DETAILED ACTION
This Office action details a non-final action on the merits for the above referenced application No. Claims 1, and 3-16 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 24 Dec. 2025 has been entered.
Status of Claims
Claim 1 is amended. Claim 2 is cancelled.
Response to Amendment
The amendments filed on 24 Dec. 2025 has been entered.
The declarations under 37 CFR 1.132 filed 24 Dec. 2025 are insufficient to overcome the rejection of claim as set forth below because of the reasons set forth below.
Dr. Burak declares that following catabolism and/or metabolism the instant radioimmunoconjugates are eliminated about 40% post administration thus retaining about 60% of the total radioactivity in the body. The radioimmunoconjugates of the invention unexpectedly reduce total radioactivity in the body at least 3-fold thereby reducing off target toxicity. The data presented clearly demonstrate that [177Lu]-compound-B-HuMIgG and [177Lu]-compound C-HuMIgG are unexpectedly superior to [177Lu]-compound A-HuMIgG. The data presented clearly demonstrate that [177Lu]-compound B-HuMIGF-1R and [177Lu]-compound C-HuMIGF-1R are unexpected superior to [177Lu]-compound A-HuMIGF-1R exhibiting much higher total excretion of radioactive metal at 7 d post administration. It could not have been predicted that compounds of formula I would result in reducing total radioactivity by increasing the excretion of catabolic/metabolic products. The comparative data clearly demonstrate that [177Lu]-compound B-HuMIGF-1R, [177Lu]-compound C-HuMIGF-1R, [177Lu]-compound C1-HuMIGF-1R, [177Lu]-compound C2-HuMIGF -1R and [177Lu]-compound C3-HuMIGF-1R are unexpectedly superior to [177Lu]-compound A-HuMIGF-1R. The radioimmunoconjugates were effective at reducing total radioactivity by increasing the catabolic/metabolic produced while maintaining the pharmacokinetics of the intact molecule.
The Dr. Burak’s declarations filed 24 Dec. 2025 have been fully considered but they are not persuasive. A declaration of unexpected results must contain a comparison with the closest prior art in order to be effective to rebut a prima facie case of obviousness. See In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). The closest prior art is Valliant who teaches methods of radiation treatment planning and radiation treatment using antibody conjugates including DOTA conjugated antibody conjugates comprising a residualizing linker carrying ionic groups expected to affect the pharmacokinetics and excretion profile of the antibody conjugate. Suitable radiometals include 177Lu and 225Ac. None of the Dr. Burak declarations nor the instant specification contain a comparison with prior art of Valliant. A showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. Instant claim 1 allows for metal complexes wherein the metal is selected from Bi Pb, etc, and such metals included stable metal isotopes. In the case of the stable metal isotopes, the claimed compounds of formula I would not be expected to be more effective at reducing total radioactivity. In addition, each of the examples in the declarations and specification use 177Lu as the radiometal. For example, 47Sc would be expected to exhibit different thermodynamic and kinetic stability with the DOTAGA chelator and therefore show a different pharmacokinetic and excretion profile. Accordingly, the claims are not commensurate in scope with the examples of unexpected results.
Expected beneficial results are evidence of obviousness. See In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). Jamous teaches that the PEG spacers such as the claimed PEG spacer leads to an improved pharmacokinetic profile accelerating washout from excretory organs such as kidney and liver. Accordingly, a person of ordinary skill would have expected to the claimed antibody conjugates comprising a short PEG spacer such as the claim PEG3 spacer to exhibit high total excretion of radioactive metal at 7 d post administration.
Response to Arguments
The rejection of claims 1, 3-14 and 16 under 35 USC 103 as being unpatentable over Valliant et al. (WO 2015/073575 A2; published 21 May 2015), in view of Hoffman et al. (US 2006/0067886 A1; published 30 Mar. 2006) and Price et al. (Chem. Soc. Rev.; published 2014) is withdrawn.
