DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 87-179 are under consideration.
Rejections Maintained
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.
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Claims 87-161 and 176-178 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 73-106 of copending Application No. 18/554745 (Published as US 20240209090A1 on 6/27/2024) in view of Han (Han, et al., WO 2019/094395 A2; Published 05/16/2019, of record) and Govindan (Govindan, et al., Cytotoxic Payloads For Antibody-Drug Conjugates; Chapter 8; Published 2019, of record).
The copending claims are directed to anti-FOLR1 binding agents (copending claim 73) as well as conjugates thereof (copending claim 95). Regarding the CDR sequences recited in instant claim 87, the VH and VL CDR sequences recited in copending claim 74 are identical to VH CDR 1, 2 and 3 of instant SEQ ID NOs: 30, 31 and 32 respectively and VL CDR 1, 2 and 3 of instant SEQ ID NOs: 33, 34 and 35, respectively (copending claim 74). Regarding the VH and VL sequences recited in instant claims 88-89, 108 and 176, the VH and VL sequences of copending SEQ ID NO: 21 and 22, respectively are 100% identical to instant SEQ ID NOs: 26 and 27 (copending claim 80). Regarding claims 90-107, 109-144 and 176-177, the copending claims are directed to binding agents comprising: 1) IgG1 constant regions (copending claim 86), 2) a LC constant region of the kappa type (copending claim 89), 3) HC constant chain mutations L234A and L235A (“LALA” mutations; intrinsically decrease Fcgamma-R binding) and 4) p load is 8 (copending claim 99) as well as pharmaceutical compositions comprising such conjugates further comprising pharmaceutically acceptable carriers (Copending claim 104). Regarding claims 145-161 and 178, copending claim 105 is directed to methods of treating FOLR1+ cancer, said methods comprising administering pharmaceutical compositions comprising the conjugates of the ‘745 Application to a subject in need thereof (Copending claim 105).
The ‘745 Application does not teach the drug-linker moiety of the conjugate of the ‘745 Application comprises structure PA038 (recited in instant claims 87, 108, and 176).
Han teaches on the subject of hydrophilic linkers for antibody-drug conjugates (Han, Title/Abstract). Han teaches that the conjugates of Han are of Formula (I) (Han, ¶ 093):
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128
202
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… wherein BA is a binding agent, L is a trivalent linker, PA is a payload and HL is a hydrophilic moiety (Han, ¶ 093).
Han teaches that in specific embodiments, the conjugates of Han can also be expressed as (Han, ¶ 0101):
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Han also teaches that a specific embodiment of Han is (Han, ¶ 0144):
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174
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The structure of Han depicts a maleimide stretcher unit as the point of attachment to the antibody. The glutamic acid to which the sugar unit is bound in the structure of Han and reads on an AA unit having 1 subunit. The structure of Han depicts a linker comprising a valine-citrulline linker linked to a self-immolative p-amino benzoic acid moiety. Han also teaches that BA is an antibody or antigen-binding fragment thereof and that the variable “n” is 1-30 (Han, ¶ 0144). Han teaches pharmaceutical compositions comprising pharmaceutically acceptable excipients comprising the conjugates of Han (Han, ¶ 0186).
Govindan teaches that ADCs comprising exatecan were at the clinical stages of development before the effective filing date of the instant application.
It would be prima facie obvious to one of ordinary skill in the art to conjugate the anti-FOLR1 antibody of the ‘745 Application to the drug-linker moiety of Han. One of ordinary skill in the art would be motivated to do this because the copending claims lack a complete and distinct drug-linker moiety, which the Han reference provides. One of ordinary skill in the art would have a reasonable expectation of success conjugating the anti-FOLR1 antibody of the ‘745 Application to the drug-linker moiety of Han because: 1) the ‘745 teaches that the antibody of the ‘745 Application is suitable for conjugation to drug-linker moieties and 2) the drug-linker moiety of Han is a drug linker-structure taught to produce functional conjugates in the prior art.
