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/Restriction
Applicant's election with traverse of Invention II and HG-PL2 in the reply filed on 31MAR2026 is acknowledged.
The traversal is on the grounds that Applicant’s claim amendments to independent claim 1, wherein the compounds of Formula I have been amended to the more limited compounds of Formula II or III, which both comprise the same partial linker structure of:
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and therefore Applicant argues that the partial linker structure constitutes a special technical feature shared by groups I-V. Applicant’s argument that the presently elected structure reduces premature cleavage of the linker in vivo by retro-Michael addition because the linker does not contain a -CH2-CH2-O-C(O)- structure and that the HG-PL1 scaffold (i.e.,
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, wherein MMAE is a microtubule inhibitor) is more cytotoxic than the DS2801 scaffold (i.e.,
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, wherein DXd is a topoisomerase inhibitor) have been fully considered but are not found persuasive because:
i) Applicants argument regarding the selected partial linker structure does not contain the -CH2-CH2-O-C(O)- structure is unclear because a) the retro-Michael addition examples pertain to -O-CH2-CH2-C(O)- or CH2-O-C(O) (presumably referring to the linkers in the branches of the partial linker structure) but there is no specific evidence that the currently elected structure is more stable than alternative linker structures and b) the potential branched linker structures of the originally filed claim 1 included the -CH2-CH2-O-C(O)- structure (i.e., e =2 and f = 0), the -O-CH2-CH2-C(O)- (i.e., f = 2) and CH2-O-C(O) structure (i.e., e =1, f = 0) which would presumably undergo retro-Michael addition. Furthermore, the solution of the retro-Michael addition of the selected partial linker structure will not solve the retro-Michael addition of the maleimide-thiol conjugation which more typically results in detrimental off-target toxicity.
ii) The comparison of the “linker structure” is not a true comparison because the differences between the scaffolds are vast (i.e., linker structure between the maleimide and the cleavable peptide (i.e., Val-Cit-PAB vs Gly-Gly-Phe-Gly), addition of PEG in HG-PL1 scaffold, the drug and its mechanism of action, and the number of drugs per “linker structure”).
iii) The currently selected partial linker structures from the vast number recited in the originally filed claim 1 are not considered a special technical feature because the partial linker structure does not make a contribution over the prior art in view of Dupuy, et al., (Syn Comm, 2001, 31, 1307-1313), herein referred to as “Dupuy” and in further view of Izadi, et al., (Biomaterials, 2018, 182, 191-201, supplemental information, p 5), herein referred to as “Izadi.” Dupuy teaches the (PhCH2)2N-C(CH2OCH2CO2t-Bu)3, which can be used to prepare tripodal branched ligands, which are convenient to synthesize. Deprotection of the dibenzyl amine group forms the H2N-C(CH2OCH2CO2t-Bu)3, which can be reacted with the COOH modified PEG-Mal (i.e.,
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, wherein n = 2) taught by Izadi, which is used for thiol-reactive pegylation to form the Mal-PEG2-C(O)-NH-C(CH2OCH2CO2t-Bu)3 structure. The tBu can be deprotected forming
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, wherein R is a OH group. Therefore, it would have been obvious to one of ordinary skill in the art, before the priority date of the instant application, to modify the tripodal ligand precursor taught by Dupuy for thiol-maleimide conjugation as taught by Izadi because a tripodal ligand provides the opportunity to deliver three payloads per one conjugation site and the Mal-PEG2-COOH provides a simple protein bioconjugation moiety. One would have been motivated to do so, given the suggestion by Dupuy that the precursor can be used in the development of tripodal branched ligands. There would have been a reasonable expectation of success, given the knowledge that the linker of Izadi is easily conjugated to a thiol and reaction of a carboxylic acid with a primary amine to form an amide bond is general protein chemistry. Thus the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the common matter linking together the independent claims,
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, do not comprise a single general inventive concept because prior art, Dupuy, in further view of Izadi discloses the technical feature as defined above and furthermore, no special technical feature exists for groups I-V, because it does not define a contribution over the prior art.
