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 .
Applicants' arguments, filed February 20, 2026, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Response to Amendment
The declaration under 37 CFR 1.132 filed February 20, 2026 is insufficient to overcome the rejection of claims 1, 9 – 11, 18 – 20, 22 – 25, 29, 44, 45 and 48 based upon Nittol (WO 2014/145090) in view of Roosenburg et al. (Mol Pharm, 2014), Uehara et al. (Bioconjugate Chem, 2014) and Tumey et al. (Bioconjugate Chem, 2014) further in view of Morinaka et al. (US 2019/0269804) as set forth in the last Office Action because: the declaration does not actually carry out experiments with the construct of Uehara et al. and do not explain how an expected value of 70% for both the control comparison compound in the declaration and the compound of Uehara et al. were arrived despite the difference in time points and methodologies used and therefore if the results demonstrated are in fact unexpected cannot be determined.
Applicants present results comparing the magnitude of the effect of inclusion of the amino acid segment Met-Ile on two compounds with DOTA as the chelator moiety and either a thiourea or urea group as part of the linker between the DOTA chelator moiety and the rest of the linker proximal to the Met-Ile amino acid segment when present. Renal clearance rates of each compound +/- the Met-Ile segment is calculated per the formula in section 8 of the declaration from the amount of gadolinium in the kidneys determined using ICP-MS 24 hours after each compound was administered. Those results are shown in the table on top of p 4 of the declaration with the “reference conjugate” having the linker comprising a thiourea that is attached via a chelator ring carbon atom and the claimed compound (not the elected species but rather compound 4 of claim 1) having the linker comprising a urea that is attached via a chelator ring nitrogen atom. The obtained percentages of 70% and 94.66% is the reduction in kidney accumulation that occurs when the Met-Ile amino acid segment is added to the compound next to the thiourea or urea respectively. Section 8 of the declaration states that the 70% reduction confirms the expectation of similar results based on Uehara et al to establish what the expected results would be. The results for the claimed compound of a 94.66% reduction when the Met-Ile amino acid segment is added far exceeds the 70% reduction that would be expected with technical advantages that could not have been predicted from Uehara et al. The synergistic differences brought about by the presence of urea linkage compared to a thiourea (O vs S but otherwise identical) and the change in attachment atom on the chelator ring would not have been expected by an ordinary researcher. The other references in the rejection also do not provide a basis for predicting the superior technical advantages demonstrated for our conjugate.
The evidence in the declaration is insufficient to provide evidence of unexpected results sufficient to outweigh the prima facie case of obviousness.
Applied prior art Uehara (IT = iminothiolane; Fab fragment from HERCPETIN®)
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337
941
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Declaration Reference Compound (Fab5 is anti-human MUC1)
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226
698
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Claimed compound from Example 67 (Fab2 is anti-CEACAM5)
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218
709
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The Examiner understands that the change in chelator moiety from that in Uehara et al. eliminates one potentially confounding variable but multiple other variables still remain that have the potential to alter the expected results which if taken into consideration when determining the expected result for the elected species, were not clearly explained. Section 8 of the declaration states that “an ordinary researcher in the field would expect … results similar to Uehara’s NOTA-based conjugates.” As the Examiner understands the information presented, the expected result of 70% reduction in kidney accumulation for the control compound is based on the data provided in Uehara et al. but the Examiner was unable to locate such a value in this reference. Uehara et al. did study the renal accumulation of conjugates that differed in the absence or presence of the Met-Ile linker but used a gamma counter to measure the amount of radioactivity in tissues of interest at various time points (p 2044, col 1, ¶ 5). The longest time point was 6 hours while the only time point reported in the declaration is 24 hours. Using the raw numbers from Table 1, at 6 hours, the addition of the Met-Ile reduced the amount of radioactivity in the kidney by about 88% (raw values of 12.41 and 101.02 inputted into the formula at the bottom of p 3 of the declaration). It is not clear to the Examiner if the quantification method (ICP-MS vs gamma counter) would have any effect and more importantly, is how the results from 6 hours in Uehara et al. would extrapolate to 24 hour time frame set forth in the declaration which has not been addressed and if the particular metal ion used affects the results. The tests were carried out with Gd while claim 11 requires a copper isotope. These makes it less understandable how the expected value of 70% of the control compound was expected from Uehara et al. as even if data at the same time point was provided, it would appear that one of ordinary skill in the art would need to expect the same results for a different chelator and different metal complexed with the chelator conjugated to a different antibody. While each of these differences may not necessarily affect the expected results, no explanation has been given as to why the reasonable expectation is not none of these factors would alter the expected results.
