DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 1-5, 7-9, 11-22, 25-29, 40, 44, and 48-51 are pending in this application.
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2 Jun. 2025 has been entered.
Status of Claims
Claims 1-5, 7, 13-18, 21, and 28 are amended. Claims 3-5, 15-17, 20-22, 26, and 28-29 are withdrawn. Claims 6, 10, 23-24, 30-39, 41-43, and 45-47 are cancelled.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11 Aug. 2025 has been considered by the examiner.
Response to Amendment
The amendments filed on 2 Jun. 2025 have been entered.
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) 1-2, 7-9, 11-14, 18-19, 25, 40, 44, and 48-51 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al. (WO 2018/183906 A1; published 4 Oct. 2018), in view of Platzak et al. (US 2002/0068037 A1; published 6 Jun. 2002) and Liu et al. (Bioconjugate Chem.; published 2002) for the reasons cited in the Office action filed on 31 Jan. 2025.
Applicants Arguments
Applicants assert that Wilson does not teach the incorporation of a conjugation site at the positions specified in the instant claims. Wilson teaches that the moiety connecting the macrocycle to the pyridine rings must be linear, unsubstituted methylene group or chain of up to three methylene groups. Even if one skilled in the art would so motivated, they would not have sought to modify the compounds of Wilson at the positions corresponding to variables L1 and L2 because Wilson teaches only unsubstituted methylene groups may be present at these positions. Liu does not remedy the deficiencies of Wilson. While DOTA and TOPA are both chelators., these compounds possess significantly different structures. None of the cited references possess any teaching or suggestion that specific structural modifications to a DOTA chelator would have an equivalent effect when corresponding structural modification are made to a TOPA chelator. Without benefit of hindsight, one or ordinary skill in the art would not look to the chelators of Liu (DOTA) to assess possible modifications to the chelators of Wilson (TOPA). Liu does not possess any teaching or suggestion that repositioning the linker from the pyridine group would even be tolerated. Linkers bound to the 4-position relative to the nitrogen of the pyridine group as in Wilson are oriented 180o away from the coordination site. The methylene positions of the instant claims are more proximal to the metal ion in the radiolabeled complex and it is not evident that this position in particular would tolerate a linker as described in the instant claims and not interfere with metal binding. Applicants have shown that this position is tolerated and permits 99.9% binding of Ac-225. Although Platzek does teach conjugation of a biomolecule to a DOTA chelator, there is no teaching in this reference that would lead one of ordinary skill in that the art to assume that a TOPA chelator will behave in a similar fashion as DOTA.
Applicant's arguments filed 2 Jun. 2025 have been fully considered but they are not persuasive. Wilson does not provide any teaching or suggestion that a PEG linker moiety attached to an isothiocyanate such as PEG-NCS should not be attached to the methylene unit at the arms bridging the pyridine carboxylate and macrocyclic ring structure of macropa. Instead Wilson merely provides for macropa-NCS and provides for the general formula such as (I-h)
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wherein L1 and L2 may be -(CH2)p- where p is 1, 2, or 3. At for example [0019], alkyl groups may be substituted or unsubstituted. Since Wilson does not provide any reason or motivation other than the example macropa-NCS for incorporating a NCS group directly on the pyridinyl where it can influence N,O donor atoms by at least inductive effects, a person of ordinary skill art in view of the knowledge of one of ordinary skill in the art would have seen Wilson as incomplete. Although macropa-NCS and DOTA are structurally different, Wilson alone teaches macropa-NCS and DOTA together. At for example [0146], Wilson teaches the conjugation of macropa-NCS and p-SCN-Bn-DOTA to trastuzumab and starting at [0152], Wilson teaches 225Ac radiolabeling of Tmab conjugates. In the case of p-SCN-Bn-DOTA, the p-SCN-Bn- linker is attached to the macrocycle rather than a chelator arm. Liu teaches p-SCN-Bn-DOTA and a wide range of other chelators optionally comprising a pyridine carboxylate arm and optionally complexing an actinide. When discussing attachment positions of biomolecules, Liu teaches that there at generally three possible approaches to attach a biomolecule to a chelator. In the second approach, the linker for attachment to the biomolecule is placed at an acetate arm, for example as in
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. Liu goes on to warn that the position for the conjugation of a biomolecule can significantly change the thermodynamic stability and kinetic inertness of the metal complex. In the case of macropa-NCS, a person of ordinary skill in the art would have understood that the -NCS can provide an electron withdrawing effect that weakens thermodynamic stability and kinetic inertness. The repositioning of the -NCS linker moiety of macropa-NCS to the methylene unit of the macropa arm is a finite identified predictable solution that yielded no more than predictable results and is therefore obvious. Platzek provides for the 10-(9-isothiocyanato-2-hydroxy-4,7-dioxanonyl)-1,4,7-triscarboxymethyl-1,4,7,10-tetraaacylcododecane that places PEG2-NCS linker moiety at a methylene unit of a coordinative chelator arm. Platzek teaches that conjugate showed good compatibility and good water solubility. The -NCS enables forming antibody conjugates. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the macropa-NCS in Wilson by repositioning the -NCS linker moiety to the methylene unit of the chelator arm using PEG-NCS because the repositioning and PEG-NCS would have been expected to provide 225Ac-labeled antibody conjugates having good compatibility and good solubility and wherein the 225Ac complex has optimal thermodynamic stability and kinetic inertness.