Furthermore as discussed in the requirement for restriction mailed on 04FEB2026 and as described further below the compounds and conjugates thereof as a whole lack a technical feature due to:
i) the difference in conjugation technique (i.e., the maleimide reacts with a thiol of the targeting moiety, whereas the bicyclononyne structure requires modification of the targeting moiety to include an azide moiety) (i.e., Inventions I-V),
ii) the difference between a compound comprising a hydroxyl group or an -O-PG2 as the reactive group and a compound comprising an additional linker comprising PEG-Val-Cit-PAB-reactive group results in a non-cleavable vs a cleavable linker structure for covalently binding the drug moiety (i.e., Inventions I-V),
iii) the difference between a compound of Formula II or III, wherein R is a OH group, O-hydroxyl protecting group, or an additional linker/spacer group and a carboxyl group, -OH group, or protecting group and a conjugate comprising the compound and essentially any drug moiety (i.e., small molecule), wherein the linker with a protecting group only will have a different activity in vitro and/or in vivo than the linker with essentially any drug, and the drug choice (i.e., antibiotic vs antiviral vs anti-cancer) affects disease therapy efficacy, for example an antibiotic or an antiviral would likely be ineffective in treating a patient having cancer (i.e., Inventions I-V),
iv) the difference between the conjugate comprising the compound and essentially any drug moiety and the conjugate further comprising essentially any antibody or fragment thereof, peptide, aptamer, small molecule, etc., with specificity to an undisclosed target (e.g., rifamycin conjugated to the linker would change the properties of the antibiotic, but is expected to still treat a bacterial infection, whereas an anti-HER2 antibody conjugated to rifamycin would deliver an antibiotic to a HER2-expressing cell which is likely to be ineffective in treating a bacterial infection or a HER2-expressing cancer; however, an anti-lipoteichoic acid antibody conjugated to a rifamycin would be effective in treating a bacterial infection or an anti-HER2 antibody conjugated to an anti-cancer cytotoxin would be effective in treating a HER2-expressing cancer) (i.e., Inventions II, III, and V), and
v) the difference between a conjugate comprising a targeting moiety and one or more compounds comprising a protecting group or OH group, and/or additional linker group and protecting group (i.e., Invention IV) and the conjugate comprising the compound and essentially any drug moiety and the conjugate further comprising essentially any antibody or fragment thereof, peptide, aptamer, small molecule, etc., with specificity to an undisclosed target (i.e., Invention III). Thus the instant claimed invention has been found to lack unity of invention.
The requirement for restriction and election of species are still deemed proper and are therefore upheld. It is noted that the election of Invention II, of claims 7-8, 14, and 21-22 which are dependent on independent claim 1, requires examination of claim 1.
Claims 2-3, 5, 9-13, 17-20, and 22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species.
Claim Status
Claims 1, 9-10, and 21-22 have been amended.
Claims 4, 6, and 15-16 have been canceled.
Claims 1-3, 5, 7-14, and 17-22 are pending in the instant application (i.e., Claim(s) 1 is/are independent).
Claims 2-3, 5, 9-13, 17-20, and 22 are withdrawn.
Claims 1, 7-8, 14, and 21 are examined on the merits.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/CN2022/074523, filed 28JAN2022, which claims foreign priority under 35 U.S.C. 119 (a)-(d). The certified copies of Chinese Application No. 202111671761.6 filed on 31DEC2021 and Chinese Application No. 202110116059.7 filed on 28JAN2021 have been received and are acknowledged. Examiner notes that there are no translations for Chinese Application No. 202111671761.6 filed on 31DEC2021 and Chinese Application No. 202110116059.7 filed on 28JAN2021.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 15AUG2023 and 09JAN2026 is/are acknowledged and the references cited therein have been considered.
Specification
The disclosure is objected to because of the following informalities:
The use of the term Herceptin (p 122-135), which is a trade name or a mark used in commerce, has been noted in this application. The term 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.
Appropriate correction is required.
Claim Objections
Claims 1 and 7-8 are objected to because of the following informalities:
Claim 1 appears to have two “.” at the end of the claim.
Claim 7 contains a typographical error: “an” between “via” and “R group.” should be replaced with “the” in line 2 of the claim.
