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 .
Claims 26-32 and 34-50 are under consideration.
Rejections Maintained
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 34-40 and 42-50 is/are rejected under 35 U.S.C. 103 as being unpatentable over Boghaert (Boghaert, et al., WO2017214282A1; Published 12/14/2017; Priority to 06/08/2016 via US 62/347,416).
Boghaert teaches on the subject of anti-EGFR antibody-drug conjugates (ADCs) that inhibit Bcl-Xl (Boghaert, Abstract).
Boghaert teaches the linker-crosslinker moiety IVb.2 of Boghaert (Boghaert, Claim 50):
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(Note: @ = attachment point to antibody and wavy line is attachment point to drug)
Note that the moiety IVb.2 of Boghaert would be the same as the second compound from the top of claim 40 (pre-conjugation), the second compound from the top of claim 47 (pre-conjugation) and the second compound from the top of claim 48 except for the lack of the R2 group on moiety IVb.2 of Boghaert. Boghaert also teaches linker moieties comprising the following self-immolative assembly:
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… wherein:
p is 0-5
Ra is H
q is 0 or 1
Ry is H or C1-4alkyl-(O)r-(C1-4alky)s-G1
G1 is SO3H, CO2H or PEG 4-32
R is 0 or 1
s is 0 or 1
(Bogheart, Claim 39).
Regarding claim 49, Boghaert teaches pharmaceutical compositions comprising the conjugates of Boghaert and a pharmaceutically acceptable carrier. Regarding claim 50, Boghaert teaches methods of treating breast cancer, said methods comprising administering such compositions (Boghaert, claim 87).
Boghaert does not teach moiety IVb.2 of Boghaert comprising a -CH2-SO3H group attached to the p-amino benzoic acid (PAB) moiety.
It would be prima facie obvious to one of ordinary skill in the art to attach a -CH2-SO3H (methylene sulfonic acid) to the PAB moiety of moiety IVb.2 of Boghaert in view of the teachings of Boghaert. One of ordinary skill in the art would be motivated to do this in order to arrive at a linker moiety taught in the art to be suitable for ADC use. It is clear that moiety IVb.2 of Boghaert:
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Follows structure IVb of Boghaert:
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(Ra= H, p=4; peptide= Val-Cit; Ry= H; q =0). In the case of moiety IVb.2 Ry = hydrogen, however -CH2-SO3H is also a permissible moiety for Ry as taught by Boghaert (r = 0; s =0; G1 = SO3H). As such, one of ordinary skill in the art would have a reasonable expectation of success adding a methylene sulfonic acid group to the PAB of moiety IVb.2 of Boghaert because Boghaert teaches that -CH2-SO3H is a permissible moiety for the Ry group on the PAB of the linkers of Boghaert.
Please note that the resultant structure would be identical to the second compound from the top of claim 40 (pre-conjugation), the second compound from the top of claim 47 (pre-conjugation) and the second compound from the top of claim 48 with Ra = -CHSO3H and satisfies all of claims 34-40 and 42-50.
Response to Arguments
Applicant's arguments filed 3/30/2026 have been fully considered but they are not persuasive.
Applicant chose to group all Remarks regarding 35 USC 103 rejections together and, as such, all Remarks will be addressed collectively here.
Applicant’s arguments center around the PAB self-immolative linker group and the applied Boghaert reference in particular. Applicant argues that self-immolative linkers are known to cause poor solubility and aggregation of conjugates and certain PAB type self-immolative linkers containing hydrophilic groups disclosed in Boghaert lead to high aggregation. Applicant argues that ADCs comprising the instant claimed PAB linkers exhibit low aggregation levels, good stability, desirable levels of drug loading and expected pharmacological activity, as demonstrated by the data disclosed in the specification. Applicant contrasts with Boghaert, saying that Boghaert’s examples incorporating glucuronic acid groups show a high percentage of aggregation. Applicant also notes that Generic structure IVb of Boghaert encompasses a large number of possible compounds and none of the exemplary embodiments have a sulfonic acid in the PAB portion of the structure.
In response, PAB linkers comprising sulfonic acid groups are encompassed by General structure IVb of Boghaert and, as such, are taught by Boghaert. The fact that Boghaert does not provide exemplary PAB sulfonic acid embodiments and the performance of other exemplary embodiments of Boghaert do not affect the fact that Boghaert teaches PAB linkers comprising sulfonic acid groups sufficient to establish a prima facie case of obviousness.
Applicant mentions data offered in support of the claims. In order for evidence offered in support of claims to rebut a prima facie case of obviousness, those data must show results that are unexpected (See MPEP 716.02(a)). In the instant case, Applicant has presented no data that demonstrate results that are unexpected. A conjugate having the properties cited by Applicant (low aggregation levels, good stability, desirable levels of drug loading and expected pharmacological activity) would be entirely expected if one of skill in the art were to start with the various parameters taught by Boghaert and arrive at the instant claimed linkers via routine optimization.
Claim(s) 26-32, 34-40 and 42-50 are rejected under 35 U.S.C. 103 as being unpatentable over Boghaert (Boghaert, et al., WO2017214282A1; Published 12/14/2017; Priority to 06/08/2016 via US 62/347,416) as applied to claims 34-40 and 42-50 above and in further view of Iyer (Iyer, et al., WO 2019/051489 A1; Published 03/14/2019, of record).