The rejection of claims 1, 3-14 and 16 under 35 USC 103 as being unpatentable over Valliant et al. (WO 2015/073575 A2; published 21 May 2015), in view of Hoffman et al. (US 2006/0067886 A1; published 30 Mar. 2006) and Price et al. (Chem. Soc. Rev.; published 2014) , in further view of Fleuren et al. (Mol. Oncol.; published 2014) is withdrawn.
In view of Applicants amendments, the rejection of claims 1, and 3-16 on the ground of non-statutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,093,741 B1, in view of Valliant et al. (WO 2015/073575 A2; published 21 May 2015), Hoffman et al. (US 2006/0067886 A1; published 30 Mar. 2006) and Fleuren et al. (Mol. Oncol.; published 2014) is withdrawn.
In view of Applicants amendments, the rejection of claims 1, and 3-16 on the ground of non-statutory double patenting as being unpatentable over claims 1-40 of U.S. Patent No. 11,433,148 B1, in view of Valliant et al. (WO 2015/073575 A2; published 21 May 2015), Hoffman et al. (US 2006/0067886 A1; published 30 Mar. 2006) and Fleuren et al. (Mol. Oncol.; published 2014) is withdrawn.
New Grounds of Rejection
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, and 4-14 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.
In addition, the recitation of wherein the metal of said metal complex is selected from the group consisting of Bi, Pb,…, a lanthanide, an actinide, or is indefinite because the claim is directed to a method of radiation treatment planning or radiation treatment and it is not clear how radiation treatment planning or radiation treatment can be done using a metal that is not radiometal and suitable for diagnosis and/or therapy. Claims 4-14 depend to claim 1 and fall therewith.
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 14-16 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 case, claims 14-16 depend to claim 1 and recite 225Ac or a progeny thereof; however, while claim 1 does recite 225Ac, it does not recite or progeny thereof and it is not clear if claims 14-16 further limit claim 1. 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.
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 and 3-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Valliant et al. (WO 2015/073575 A2; published 21 May 2015), in view of Jamous et al. (Nucl. Med. Biol.; published 2014) and Price et al. (Chem Soc. Rev.; published 2014; see attached 892), in further view of Fleuren et al. (Mol. Oncol.; published 2014).
Valliant et al. teach residualizing linkers and uses thereof (see title). Valliant et al. teach a method of treating cancer the method including administering to a subject in need thereof a foregoing conjugate. Valliant et al. teach a method of radiation treatment planning, the method including administering to a subject in need thereof any of the foregoing conjugates or pharmaceutical compositions. Valliant teach a method of treating cancer the method comprising administering to a subject in need thereof a first dose of any of the foregoing conjugates in an amount effective for treatment planning followed by administering a second dose of any of the foregoing conjugates in a therapeutically effective amount. In a certain embodiment the first dose and the second dose are either the same or different. The cancer is a solid tumor cancer for example breast cancer, etc. The method further includes administering an antiproliferative agents and any of the forgoing conjugates or compositions and the antiproliferative are administered within 28 d of each other (see pgs. 17, 27). Valliant et al. teach polypeptide-linker-detection agent conjugates where the polypeptide may be an IgG. The antibodies may be human or humanized antibodies. The antibodies may be of any type (IgG) and class (IgG1) (see pgs. 31-33). Radioisotopes and radionuclides include 111In and 225Ac. Chelating agents include edta, etc (see pg. 35). Antiproliferative agents include immunomodulators (see pg. 41). Valliant et al. teach a conjugate of formula
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wherein a metal is chelated to the structure (see pg. 11, claim 156) and conjugates of formulas
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and
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wherein iodine is 123I, 124I, 125I or 131I (see pg. 9). These compounds read in part on a compound of instant formula I A-L1-(L2)n-B wherein A is an imaging moiety such as a chelating moiety, L1 is a C8 alkyl. Valliant et al. teach residualizing linkers designed to retain the label intracellularly after lysosomal degradation of the internalized polypeptide conjugate. Valliant et al. teach linkers of formula II wherein L1, L2, and L3 may be absent/C1-C6 alkyl/heteroalkyl, R6 and R7 may be L4-B where L4 is C1-C6 alkyl/heteroalkyl. The linker portion of the module may be any length or lipophilicity to allow for enhanced physiochemical properties and biological activity (see pg. 37).