Claim 8 contains a typographical error: “mono” should be inserted prior to “methyl auristatin E,….”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1, 7-8, 14, and 21 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.
Claim 1 recites the limitation "R is…; wherein n2 is…; the PG1 is an amino-protecting group, the amino-protecting group is selected from acetyl,…and Fmoc;…." In this instance there is no recitation of a PG1 group in the currently amended claim and therefore there is insufficient antecedent basis for this limitation in the claim. Claims 7-8, 14, and 21 are also rejected since they depend on claim 1, but do not remedy this deficiency.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 7-8, 14 and 21 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. In this instance, claim 7 fails to further limit the subject matter of the compounds of claim 1, upon which they depend because the conjugate of claim 7 broadens the structures of “the compounds of Formula II or III” of claim 1 by chemically modifying the compounds of Formula II or III with essentially any drug moiety (i.e., small molecule) to form new structures, which in this instance are attributed to Formula IV and V, respectively (i.e., covalently binding a drug moiety via [the] R group). Claims 8, 14, and 21 are also rejected since they depend on claim 7, but do not remedy this deficiency. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Written Description
Claims 1, 7-8, 14, and 21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Scope of the claimed genus:
Applicant has broadly claimed a compound of Formula II or III, or a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof,
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, wherein R is -OH, -O-PG2,
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and a conjugate comprising the compound of claim 1 and a drug moiety wherein the compound is covalently bound to the drug moiety via the R group (i.e., claims 1 and 7). In this instance, exclusive of the tautomers, stereoisomers, pharmaceutically acceptable salts and combinations thereof, there are minimally 484 compound structures recited in claim 1, which is exponentially broadened in the conjugate of claim 7 and the pharmaceutical composition of claim 14, wherein essentially any drug moiety (i.e., small molecule) may be covalently bound via the R-group. In claim 8, the drug moiety is limited to one or more of eribulin, (mono)methyl auristatin E, and SN-38, which when limited to only one, results in 1452 total compounds exclusive of tautomers, stereoisomers, pharmaceutically acceptable salts and combinations thereof. Additionally, the Rx group of claim 21 should be a closed Markush group to limit the structures to the specified chiral centers (i.e., stereoisomers).
Furthermore, due to the nature of the open language used in claim 7, it is unclear what the scope of a “conjugate” encompasses. The specification teaches that a conjugate of the second aspect comprises the above compound (i.e., Formulas II or III) and a drug moiety to which the compound is covalently bound via an R group, the drug moiety is a small molecule drug or is called a payload and the conjugate further comprises a targeting moiety to which one or more of the conjugates are covalently bound via an A group (i.e., maleimide or bicyclononyne) (¶0033-0034). The specification further teaches that the conjugate of the third aspect comprises a targeting moiety and one or more of the above compounds, wherein the one or more compounds (i.e., Formulas II or III without a drug covalently attached) are covalently bound to the targeting moiety via an A group (i.e., maleimide or bicyclononyne) (¶0035).Thus the scope of the term “conjugate” is not clearly defined, in one instance it is the linker-drug conjugate which optionally comprises a targeting moiety and in another instance it is a targeting moiety-linker structure conjugate, wherein in both cases the targeting moiety structure and target are unspecified.