The teachings of Boghaert are discussed above. In addition, moiety IVb.2 of Boghaert modified to comprise a methylene sulfonic acid as discussed above reads on all of the limitations of claims 26-32 exclusive of the X and R1 variables of claim 26. Regarding claim 26, the moiety IVb.2 of Boghaert modified to comprise a methylene sulfonic acid also satisfies all of the limitations of Formula (I) of claim 26 except for R1 and X. Regarding claim 28, the -SO2OH group on the sulfonic acid-modified moiety IVb.2 of Boghaert also satisfy all limitations related to R2 of claim 28. Regarding claim 29, the citrulline amino acid residue present in the sulfonic acid-modified moiety IVb.2 of Boghaert also satisfies all of the limitations related to A1 of claim 29. Regarding claim 30, the isopropyl side chain of the valine moiety present in the sulfonic acid-modified moiety IVb.2 of Boghaert also satisfies all of the limitations related to A2 of claim 30. Regarding claim 31, the valine-citrulline moiety present in the sulfonic acid-modified moiety IVb.2 of Boghaert also satisfies all of the limitations of claim 31 related to A1 and A2, with the valine side chain and citrulline side chain are R3 and R4 of claim 31, respectively.
Boghaert does not teach the p-aminobenzyl compound of Formula (I) of claim 26, wherein R1 is a hydroxy group and X is a protecting group.
Iyer teaches of a method of producing a maleimide-comprising drug-linker moiety starting from a p-aminobenzyl compound comprising a hydroxy group on one end and an Fmoc protecting group on the other end (Iyer, p 118, line 5):
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Please note that the starting material of Iyer satisfies all of the limitations of claim 26 except for the sulfonic acid or sulfonate moiety at position R2 and the positions corresponding to X and R1 of instant claim 26 are pointed out with arrows.
It would be prima facie obvious to one of ordinary skill in to combine the teachings of Boghaert with respect to the ADC linker comprising a sulfonic acid substituted p-aminobenzyl moiety with the method of making conjugation-ready ADC drug-linker moieties taught by Iyer. The net result of this combination would be a method of making conjugation-ready ADC drug-linker moieties that is identical to the method of Iyer and that uses a starting material that is a Fmoc protected, hydroxyl-comprising p-aminobenzyl moiety, wherein the benzyl group comprises a sulfonic acid substituent as a starting material. One of ordinary skill in the art would be motivated to do this in order to develop an art-equivalent method of making the compounds taught by Boghaert. One of ordinary skill in the art would have a reasonable expectation of success starting with a Fmoc protected, hydroxyl-comprising p-aminobenzyl moiety, wherein the benzyl group comprises a sulfonic acid substituent and using the method of Iyer to make the conjugation-ready drug-linker compounds of Boghaert because the starting material of Iyer and the required starting material for the combined method of Burger and Iyer differ only by the presence or absence of the sulfonic acid moiety on the p-aminobenzyl group and this moiety is not involved in the chemistry of the method of Iyer,
Response to Arguments
Applicant’s arguments addressed above.
Claim(s) 34-50 are rejected under 35 U.S.C. 103 as being unpatentable over Boghaert (Boghaert, et al., WO2017214282A1; Published 12/14/2017; Priority to 06/08/2016 via US 62/347,416) as applied to claims 34-40 and 42-50 above and in further view of MedChemExpress (MedChemExpress (2016) Val-Cit-PAB-MMAE; URL= https://www.medchemexpress.com/Val-Cit-PAB-MMAE.html?srsltid=AfmBOornE4mhovOUHnXmB816-YzUIQYr_si6BpcfSzHGgOvq8dwSMkQ9 ; Published 9/4/2016; Accessed 04/18/2025, of record)
The teachings of Boghaert are discussed above.
The teachings of Boghaert do not teach the sulfonic acid-modified compounds of Boghaert discussed above wherein the D moiety is MMAE.
MedChemExpress teaches that Val-Cit-PAB-MMAE were commercially available drug-linker moieties as early as 2016 (MedChemExpress, p 1-2).
It would be prima facie obvious to one of ordinary skill in the art to combine the sulfonic acid-comprising p-aminobenzyl linker-drug taught by Boghaert discussed above with the MMAE taught by MedChemExpress. The net result of this combination would be the p-aminobenzyl linker-drug moiety taught by Boghaert with the MMAE taught by MedChemExpress. One of ordinary skill in the art would be motivated to do this in order to form a linker-drug moiety comprising a drug unit that is known in the art to be useful in ADCs comprising Val-Cit-PAB moieties. One of ordinary skill in the art would have a reasonable expectation of success using MMAE as the drug unit in the p-aminobenzyl linker-drug moiety taught by Boghaert because MedChemExpress teaches that Val-Cit-PAB-MMAE were well accepted in the art to the point that they were commercially available well before the effective filing date of the instant application and this would lead one of skill in the art to reasonably assume that MMAE would also be a useful drug moiety for the linker-drug moiety taught by Boghaert based on the fact that only pertinent difference between two self-immolative spacers is the presence of the sulfonic acid group on the drug-linker taught by Boghaert.
Response to Arguments
Applicant’s arguments addressed above.
Conclusion
Claims 26-32 and 34-50 are rejected.
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sydney Van Druff whose telephone number is (571)272-2085. The examiner can normally be reached 10 am - 6 pm.
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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