Additionally, any evidence of unexpected results must be reasonably commensurate in scope with the claims. All of the claimed compounds have the same linker attachment to the ring of the chelator moiety but contain additional differences in the remaining structure. The compounds tested most closely align with the fourth compound of claim 4 and even if the results were found to be unexpected, the results must extrapolate to full scope of the claims. The right hand portion of the two molecules reported in the declaration do not match the elected species containing a ring-opened succinimide group and has fewer functional groups than the compounds tested. The tested compounds contain a sulfur atom, alkyl chain and an imine at the attachment point to the biomolecule that are not present in the other claimed compounds. The second and third claimed compounds are the ring opened versions of the first claimed compound but the fifth and final claimed compound contains an additional thiourea, phenyl ring and thioamide group at the attachment point to the biomolecule. If the changing of a carbonyl to a thiocarbonyl in a urea/thiourea group has such a large effect on renal clearance, it then becomes difficult to extrapolate such alleged unexpected results to the full scope of the claimed compounds given these additional structural differences that are much greater than substitution of a sulfur with an oxygen.
The basis for concluding that 70% is the expected result from Uehara and extrapolating any unexpected results to the full scope of the claimed components is insufficient to outweigh the prima facie case of obviousness and therefore the rejection is MAINTAINED.
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.
Claim(s) 1, 9 – 11, 18 – 20, 22 – 25, 44, 45, and 48 were rejected under 35 U.S.C. 103 as being unpatentable over Nittol (WO 2014/145090) in view of Roosenburg et al. (Mol Pharm, 2014), Uehara et al. (Bioconjugate Chem, 2014) and Tumey et al. (Bioconjugate Chem, 2014) further in view of Morinaka et al. (US 2019/0269804). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed September 23, 2025 and those set forth herein.
Applicants traverse this rejection on the grounds that not all claim limitations are disclosed or suggested by the cited references. The pending claims recite a specific linker demonstrated to have a technical effect of such a linker with or without the Met-Ile portion exhibited different kidney reduction and those with Met-Ile having a greater reduction. The Office Action fails to address this point and continues to rely on the Z1-Y-X-W moieties of Nittol but Nittol does not disclose the recited space moiety. No reasoning to arrive at the recited spacer from the infinite number of Z1-Y-X-W generically disclosed spacer options has been provided. The other cited references similarly fail given the thiourea linkers in Morinaka and Uehara; the lack of spacer moieties in Roosenburg and Tumey discloses succinimide ring opening chemistry, not spacer moieties.
These arguments are unpersuasive. There are not an infinite number of Z1-Y-X-W spacer moieties in Nittol although there are a large number of possibilities including both urea and thiourea linkages (e.g., when the second option for Y in ¶ [0009] given the possible overall structure and possible values for R1, R3 and R17). The additional applied references provide specific details as to benefits of the selection of, for example, the dipeptide of Met-Ile as taught by Uehara et al. While no single reference teaches the exact structure of the claimed linker, the structure of the claimed linker is rendered obvious as discussed in greater detail in the September 23, 2025 Office Action.
Applicants also argue that the combination of Nittol and Roosenburg is improper and the combination requires a change in the fundamental purpose, replacement of a cytotoxic drug with an imaging chelator, adoption of a small peptide imaging system to a large antibody therapeutic system and reconciliation of incompatible pharmacokinetic requirements. The conjugates of Nittol would not reasonably be expected to be cleaved in non-tumor tissue and the materials in Roosenburg image based on a receptor overexpressed on cancer cells, addressing fundamentally different problems requiring incompatible design considerations relating to imaging and therapeutic effects. Nittol uses antibodies and requires long circulating times while Roosenburg uses substantially smaller peptides with rapid clearance times. One of ordinary skill would have no reason to substitute the cytotoxic drug of Nittol with the diagnostic imaging chelator of Roosenburg.
These arguments are unpersuasive. "The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference .... Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 413,425 (CCPA 1981) MPEP 2145(III). Therefore all features of the conjugates in the secondary reference need not be incorporated into the primary reference. The rejection does not require replacement of the antibodies, that provide the selective and specific delivery to the desired tissue based on the antibody selected, with a peptide as in Roosenburg et al. One of ordinary skill in the art, when their knowledge and also based on the combined explicit, implicit and inherent teachings of all of the applied prior art references is considers, is aware that targeted-conjugates can use antibodies or peptides for targeting purposes and can be conjugated to therapeutic moieties for therapeutic purposes or to imaging agents for imaging purposes and such changes do not result in the presence of a chelator with an isotope such as 64Cu radionuclide patentably distinguishing the instant claims over the applied prior art.
Applicants also argue that two other Uehara references, referred to as Uehara3 and Uehara4, without complete citations being provided, teach the Met-Val-Lys linker being preferred over the Met-Ile linker with no performance parameter of Met-Ile being superior to Met-Val-Lys. One having ordinary skill would have no credible reason to look to Uehara3 or Uehara4 when contemplating a Met-Ile linker as presently claimed. A list of all the required changes is set forth in paragraph bridging p 19 and 20 of the remarks filed February 20, 2026.
These arguments are unpersuasive. Even if found in a single document, “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). MPEP 2123, emphasis added. Not all possible linker applications for all possible combinations were studied and therefore that another linker provides a slightly larger improvement does not take away from the fact that an Met-Ile linker improved renal clearance as disclosed in the applied Uehara et al. reference. The Examiner was unable to locate any teachings in Nittol of suppressed renal elimination being a required feature of all constructs and the arguments do not address all of the applied prior art documents that are relied upon to teach all of the claim limitations.