State of the relevant art:
McCombs, et al., teach that targeted drug conjugates or antibody drug conjugates (ADCs) have emerged as an important pharmaceutical class of drugs designed to harness the specificity of the targeting moiety or antibody with the potency of small molecule therapeutics (McCombs, et al., AAPS J, 2015, 17, 339-351, herein referred to as “McCombs”). McCombs further teaches that such targeted drug conjugates can potentially minimize dose-limiting toxicities while maximizing desired therapeutic effects. Yet, initial ADCs pairing standard anti-cancer agents, such as doxorubicin, were ineffective in clinical trials, which were linked to (1) the limited number of drug molecules that can be conjugated to one antibody without affecting antigen binding and (2) the limited number of antigens on target cell surfaces, preventing therapeutic levels of drug accumulation in cells (see introduction section). To date, the most successful approaches to overcome these challenges are improved linker technology and the selection of extremely potent drugs to the pair with the antibody. Innovations in linker design are focused on multiple issues ranging from serum stability to mechanism of release to drug to antibody ratio (DAR). At the most basic level, linkers provide a functional handle for efficient conjugation to antibodies through bioconjugation (see Linker section). More sophisticated linkers increase effector solubility, improve stability throughout the production process, prevent premature drug release, and facilitate the liberation of active drug at the target. Critical aspects of linker chemistry include the functionality that allows conjugation to antibody, the mechanism for drug release, and the physical properties of the linker itself. Ultimately the optimal combination of linker and conjugation chemistry must be uniquely tailored to correlate each unique facet: the targeting moiety or antibody, the drug molecule, and the profile of the disease to be treated. The greatest advantage of using non-cleavable linkers is their increased plasma stability when compared to many chemically labile linkers (see Non-cleavable linkers section). Despite the limited “bystander” effect, the resistance to cleavage outside of target cells may actually increase the specificity of drug release. One proposed mechanism for the decreased efficacy of non-cleavable linked ADCs is that drugs bearing charged amino acids suffer from decreased membrane permeability, limiting their ability to kill nearby cells. A major motivation for employing cleavable linkers is to improve this “bystander” effect.” Overall, enzymatically cleavable linkers (i.e., Val-Cit-PAB) provide antibody drug conjugates with plasma stabilities comparable to that of non-cleavable linkers while boasting a more defined method of drug release compared to disulfide-linked or acid-labile linkers (see Enzymatically cleavable linkers section). The ability to pair these linkers with self-immolative chemical groups (i.e., PAB) bestows the release of free drugs with minimal derivation; the main constraint being the requirement for the drug to bear an amine or hydroxyl group to conjugate with PAB. The selection of linker should depend on the application and conditions a given antibody is likely to encounter. The basic criteria for selecting the ADC payload are solubility, amenability to conjugation, and stability (see Payload section). Lipophilic drugs readily pass cell membranes and therefore have a greater potential to escape the lysosome after release. Conversely, a potential payload must be sufficiently soluble to allow for conjugation to the antibody in aqueous buffers as high concentrations of organic solvent lead to antibody scaffold denaturing. The low solubility of many candidate payloads may be balanced by hydrophilic linkers, such as those containing sulfonates or poly(ethylene glycol), allowing for higher DAR than hydrophobic linkers such as SMCC. Many potent drugs lack chemically functional handles that are necessary for conjugation. Modification to incorporate such handles can have deleterious effects on drug action. Likewise, conjugated drugs that are not released as the free, parent form may suffer decreased efficacy as is often seen when paired with non-cleavable linkers. Self-immolative linkers such as PAB facilitate the release of appended drugs back to the original unconjugated form; however, the PAB moiety itself is hydrophobic and may limit the use of certain payloads. As with solubility, a balance must be found between amending candidate drugs to allow conjugation and maintain efficacy. Following conjugation, the payload must remain stable in circulation, through cellular processing and release, to reach the cytosolic target. The vast majority of ADC payloads in clinical trials fall into two categories: anti-mitotic (e.g., maytansinoids or auristatins) or DNA damaging (e.g., duocarmycin, PBD, calicheamicins and doxorubicin). Typically, a DAR > 4 can diminish ADC solubility, impair binding, and influence PK. In addition, cellular trafficking of ADCs is restricted by the target antigen.
Furthermore, Su, et al., teaches the specific components of the linker which determine both efficacy and adverse effects of targeting drug conjugates or ADCs:
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(Su, et al., Acta Pharm Sin B, 2021, 11, 3889-3907, see Abstract and Fig 1).
Accordingly, the skilled artisan would be unable to envisage the conjugate comprising all potential tautomers, stereoisomers, pharmaceutically acceptable salts and combinations thereof for the branched linker comprising either a cleavable (Val-Cit-PABC) or non-cleavable linker (i.e., R is -OH or -O-hydroxyl protecting group), potentially a PEG with 7-11 repeating units, and all potential small molecule drugs that may or may not need modification for conjugation to the PAB or for conjugation to the linker or pharmaceutical compositions thereof a priori given the current state of the linker-drug conjugate arts.