Valliant et al. do not teach administering to the subject in need thereof an effective amount of a compound having the structure of formula I wherein the compound is
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.
Jamous et al. teach PEG spacers of different length influence the biological profile of bombesin based radiolabeled antagonists (see title). The introduction of low molecular weight polyethylene glycol may lead to improved pharmacokinetics, in particular to lower kidney uptake and short retention in the kidneys without causing loss of affinity (see pg. 465). Jamous et al. teach structural formulae of four conjugates: MJ1, MJ2
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, MJ3
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, and MJ4
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(see Fig. 1). The PEG spacers do not influence the absolute tumor uptake but the pharmacokinetics of the radiopeptides resulting in impressive tumor to kidney ratios (see pg. 468). The presence of the PEG4 spacer in 177Lu-DOTA-PESIN led to an improved pharmacokinetic profile accelerating the wash out from the excretory organs such as kidney and liver when compared to bombesin having alkyl spacers (see pg. 468). The derivatives having the PEG4 as spacer showed increased tumor to kidney ratios and faster background clearance compared to the one having a Gly-aminobenzoic acid as spacer (see pg. 469).
Price et al. teach matching chelator to radiometals for radiopharmaceuticals (see title). For therapy applications particle emitters such as 111In and 225Ac are being heavily investigated typically in conjunction with antibody vectors (immunoconjugates) or peptides (see pg. 260). Price et al. teach that DOTA is the primary workhorse chelator for radiometal chemistry, and is currently the gold standard for isotopes including 111In and 225Ac. Some common bifunctional DOTA derivatives use one of the carboxylic arms for the site of vector conjugation, effectively blocking one of the coordination arms. DOTAGA solves this problem by conjugating to vectors through the carbon backbone and side arm functionalization. This DOTA derivative retains its maximum potential denticity as well as the same thermodynamic stability and kinetic inertness as unadulterated DOTA (see pgs. 266-267).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the methods of Valliant et al. (methods of radiation treatment planning and radiation treatment wherein the method comprises administering to a subject in need thereof an effective amount a DOTA-linker-antibody complex such as a 111In or 225Ac complex) so that the compound is
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(antibody-PEG3-DOTAGA) as taught by Valliant et al., Jamous et al., and Price et al. because the PEG3 linker would have been expected to provide an equivalent antibody conjugate suitable for radiation treatment planning/radiation treatment advantageously exhibiting an accelerated excretion profile and fast background clearance and because the DOTAGA chelator would have been expected to advantageously enable chelation of radiotherapeutic metals including 111In and 225Ac such that conjugate to the targeting vector does not block one of the coordinating arms providing maximum potential denticity.
It would have been obvious to person of ordinary skill in the art to further modify the methods of Valliant et al. by further substituting the antibody of the obvious antibody-PEG3-DOTAGA complex with a human or humanized IgG antibody that does not specifically bind to IGF-1R as taught by Valliant et al.. because it would have been expected to provide an equivalent targeted antibody conjugate suitable for use in radiation treatment planning/radiation treatment. There would have been a reasonable expectation of success since Valliant et al. teach that the antibody may be a human or humanized IgG antibody of any type (IgG1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Valliant et al. by further forming a 225Ac-DOTAGA-PEG3-human/humanized IgG antibody that does not bind specifically to IGF-1R and then administer an effective amount of that complex to a subject in need thereof optionally repeatedly (first and second doses that the same or different) as taught by Valliant et al. and Price et al. because it would have been expected to advantageously enable radiotherapy over time using a radionuclide well suited for delivering massive toxicity to target cells. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Valliant et al. by further administering an antiproliferative agent or an immunomodulatory agent optionally wherein the compound of formula I and the antiproliferative agent are administered within 28 d of each other or the compound and the immunomodulatory agent are administered within 90 d of each other as taught by Valliant et al. because it would have been expected to advantageously enable combination therapies with other agents. The time between treatments of the compound of formula I and the antiproliferative agent/immunomodulatory agent are result effective variables that a person of ordinary skill in the art would have been motivated to modify at the time of the invention. A person of ordinary skill in the art would have arrived at a time within 28 d for the antiproliferative agent and a time within 90 d for the immunomodulatory agent in order to achieve optimal combinatorial (a synergistic) effect.
