with NH. To clearly see the exchange, an ester, C(O)-O-R, is also bioisosteric with an amide, C(O)-NH-R, because O and NH are classical bioisosteres “according to Grimm”. See Patani 1996 at 3148, right column, Table 2, discussed below. Patani 1996 has been cited thousands of times by numerous authors for its review of “Bioisosterism: A Rational Approach in Drug Design”. See Patani 1996 at Title. On the first page, it explains that “Bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents.” Patani 1996 at 3147. The approach was considered “intuitive”, id., and had its roots back to 1919, id. at 3148. Bioisosteres are “Compounds or groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties...”. Id. “The critical component for bioisosterism is that bioisosteres affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other.” Id. “Bioisosteres have been classified as either classical or nonclassical.” Id. One such group of classical bioisosteres were those “according to Grimm”, see Patani 1996 at 3148, Table 2 and surrounding text (third column shows the O and NH exchange): PNG media_image33.png 439 571 media_image33.png Greyscale Patani 1996 at 3148, Table 2. Accordingly, the exchange of O with NH, and even CH2, results in classical bioisosteres, that by definition, affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other. ERBITUX Label ERBITUX Label at 1 teaches the FDA approved antibody cetuximab that was marketed under the name ERBITUX. The antibody specifically binds EGFR. See id. at 11 (“Cetuximab is an epidermal growth factor receptor (EGFR) antagonist. It is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR).”). Approved indications were for head and neck, as well as colorectal cancers. Id. at 1. See also, id. at 13 (“Cetuximab binds specifically to the EGFR on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha.”) (emphasis added). Abdel-Aziz 2013 Abdel-Aziz 2013 teaches that EGFR expression is increased in patients with acute leukemias. See, e.g., Abdel-Aziz 2013 at Abstract (“Background: Pretreatment serum p53 and epidermal growth factor receptor (EGFR) were assessed using enzyme-linked immunosorbent assay (ELISA) in patients with acute leukemia to analysis their roles in characterization of different subtypes of the disease. Materials and Methods: Serum samples from thirty two patients with acute myeloid leukemia (AML) and fourteen patients with acute lymphoid leukemia (ALL) were analysed, along with 24 from healthy individuals used as a control group.Results: The results demonstrated a significant increase of serum p53 and EGFR in patients with AML (p<0.0001) compared to the control group. Also, the results showed a significant increase of both markers in patients with ALL (p<0.05, p<0.0001 respectively).”). See also, Abdel-Aziz 2013 at 4297, Table 2: PNG media_image34.png 328 1262 media_image34.png Greyscale Abdel-Aziz 2013 at 4297, Table 2. US’630 US’630 teaches additional conjugates similar to those of US’343 and CN’676. See, e.g., US’630 at Abstract (“The compounds according to the present invention comprise an antibody binding terminus (ABT) moiety covalently bonded to a cell binding terminus (CBT) through a linker and optionally, a connector molecule.”). US’630 exemplifies many linkers ordinary chemists used in constructing conjugates. Most of the linkers were connected using simple click chemistry. See, e.g. US’630 at col. 3 (“FIG. 11 shows Scheme 3a which is directed to the synthesis of intermediate 15, and proposed access to azide intermediate 16 to be used in click chemistry.”). In particular, US’630 teaches that linker length and composition represented a result effective variable that could be modified by routine experimentation to tune efficacy towards a biological target. For example, US’630 at col. 60 teaches the “Dependence of Linger Length on Binding Affinity”. It exemplifies standard oxyethylene and alkyl linkers connected by a triazole moiety. The triazole moiety results from standard click reactions. This is the same “linker” used in the elected species compound: PNG media_image35.png 703 577 media_image35.png Greyscale US’630 at col. 60. To confirm that the standard oxyethylene – triazole - alkyl portion itself constituted a “linker”, see, e.g., US’630 at Fig. 14B, shown below: PNG media_image36.png 391 944 media_image36.png Greyscale US’630 at Fig. 14B. The oxyethylene and alkyl portions could be swapped because O and CH2 were known classical bioisosteric exchanges according to Grimm. The elected species compound was obvious at the time of filing Accordingly, a chemist of ordinary skill in the art at the time of filing would recognize that the folate receptor ligand-antibody-drug conjugates of US’343 and the folate receptor ligand-antibody conjugates of CN’676 represented a class of targeted chemotherapy drugs. US’343 taught incorporation of the anti-EGFR antibody cetuximab into folate receptor ligand-antibody-drug conjugates. CN’676 taught the incorporation of an unspecified anti-EGFR antibody into folate receptor ligand-antibody conjugates. From CN’676, it was known that conjugating an antibody