Description of representative species in the specification:
MPEP § 2163 states that “a representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
To support such broad claims, the specification teaches ten (i.e., HG-PL1-10) of the potential 1452 compounds exclusive of tautomers, stereoisomers, pharmaceutically acceptable salts and combinations thereof of claim 8 in examples 5-14, wherein eight of the structures comprise the maleimide bioconjugation handle, of which four comprise MMAE (i.e., HL-PG1-2 and HL-PG9-10), two comprise eribulin (HL-PG3-4) and two comprise SN38 (i.e., HL-PG5-6), and two comprise the bicyclononyne bioconjugation handle, of which both comprise eribulin (i.e., HL-PG7-8). Four of the linker-drug conjugates (i.e., HL-PG1-4) were conjugated to trastuzumab (i.e., Herceptin®) using two different TCEP to ligand ratios, resulting in eight ADCs having varied DARs in Examples 15-18. The cytotoxicity of the eight ADCs (i.e., HG-ADC-1-D2, -D4, HG-ADC-2-D1, -D2, HG-ADC-3-D1, -D2, HG-ADC-4-D1, and -D2), DS8201, eribulin, MMAE, DS8201 scaffold (i.e., deruxtecan) and the HG-PL1 ligand were evaluated. The IC50 of the HG-ADCs ranged from 0.0068-0.056 nM, DS8201 was 0.153 nM, Eribulin was 0.22 nM, MMAE was 0.13 nM (Table 4). The IC50 was not determined for HG-PL1 or deruxtecan, however the max cytotoxicity was 49.5% and 9.38%, respectively (Table 4). However, given the immense breadth of the claims and the depth and diversity of the linker-drug repertoire as described above, such a disclosure would not reasonably be considered representative of the genus: conjugate comprising all potential tautomers, stereoisomers, pharmaceutically acceptable salts and combinations thereof for the branched linker comprising either a cleavable (Val-Cit-PABC) or non-cleavable linker (i.e., R is -OH or -O-hydroxyl protecting group), potentially a PEG with 7-11 repeating units, and all potential small molecule drugs that may or may not need modification for conjugation to the PAB or for conjugation to the linker or pharmaceutical compositions thereof.
Identifying characteristics and structure/function correlation:
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002). Recent court cases have emphasized the need for correlation between a well-defined structure and recited functional limitations
To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed conjugate comprising potential tautomers, stereoisomers, pharmaceutically acceptable salts and combinations thereof for the branched linker comprising either a cleavable (Val-Cit-PABC) or non-cleavable linker (i.e., R is -OH or -O-hydroxyl protecting group), potentially a PEG with 7-11 repeating units, and the vast number of small molecule drugs that may or may not need modification for conjugation to the PAB or for conjugation to the linker or pharmaceutical compositions thereof.
Although the specification discloses the modifications necessary to conjugate SN38, eribulin, or MMAE to each branch of the R linker group via a PAB moiety and comprises a specific branched linker structure, there is no evidence that all small molecule drugs would be able to be conjugated via a PAB moiety, that all small molecule drugs would be effective upon conjugation or upon release, or that in the instance of non-cleavable linkers that steric hindrance would not be an issue for conjugation of a small molecule drug and if steric hindrance was not a problem that the pharmacokinetic properties were going to be balanced for efficacy (i.e., SN38). Furthermore, the difference between the when a drug is conjugated via a -OH group on the branches vs a PEG4-(PEG7-11)-Val-Cit-PAB group on the branches highlights the variation of structure and the lack of predictability in how each would function as a linker-drug conjugate and in the instance when the linker-drug conjugate further comprises a targeting moiety.
Therefore, claims 1, 7-8, 14, and 21 as presently claimed are rejected because the specification does not provide sufficient description to reasonably convey to one skilled in the relevant art that the inventor, or joint inventor at the time the application was filed had possession of the broadly claimed invention.
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.