Valliant et al. do not further teach that the compound of formula I in said first dose comprises 111In and the compound of formula I administered in said second dose comprises 225Ac or a progeny thereof.
Fleuren et al. teach theranostic applications of antibodies in oncology (see title). Fleuren et al. teach that antibody theranostics combine the diagnostic and therapeutic potential of an antibody thereby selecting those patients who are most likely to benefit from antibody treatment (see abstract). Fleuren et al. teach 111In-labeled antibodies for theranostic tests (see table 2). Fleuren et al. teach 111In-trastuzumab SPECT (IgG antibody that does not bind IGF-1R; see pg. 805). For 177-J591 and 90Y-J591 RIT selection, 111In-J591 imaging can be performed since distribution patterns are generally comparable (see pg. 808). 111In-girentuximab was used for diagnostic imaging, and only patients with visible CAAIX-targeting received high dose 177Lu-girentuximab (see pg. 808).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify the methods of Valliant et al. by further forming a 111In-DOTAGA-PEG3-IgG antibody complex that does not bind specifically to IGF-1R and then administer a first dose of that complex prior to administering the obvious 225Ac-DOTAGA-PEG3-IgG antibody complex that dose not bind specifically to IGF-1R for radiation treatment as taught by Fleuren et al. because it would have been expected to advantageously enable therapeutic applications wherein the first dose of the 111In-DOTAGA-PEG3 IgG antibody complex enables patient selection and monitoring.
Applicants Arguments
Applicants assert that each of the compounds of Valliant require compounds of formula I. A person of ordinary skill would not substitute for a different compound that is not encompassed within the genus of the formula. Applicants assert impermissible hindsight. Such a modification would render Valliant unsatisfactory for its intended purpose. Valliant is silent about reducing total radioactivity by increasing the extent of excretion of the catabolic/metabolic products. The conclusion of Price demonstrates the complexity of preparing radioimmunoconjugates. One of ordinary skill would have no reason to combine Price with any of the other cited references. Fleuren merely relates to general approaches for theranostic applications of antibodies in oncology. Fleuren provides no teaching or suggestion of making and using radioimmunoconjugate for radiation therapy.
Applicant's arguments filed 24 Dec. 2025 have been fully considered but they are not persuasive. The Dr. Burak declarations were found ineffective for the reasons discussed above. Valliant provides for methods of radiation treatment planning and radiation treatment wherein the methods comprise administering to a subject in need thereof an effective amount of an antibody conjugate comprising an antibody including a human IgG antibody that does not bind specifically to IGF-1R. According to Valliant, the linker portion of the antibody conjugate leads to better target to non-target ratios and therapeutic effects. Jamous provides for PEG linkers that influence the biological profile of the peptide targeting agents. The short PEG spacer led to improved pharmacokinetic profile accelerating wash out from the excretory organs such as the kidney and liver. The study shows that pegylation effectively enhances the radiotherapeutic efficacy improving tumor targeting and prolonging tumor retention. The derivatives having a short PEG spacer showed increased tumor-to-kidney ratios and faster background clearance. A recognized advantage is the strongest reason to combine. It would have been obvious to a person of ordinary skill in the art before the effective filing to modify the methods Valliant by substituting the linker portion of antibody conjugates with a PEG3 as taught by Jamous because the PEG3 linker would have been expected to advantageously enable accelerated washout from excretory organs leading to enhanced radiotherapeutic efficacy improving tumor targeting and prolonging tumor retention. The purpose of Valliant is to provide antibody conjugates for radiation treatment planning or radiation treatment. The substitution of the linkers in Valliant with a PEG3 linker taught and suggested by Jamous would have been expected to result in an antibody conjugate capable of enhanced radiation treatment planning or radiation treatment. The proposed modification would not have changed the principle of operation of Valliant. Both Valliant and Jamous relate to radiation treatment planning or radiation treatment. A person of ordinary skill in the art would have reasonably considered Valliant and Jamous in combination without the benefit of hindsight analysis. Price teaches the DOTAGA as advantageous in comparison to the DOTA chelator. The DOTAGA retains maximum potential denticity as well as thermodynamic stability and kinetic inertness as unadulterated DOTA. A recognized advantage is the strongest reason to combine. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Valliant so that the DOTAGA chelator replaces the DOTA chelator because the DOTAGA chelator would have been expected to advantageously enable chelation of radiometals such as 111In and 225Ac while retaining maximum denticity. Fleuren teaches and motivates forming a 111In-DOTAGA-PEG3-IgG antibody that does not bind specifically to IGF-1R and then administer a first dose of that complex prior to administering the obvious 225Ac-DOTAGA-PEG3-IgG antibody complex that does not bind specifically to IGF-1R for radiation treatment because it would have been expected to advantageously enable a first dose of 111In-DOTAGA-PEG3-IgG antibody that enables patient selection and monitoring.