It would be prima facie obvious to one of ordinary skill in the art to start with the structure of Han present in the conjugate collectively taught by the ‘745 Application and Han, move the PEG moiety in between the glucamide and the lysine residue, increase the number of PEG repeat units and add another glucamide to arrive at the instant claimed structure PA038 conjugated to the anti-FOLR1 of the ‘745 Application, which is identical to the instant claimed subject matter. One of ordinary skill in the art would be motivated to make such a change in order to arrive at an art hydrophilic equivalent linker to the linkers of Han. The only difference between the linker component of the conjugates of Han and the linker component of PA038 is the position of the PEG moiety, the number of PEG repeat units and the number of glucamide units. Regarding the placement of the PEG moiety, the intended purpose of the PEG moiety in both the instant application and Han is to add hydrophilicity to the molecule. The PEG moiety would add hydrophilicity no matter where it was added. Regarding the number of PEG repeat units, the exact number of repeat units is a matter of routine optimization (see MPEP § 2144.05). In the instant case the parameter being optimized is the number of PEG repeat units and the rationale would be balancing the decreasing increased hydrophilicity added by each PEG repeat vs the bulk added to the molecule by each PEG repeat. Regarding the additional, glucamide unit, Han teaches that the HG of the formulae of Han is permitted to comprise one or more than one terminal sugar moiety (Han, ¶ 094). One of ordinary skill in the art would have a reasonable expectation of success starting with the structure of Han present in the conjugate collectively taught by the ‘745 Application and Han, moving the PEG moiety in between the glucamide and the lysine residue, increasing the number of PEG repeat units and adding another glucamide to arrive at the instant claimed structure PA038 because: 1) the PEG group would still provide hydrophilicity irrespective of where it is positioned, 2) the number of PEG repeat units is a matter of routine optimization with a clearly articulated rationale (see above) and 3) Han teaches that more than one terminal sugar may be present in the linker.
It would be prima facie obvious to one of ordinary skill in the art to further modify the teachings of the ‘745 Application and Han to substitute the MMAE of Han for the exatecan of Govindan. One of ordinary skill in the art would be motivated to make incorporate exatecan into the linker of Han and the antibody of the ‘745 Application in order to arrive at a conjugate comprising a drug that is suitable for clinical use. One of ordinary skill in the art would have a reasonable expectation of success using exatecan in the ADCs comprising the linkers of Han conjugated to the anti-FOLR1 antibodies of the ‘745 Application because Govindan teaches that exatecan was a known clinically suitable drug moiety before the effective filing date of the instant application.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 04/16/2026 have been fully considered but they are not persuasive.
Applicant begins by stating that the instant claimed ADC comprises three components: the FOLR1 antibody, a linker and a cytotoxic drug, with the latter two corresponding to PA038 of the instant claims. Applicant also acknowledges that the teachings of the ‘745 Application were used to provide teachings related to the antibody, Han was used to provide teachings related to the linker and Govindan was used to provide the teachings related to the exatecan cytotoxic drug. Applicant argues that the combined references does not provide one with the instant claimed ADC, citing that four structural modifications are required: 1) Moving the position of the PEG, 2) changing the number of PEG repeat units, 3) changing the terminal sugar of the linker and 4) substituting the MMAE of Han for the exatecan of Govindan. Regarding the linker component (modifications 1-3 from above), Applicant argues Han provides no specific motivation for making the specific modifications that would result in the instant claimed PA038 structure. Applicant specifically argues that the Han reference does not provide motivation to move the PEG moiety to the specific position corresponding to the PEG attachment point of PA038. Applicant also specifically argues that Han provides general but not specific motivation to change the terminal sugar to the corresponding terminal sugar of PA038. Applicant also specifically argues that Han only provides general but not specific motivation to alter the number of PEG repeat units.