to a folate receptor dramatically increased cancer cell binding, compared to antibody alone. There was a reasonable expectation of success in using compound 75 of Marsham 1999 as the folate receptor ligand because from Marsham 1999 it was known that the compound targeted folate receptors. Further, from Marsham 1999, it was also transported into cells and affected folylpolyglutamate synthetase. This provided relevance to the hard-to-treat leukemias. Further, there was a reasonable expectation of success that in using the amide bioisostere of compound 75 of Marsham 1999 because from Patani 1996 the compounds would affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other. From the ERBITUX Label, it was known that cetuximab targets EGFR on both normal and tumor cells. Further, from Abdel-Aziz 2013, it was known that patients with acute leukemias had a “significant increase” in serum EGFR. Therefore, there was an additional nexus between EGFR and compound 75 of Marsham 1999 and its amide bioisostere, which had additional potential use in leukemias. Standard oxyethylene – triazole – alkyl linkers were known for conjugate drugs, as shown in US’630. Further, the linker length and composition represented a result effective variable that could be modified by routine experimentation to tune efficacy towards a biological target, as shown in US’630. Therefore, there was a reasonable expectation of success in arriving at the elected species compound, using it in assays towards cancer lines, and eventually for treating patients. It represented no more than combining a bioisostere of a known folate receptor ligand to a known linker bound to a known antibody and falls in the exact same class of drugs already known from US’343 and CN’676. PNG media_image4.png 235 1104 media_image4.png Greyscale Elected species compound Accordingly, claims 1, 11, 13, 18, 20, 22, 24, 32, 55, 56, 58, 62, 74, 76, 81, 84, 85, 88, 94, and 99, all of which encompass this compound, were obvious at the time of filing. 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. Provisional NSDP to US’779 Claims 1, 11, 13, 18, 20, 22, 24, 32, 55, 56, 58, 62, 74, 76, 81, 84, 85, 88, 94, and 99 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 79 and 89-90 of copending Application No. 18/568,779 (reference application, or “US’779”, which published as US 20250127913 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of US’779, claim set dated 2025/04/02 recites the same cell surface folate receptor binding compound of formula (I), PNG media_image37.png 183 313 media_image37.png Greyscale with variables that exhibit near-complete overlap. However, US’779 recites that PNG media_image38.png 21 417 media_image38.png Greyscale . Accordingly, the compounds of US’779 anticipate the instant claims wherein Y is any “moiety of interest”. Further, claim 79 of US’779 recites the same cell surface folate receptor ligand used to construct the elected species compound: PNG media_image39.png 80 291 media_image39.png Greyscale Moreover, claim 90 of US’779, which depends on claims 89 and 1, recites the same use of the compounds of formula (I) in folate receptor ligand-antibody conjugates: PNG media_image40.png 369 591 media_image40.png Greyscale Claims 89 and 90 of US’779. Therefore, combining claim 79 with the folate receptor ligand-antibody conjugate taught in claim 90 results in claimed compounds that are not patentably distinct from the elected species compound. To confirm, see, e.g., the instant claims 81 and 84: PNG media_image41.png 57 635 media_image41.png Greyscale PNG media_image42.png 343 661 media_image42.png Greyscale Instant claims 81 and 84. The examiner notes that the elected species compound is never recited explicitly in any of the instant claims. Instead, as discussed throughout this office action, it is an embodiment of instant claims 1, 11, 13, 18, 20, 22, 24, 32, 55, 56, 58, 62, 74, 76, 81, 84, 85, 88, 94, and 99. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Prior Art Cited but not Applied The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure. The “moiety of interest” Y for compound I-68, and others, was disclosed by the inventors at Bristol Myers Squibb Co in WO’905.14 Its discovery was chronicled in the publication Xiao 2020.15 Nath 2020 teaches that EGFR expression correlates to poor prognosis in Acute Myeloid Leukaemia (AML). See, e.g., Nath 2020 at 749 (“This study confirms the presence of EGFR in AML and indicates that EGFR expression confers poor prognosis in AML.”). Zhang 201216 teaches additional folate ligand-drug conjugates for use in chemotherapy. Brand 201117 at 781 teaches how cetuximab affects biological systems. For example, in addition to engaging EGFR, (“Cetuximab can also induce antibody-dependent cellular cytotoxicity in vivo by recruiting immune cells to tumor cells deco rated by cetuximab (Fig. 3G).98,99”). See Brand 2011 at 782, Fig. 3, shown on the following page: PNG media_image43.png 899 884 media_image43.png Greyscale Brand 2011 at 782. The examiner did not raise “LYTAC” references in the current rejections but notes for the record that Applicant