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 and 3-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,093,741 B1, in view of Valliant et al. (WO 2015/073575 A2; published 21 May 2015) and Fleuren et al. (Mol. Oncol.; published 2014).
Claims 1-18 of U.S. Patent No. 10,093,741 B1 claim a compound comprising a structure
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wherein B is an antibody (AVE1642) and a method of treating cancer, the method comprising administering to a subject in need thereof an effective amount of the above compound in a pharmaceutically acceptable carrier wherein the cancer is a solid cancer or the cancer is breast cancer and wherein the method further comprises an antiproliferative agent, or radiation sensitizer or immunomodulatory agent and wherein the radionuclide is 225Ac or 111In.
Claims 1-18 of U.S. Patent No. 10,093,741 B1 do not claim a method wherein the antibody is a human/humanized antibody the does not specifically bind to IGF-1R. Claims 1-18 of U.S. Patent No. 10,093,741 B1 do not claim a method wherein the method comprises administering to a subject having cancer a first dose of the compound of formula I, followed by administering a second dose of the compound of formula I optionally wherein the first and second doses are the same or different optionally wherein the first dose is in an amount effective for treatment planning and the second is effective for radiation treatment optionally wherein the first dose comprises 111In or 225Ac and the second dose comprises 225Ac and optionally wherein the compound of formula I and the antiproliferative agent or immunomodulatory agent are administered within 28/90 d of each other.
Valliant et al. teach as discussed above.
Fleuren et al. teach as discussed above.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify claims 1-18 of U.S. Patent No. 10,093,741 B1 so that B is a human or humanized antibody not binding specifically to IGF-1R as taught by Valliant et al. and Fleuren et al. because the antibody that does not bind specifically to IGF-1R would have been expected to provide an equivalent antibody conjugate suitable for use in radiation treatment planning/radiation treatment of cancers such as HER2 expressing cancers. There would have been a reasonable expectation of success since Valliant et al. teach that the antibody may be a human or humanized IgG antibody of any type (IgG1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify claims 1-18 of U.S. Patent No. 10,093,741 B1 by administering a first dose of the obvious compound and a second dose of the obvious compound which is the same or different from dose optionally wherein the first dose is effective for treatment planning and the second dose is effective for radiation treatment and optionally wherein the first dose comprises 111In or 225Ac and the second dose comprises 225Ac as taught by Valliant et al. and Fleuren et al. because it would have been expected to advantageously enable treatment over time by repeated administration and/or treatment planning by imaging prior to radiation treatment. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify claims 1-18 of U.S. Patent No. 10,093,741 B1 so that the compound and the antiproliferative agent are administered within 28 d of each other or so that the compound and the immunomodulator agent are administered within 90 d of each other as taught by Valliant et al. because it would have been expected to provide an equivalent method of treatment and/or advantageously enhanced treatment by a combinatorial effect.