In response, the Han reference was applied to demonstrate the vast variety of hydrophilic linker elements that were known in the prior art before the filing date of the instant application. Han teaches a wide variety of hydrophilic moieties, from hydrophilic polymers such as PEG, organic salts, sugars, etc… Han teaches the presence of these hydrophilic moieties at various loci of the linker and Han also teaches variant degrees of linker branching as well as highly variant length of hydrophilic polymers such as PEG. Pages 71-155 of the Han reference each contain around three chemical structures, which demonstrate the variety of hydrophilic moiety identity, positioning, branching and polymer element length (Han, p 71-155). All of these highly variant moieties are taught in the prior art to be permissible for use as DC linkers. Adding known hydrophilic moieties to different positions of an ADC linker, moving hydrophilic moieties around ADC linkers and varying hydrophilic polymer length/branching degree is very routine in the prior art and all of the hydrophilic moieties, branching degrees and positions required for the structure PA038 are taught by Han and one may arrive at structure PA038 via trivial rearrangements of art elements already taught by Han. As such, a linker of structure PA038 is a prima facie obvious variant of the ADC linkers of Han. If, however, Applicant has data that demonstrate ADCs comprising structure PA038 performs unexpectedly well when compared to comparable linker moieties comprising comparable hydrophilic elements (see MPEP § 716.02(a)) and the data offered are commensurate with the scope of the claims the data is offered to support (see MPEP § 716.02(d)), then such a case of prima facie obviousness may be rebutted. Regarding Applicant’s arguments related to the exatecan in place of MMAE substitution, Govindan teaches that exatecan is a suitable cytotoxic drug for ADCs and this provides sufficient teaching to provide one of ordinary skill to swap the MMAE of Han for the exatecan of Govindan and have a reasonable expectation of success forming a functional ADC.
Applicant also makes an argument related to the level of unpredictability in the art, characterizing the design of ADCs as “complex and unpredictable”. Applicant argues, citing the Su and Zhang references, that there is unpredictability with respect to making modifications to linker structure, particularly those that could affect steric hinderance. In response, obviousness requires a reasonable expectation of success, not absolute proof of efficacy (See MPEP § 2143.02(I)). The Han reference teaches hundreds of structures (Han, p 71-155) of highly variant hydrophilic linker moieties comprising various hydrophilic elements at various loci with various degrees of branching and with different hydrophilic polymer lengths and all of these structures are taught in the prior art to be acceptable ADC linker moieties. One of ordinary skill in the art would have a reasonable expectation of success forming a functional ADC linker if all one is doing is moving around and/or substituting common and known ADC linker hydrophilic elements. If Applicant however has data that demonstrate the specific positions, branching degrees and number of repeat units are a critical combination of parameters (see MPEP § 716.01(a)) and said data is commensurate with the scope of the claims the data is offered to support, then such a prima facie case of obviousness may be rebutted.
Claims 87-179 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 73-106 of copending Application No. 18/554745 (Published as US 20240209090A1 on 6/27/2024) in view of Han (Han, et al., WO 2019/094395 A2; Published 05/16/2019, of record) and Govindan (Govindan, et al., Cytotoxic Payloads For Antibody-Drug Conjugates; Chapter 8; Published 2019, of record) as applied to claims 87-161 and 176-178 above and in further view of Ponte (Ponte, et al., Neoplasia 2016 18(12):775-784).
The teachings of the ‘745 Application, Han and Govindan are discussed above.
The collective teachings of the ‘745 Application, Han and Govindan do not teach that the ADC collectively taught by the ‘745 Application, Han and Govindan is administered in methods of treating ovarian cancer.
Ponte teaches that elevated folate receptor alpha (same as FOLR1) expression is characteristic of epithelial ovarian cancer and that the FOLR1-targeting ADC IMGN853 was tested in an IGROV-1 ovarian cancer model and observed to: 1) have synergistic antiproliferative when combined with carboplatin or doxorubicin, 2) potentiate cytotoxic activity of carboplatin via growth arrest and augmented DNA damage and 3) confer increased in vivo efficacy when combined with bevacizumab in platinum resistant EOC (Ponte, Abstract).
It would be prima facie obvious to one of ordinary skill in the art to administer the ADC collectively taught by the ‘745 Application, Han and Govindan in methods of treating ovarian cancer in view of the teachings of Ponte. One of ordinary skill in the art would be motivated to do this in order to better treat ovarian cancer. One of ordinary skill in the art would have a reasonable expectation of success administering the ADC collectively taught by the ‘745 Application, Han and Govindan in methods of treating ovarian cancer because: 1) the ADC collectively taught by the ‘745 Application, Han and Govindan a FOLR1-targeting ADC, and 2) Ponte teaches that FOLR1-targeting ADCs had demonstrated in vivo and in vitro efficacy well-before the effective filing date of the instant Application.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant did not supply any arguments specific to this rejection other than alleging that the Ponte reference does not make up for the alleged deficiencies of the ‘745 Application in view of Han and Govindan.
Conclusion
Claims 87-179 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.
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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