Claims 1, 7-8, 14, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0154018 A1 (Yurkovetskiy, et al., 07JUN2018), herein referred to as “’018” and in view of Dupuy, et al., (Syn Comm, 2001, 31, 1307-1313), herein referred to as “Dupuy,” WO 2022/155347 A1 (RP Scherer Technologies LLC, International Filing date 13JAN2022), herein referred to as “’347,” and WO 2018/039283 A1 (Fred Hutchinson Cancer Research Center, et al., 01MAR2018), herein referred to as “’283.”
‘018 teaches peptide-containing linkers for ADCs, wherein the scaffold for the linker provides the opportunity for branched linkers, which allow for delivery of three drugs (i.e., tripodal linker for delivery of three MMAE or SN38 drug moieties), and conjugation to a thiol of a protein (i.e., anti-HER2) or target or azide modified protein or target of:
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, wherein the precursor scaffold is:
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(i.e., the precursor is reacted with a maleimide-COOH to form the maleimide substituted linker) and pharmaceutical compositions thereof for treating cancer (¶0005-0006, ¶0500, ¶0506, ¶0893-0993, ¶0139-0140, p185-bottom panel, ¶1128, and ¶1139). Furthermore, ‘018 teaches that a major limitation of ADCs is the inability to deliver sufficient concentration of the drugs to the target site, which has been attempted to be overcome by attaching a large number of drug molecules to the antibody, but has resulted in antibodies which have impaired binding and/or fast in vivo clearance from the blood stream (¶0004). Thus there is a need to improve the ability to deliver a sufficient concentration of a drug to the target such that maximum cytotoxicity is achieved by developing a targeting moiety-drug conjugate that is biodegradable, biocompatible, and exhibits high drug load as well as strong binding to the target antigen (¶0004-0005).
However, they do not teach: wherein R is
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Nevertheless, Dupuy teaches the (PhCH2)2N-C(CH2OCH2CO2t-Bu)3, which can be used to prepare tripodal branched ligands, which are convenient to synthesize. Deprotection of the dibenzyl amine group forms the H2N-C(CH2OCH2CO2t-Bu)3, which can be reacted with the COOH group of the precursor scaffold of ‘018 (i.e.,
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) to form the
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structure. The tBu can be deprotected forming
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417
867
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.
Additionally, ‘347 teaches branched and pegylated linker structures for antibody-drug conjugates for delivering camptothecin or camptothecin derivatives (i.e., SN-38) for the treatment of cancer having the exemplary structure of:
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232
562
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, wherein the PEG chain of compounds 104 and 106 can be adjusted based on the choice of chain length in compounds 94 and 105, respectively. Compound 108, comprising a pentafluorphenol active ester which is coupled to a primary amine forming an amide bond. In this instance, the primary amine comprised an enzymatic cleavage peptide linker and drug shown in the box, comprising a NH2-Val-Ala-ßGlucoronide-PAB-belotecan (i.e., Topo I inhibitor) (¶00286, and p 240-scheme 19) or could be conjugated to the SN38 construct (¶00611). The primary amine of compound 109 is then reacted with a COOH group of a branched linker such as
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417
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to form the extended PEG linker with a PEG branch and a cleavable linker-drug conjugate structure.
Furthermore, ‘283 teaches the use of the enzymatically cleaved linker-drug conjugate comprising NH2-Val-Cit-PAB-MMAE for the delivery of a peptide-drug conjugate (¶0103), which in this instance could be conjugated to compound 108 of ‘347.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the branched scaffold of ‘018 by utilizing alternative tripodal structures, pegylation, and cleavable peptide structures of Dupuy, ‘347, and ‘283, which are convenient to synthesize, stable, and provide for optimal linker conjugate design. One would have been motivated to do so, given the teachings of ‘018 that there is a need to improve the ability to deliver a sufficient concentration of a drug to the target such that maximum cytotoxicity is achieved while maintaining strong binding to the target antigen and balancing the pharmacokinetics of the overall conjugate. There would have been a reasonable expectation of success, given the knowledge that the combination of modifications taught by Dupuy, ‘347, and ‘283 provided structures which were stable, able to deliver sufficient concentrations of the drug while balancing the pharmacokinetic properties and maintaining targeting of the antibody.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Conclusion
No claims are allowed.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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