Applicants also argue secondary considerations with data from the specification as filed being summarized in a table indicating the superiority of the -NH-CH2-(1,4-Ph)NH-C(C=O)- linker. Improved kidney excretion is demonstrated for conjugates of formula 1 of the instant claims compared to other components that would have been just as “motivated” for use in the disclosure of Nittol, Roosenburg, Uehara, Tumey and Morinaka. The Met-Val-Lys linker compared to Met-Ile discussed above are reiterated in this section. The results of a 4-5 fold improvement with the claimed spacer and linker far exceed what would have been expected or predicted based on the prior art with the experimental data providing compelling evidence of unexpected results that are commensurate in scope with the claims. The declaration addressed above is also discussed in remarks beginning at the bottom of p 23 of the Remarks.
These arguments are unpersuasive. At least one instance of the structures set forth in the table of the remarks appears to be inconsistent with that in specification as filed as Table 15 of the specification indicates a linker structure of -Met-Ile-NH-(CH2)2-Z1(#S) while the remarks state Z1(#N). Compound 104 was the elected species and as shown in Table 37 comprises two different ring opened succinimides in the linker but the table states “closed succinimide” which would then be compound 101 in the same table. The data shows a difference in behavior but the question remains what the expected result would be. The table does not show the complete structure of the attachment chemistry for compound 112 since as shown in table 38, not only is a thiourea group present, there is a short alkyl chain on one side of the thiourea group and -Ph-NH-C(=S)- portion on the other side. And based on the declaration discussed above, if changing from thiourea to urea causes such a large change in renal clearance, then changes elsewhere in the linker such as the addition of a thiourea group or other functional groups could also result in large effects that may or may not be unexpected. Such information has not been addressed and Applicants bear the burden of establishing what the expected results would be and explaining how the observed effects are in fact unexpected to be reasonably commensurate in scope with the claims. Side by side comparisons with compounds of the prior art have not been carried out and as discussed in greater detail in the section above regarding the declaration and will not be reiterated here.
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.
Applicants traverse the nonstatutory double patenting rejections on the same grounds as discussed above. The disclosures and claimed subject matter of US 10,507,251 and 10,517,966 are similar to Morinaka since the three patents are members of the same family and all suffer from similar deficiencies in suggesting the presently claimed conjugates. The claims in Morinaka are directed to a fluorescent label and do not comprise a 3-arm DOTA labeling moiety as presently claimed.
These arguments are unpersuasive. Each nonstatutory double patenting rejection relies on additional references to render obvious the use of a metal chelate rather than a fluorescent label and for the specific linker claimed. As discussed in greater detail above, the evidence of record does not establish evidence of unexpected results that is reasonably commensurate in scope with the claims sufficient to outweigh the prima facie case of obviousness based on the claims of each patent in view of the additional applied prior art and the knowledge of one of ordinary skill.
Claims 1, 9 – 11, 18 – 20, 22 – 25, 44, 45, and 48 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 17 of U.S. Patent No. 10,507,251 in view of Nittol (WO 2014/145090), Roosenburg et al. (Mol Pharm, 2014), Uehara et al. (Bioconjugate Chem, 2014) and Tumey et al. (Bioconjugate Chem, 2014). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed September 23, 2025 and those set forth herein.
Claims 1, 9 – 11, 18 – 20, 22 – 25, 44, 45, and 48 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 16 and 25 - 32 of U.S. Patent No. 10,517,966 in view of Nittol (WO 2014/145090), Roosenburg et al. (Mol Pharm, 2014), Uehara et al. (Bioconjugate Chem, 2014), Tumey et al. (Bioconjugate Chem, 2014) and Morinaka et al. (US 2019/0269804). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed September 23, 2025 and those set forth herein.
Claims 1, 9 – 11, 18 – 20, 22 – 25, 44, 45, and 48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 21 of U.S. Patent No. 11,679,166 in view of Nittol (WO 2014/145090), Roosenburg et al. (Mol Pharm, 2014), Uehara et al. (Bioconjugate Chem, 2014) and Tumey et al. (Bioconjugate Chem, 2014). Nittol (WO 2014/145090), Roosenburg et al. (Mol Pharm, 2014), Uehara et al. (Bioconjugate Chem, 2014) and Tumey et al. (Bioconjugate Chem, 2014). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed September 23, 2025 and those set forth herein.
Claims 1, 9 – 11, 18 – 20, 22 – 25, 44, 45, and 48 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 25 of U.S. Patent No. 12,202,908 in view of Nittol (WO 2014/145090), Uehara et al. (Bioconjugate Chem, 2014), Tumey et al. (Bioconjugate Chem, 2014) and Morinaka et al. (US 2019/0269804). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed September 23, 2025 and those set forth herein.
Conclusion
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 Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 pm.
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618