Claim(s) 1-2, 7-9, 11-14, 18-19, 25, 27, 40, 44, and 48-51 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al. (WO 2018/183906 A1; published 4 Oct. 2018), in view of Platzak et al. (US 2002/0068037 A1; published 6 Jun. 2002) and Liu et al. (Bioconjugate Chem.; published 2002), in further view of Timmermand et al. (US 2016/069009 A1; published 22 Dec. 2016) for the reasons cited in the Office action filed on 31 Jan. 2025.
Applicants Arguments
Applicants assert that there is not suggestion in Timmerman teach that a similar type of conjugation, an aryl containing macrocyclic chelator would have identical outcomes.
Applicant's arguments filed 2 Jun. 2025 have been fully considered but they are not persuasive. Both Wilson and Platzek teach antibody conjugation using the -NCS reactive group. The conjugation of an antibody to a PEG2-NCS would have been predictable to one of ordinary skill in the art before the effective filing date. Timmermand teaches and motivates the use of humanized 11B6 antibody targeting moieties since humanized 11B6 antibodies enable targeted treatment (and diagnosis) of prostate cancer. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Wilson so that the antibody conjugate is a 11B6 antibody conjugate since the 11B6 antibody conjugate would have been expected to enable treatment of prostate cancer.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 7-9, 11-14, 18-19, 25, 27, 40, 44, and 48-51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,576,986 B2, in view of Platzak et al. (US 2002/0068037 A1; published 6 Jun. 2002), Liu et al. (Bioconjugate Chem.; published 2002), and Timmermand et al. (US 2016/069009 A1; published 22 Dec. 2016) for the reasons cited in the Office action filed on 21 Jan. 2025.
Applicants Arguments
Applicants assert that the linkers of the ‘986 patent are not PEG groups. The instant claims specify that R1 is polyethylene glycol. The linkers of the instant claims are distinct from the linkers of the ‘986 patent. Platezek, Liu and Timmerman all teach DOTA chelators. There is no expectation that chelators of an entirely different structure will possess identical properties or exhibit similar optimization parameters.
Applicant's arguments filed 2 Jun. 2025 have been fully considered but they are not persuasive. The ‘986 patent claims chelators of formula
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wherein L1 is a generic linker moiety and R11 is a reactive group such as NCS. Platzek and Liu are not deficient for the reasons discussed above. It would have been obvious to a person ordinary skill in the art before the effective filing date to modify the claims of the ‘986 patent so that the L1-R11 is a PEG2-NCS as taught by Platzek and Liu because the PEG2-NCS would have been expected to enable antibody conjugates having good compatibility and good solubility.
Claims 1-2, 7-9, 11-14, 18-19, 25, 27, 40, 44, and 48-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4-5, 10-11, 15, and 35-49 of copending Application No. 17/810,316, in view of Platzak et al. (US 2002/0068037 A1; published 6 Jun. 2002), Liu et al. (Bioconjugate Chem.; published 2002), and Timmermand et al. (US 2016/069009 A1; published 22 Dec. 2016). This is a provisional nonstatutory double patenting rejection.
Applicants Arguments
Applicants assert that there is not teaching or suggestion in the ‘316 application of in Platzek, Liu, or Timmermand that would motivate one of ordinary skill in the art to select PEG moiety over other moieties recited.
Applicant's arguments filed 2 Jun. 2025 have been fully considered but they are not persuasive. The ‘316 application claims chelators of formula
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wherein -L1-R11 may be -PEG2-NSC. Platzek and Liu are not deficient for the reasons discussed above. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the claims of the ‘316 application so that the -L1-R11 is PEG2-NCS as taught by Platzek and Liu because the PEG2-NCS would have been expected to enable an antibody conjugate having good compatibility and good water solubility.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 SEAN R DONOHUE whose telephone number is (571)270-7441. The examiner can normally be reached on Monday - Friday, 8:00 - 5:00 EST.
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618