states in its priority documents that the compounds of the instant invention are LYTACs. It is unclear why Applicant removed these statements from the instant Specification. For example, see U.S. Provisional Patent Application No. 63/214,774 at 5, which states that compound I-17 is a LYTAC: PNG media_image44.png 240 1137 media_image44.png Greyscale U.S. Provisional Patent Application No. 63/214,774 at 5. See also, U.S. Provisional Patent Application No. 63/214,774 at 69, compound I-17: PNG media_image45.png 166 515 media_image45.png Greyscale U.S. Provisional Patent Application No. 63/214,774 at 69, compound I-17. US’05718 teaches LYTACs conjugated to cetuximab. US’19719 teaches LYTACs conjugated to cetuximab. Conclusion No claims allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christopher Evan Redwood whose telephone number is (571) 272-8882. The examiner can normally be reached Monday - Friday 6:15 AM - 4:45 PM. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /C.E.R./ Examiner, Art Unit 1629 /JEFFREY S LUNDGREN/ Supervisory Patent Examiner, Art Unit 1629 1 ERBITUX® (cetuximab) Label, revised 11/2020, hereinafter “ERBITUX Label”. 2 Mahato, A. K. et al, “Chemistry, Structure Activity Relationship and Biological Activity of Quinazolin -4 (3H)-One Derivatives”, Inventi Impact: Med Chem, vol. 2011, no. 1, pp. 1-6, hereinafter “Mahato 2011”. 3 Marsham, Peter R., et al. "Quinazoline antifolate thymidylate synthase inhibitors: bridge modifications and conformationally restricted analogs in the C2-methyl series." Journal of medicinal chemistry 34.7 (1991): 2209-2218, hereinafter “Marsham 1999”. 4 Park; Tae Kyo, et al., “Compound Bearing Beta-galactoside-introduced Self-immolative Linker”, U.S. Patent No. US 11065343 B2, published 2021-07-20, effectively filed 2016-12-28, Applicant IntoCell Inc., hereinafter “US’343”. 5 Luo Wenting, et al., “Dual specificity dimer, dual specificity dimer-drug conjugate and application of dual specificity dimer and dual specificity dimer-drug conjugate”, Chinese Patent Application Publication No. CN111643676A, published 2020-09-11, Applicant RONGCHANG BIOLOGICAL PHARMACEUTICAL YANTAI CO LTD, hereinafter “CN’676”. Page numbers refer to the attached Google Machine translation of the publication, referenced herein as “CN’676 Translation”. 6 Same reference applied in the section regarding anticipation. 7 Same reference applied in the section regarding anticipation. 8 Cited in section regarding 112(b). Full citation provided again: Marsham, Peter R., et al. "Quinazoline antifolate thymidylate synthase inhibitors: bridge modifications and conformationally restricted analogs in the C2-methyl series." Journal of medicinal chemistry 34.7 (1991): 2209-2218, hereinafter “Marsham 1999”. 9 Patani, George A., and Edmond J. LaVoie. "Bioisosterism: a rational approach in drug design." Chemical reviews 96.8 (1996): 3147-3176, hereinafter “Patani 1996”. 10 Cited in section regarding restriction and elections. Full citation proved again: ERBITUX® (cetuximab) Label, revised 11/2020, hereinafter “ERBITUX Label”. 11 Mohamed Mohamed Abdel-Aziz. "Clinical Significance of Serum p53 and Epidermal Growth Factor Receptor in Patients with Acute Leukemia", Asian Pacific Journal of Cancer Prevention, 14.7 (2013), 4295-4299, hereinafter “Abdel-Aziz 2013”.. 12 Spiegel; David, et al., “Chimeric Small Molecules For The Recruitment Of Antibodies To Cancer Cells”, U.S. Patent No. US 8852630 B2, published 2014-10-07, hereinafter “US’630”. 13 Hynes, John B., et al. "Comparison of the biological effects of selected 5, 8-dideazafolate analogs with their 2-desamino counterparts." Journal of medicinal chemistry 32.4 (1989): 852-856, hereinafter “Hynes 1989”. See, e.g. Hynes 1989 at 852 (“… L1210 leukemia cells …”). 14 XIAO HAI-YUN, et al., “HETEROCYCLIC COMPOUNDS USEFUL AS MODULATORS OF TNF ALPHA”, International Publication No. WO 2017023905 A1, published 2017-02-09, Application BRISTOL MYERS SQUIBB CO, hereinafter “WO’905”. 15 Xiao, Hai-Yun, et al. "Biologic-like in vivo efficacy with small molecule inhibitors of TNFα identified using scaffold hopping and structure-based drug design approaches." Journal of Medicinal Chemistry 63.23 (2020): 15050-15071, hereinafter “Xiao 2020”. 16 Zhang, Huaihong, et al. "Folate‐conjugated β‐cyclodextrin from click chemistry strategy and for tumor‐targeted drug delivery." Journal of Biomedical Materials Research Part A 100.9 (2012): 2441-2449, hereinafter “Zhang 2012”. 17 Brand, Toni M., Mari Iida, and Deric L. Wheeler. "Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab." Cancer biology & therapy 11.9 (2011): 777-792, hereinafter “Brand 2011”. 18 Bertozzi; Carolyn, et al., “Bifunctional Molecules For Lysosomal Targeting And Related Compositions And Methods”, U.S. Patent Application Publication No. US 20220025057 A1, published 2022-01-27, priority to 2018-12-19, hereinafter “US’057”. 19 Mazzone; Massimiliano, et al., “Cancer Treatment By Targeting Plexins In The Immune Compartment”, U.S. Patent Application Publication No. US 20220220197 A1, published 2022-07-14, priority to 2019-05-28, hereinafter “US’197”.