Claims 1 and 3-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-40 of U.S. Patent No. 11,433,148 B1, in view of Valliant et al. (WO 2015/073575 A2; published 21 May 2015) and Fleuren et al. (Mol. Oncol.; published 2014).
Claims 1-40 of U.S. Patent No. 11,433,148 B2 claim a compound of formula
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wherein the radionuclide is 225Ac or 111In and B is an antibody (AVE1642) and methods of treatment planning and/or radiation treatment comprising administering to a subject a diagnostically effective amount of the compound and/or administering a therapeutically effective amount of the compound optionally wherein the first dose and second dose are the same or different and wherein the cancer is solid and the cancer is a breast cancer optionally wherein the method comprises administering the compound and an antiproliferative agent within 28 d of each other or the compound and immunomodulatory agent within 90 d of each other.
Claims 1-40 of U.S. Patent No. 11,433,148 B2 do not claim a method wherein the antibody is a human/humanized IgG antibody that does not specifically bind to IGF-1R. Claims 1-40 of U.S. Patent No. 11,433,148 B2 do not claim a method wherein the compound of formula I administered in the first dose comprises 111In or 225Ac and the compound administered in the second dose comprises 225Ac.
Valliant et al. teach as discussed above.
Fleuren et al. teach as discussed above.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify claims 1-40 of U.S. Patent No. 11,433,148 B2 so that the antibody is a human or humanized IgG antibody that does not specifically bind to IGF-1R as taught by Valliant et al. and Fleuren et al. because it would have been expected to provide an equivalent conjugate and method suitable for use in radiation treatment planning/radiation treatment including HER2 expressing cancers. There would have been a reasonable expectation of success since Valliant et al. teach that the antibody may be a human or humanized IgG antibody of any type (IgG1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify claims 1-40 of U.S. Patent No. 11,433,148 B2 so that the obvious compound of formula (I) administered in the first dose comprises 111In or 225Ac and the obvious compound administered in the second dose comprises 225Ac as taught by Valliant et al. and Fleuren et al. because it would have been expected to advantageously enable radiotherapy over time (repeated doses) using a radionuclide well-suited for delivering massive toxicity to target cells and/or radiation treatment planning by imaging followed by radiotherapy (theranostic applications).
Applicants Arguments
The response filed on 24 Dec. 2025 does not address the Double Patenting rejections. Applicants assert unexpected results. Following catabolism and/or metabolism, the radioimmunoconjugates of the claimed methods are eliminated by about 40% post administration thus retaining about 60% of the total radioactivity in the body. The radioimmuno conjugates unexpectedly reduce the total radioactivity in the body by at least 3-fold thereby significantly reducing off target toxicity. It was observed that the improved excretion profile on Compound B and Compound C when conjugated to antibodies was general and reproducible.
Applicant's arguments filed 24 Dec. 2025 have been fully considered but they are not persuasive. The Dr. Burak declarations were found ineffective for the reasons discussed above. In addition, each of the above patents claim antibody conjugates using the same linker, chelator and radiometal attached to an IgG antibody as the antibody conjugates describe in the declarations of unexpected results. Therefore, the antibody conjugates in each of the above patents must be capable of producing the same unexpectedly improved excretion profiles as described in declarations. The response itself states that the improved excretion profile was general and reproducible.
Claims 1 and 3-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,191,854 B2, in view of Valliant et al. (WO 2015/073575 A2; published 21 May 2015) and Fleuren et al. (Mol. Oncol.; published 2014).
Claims 1-16 of U.S. Patent No. 11,191,854 B2 claim a compound of formula A-L1-(L2)n-B wherein the compound is selected from
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292
652
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and
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290
636
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and wherein B is a human or humanized IgG antibody or an antigen binding fragment thereof and wherein the metal of the metal complex is 177Lu or 225Ac and a pharmaceutical composition comprising a compound thereof.
Claims 1-16 of U.S. Patent No. 11,191,854 B2 do not claim the instant method of radiation treatment planning or radiation treatment comprising administering to a subject in need thereof an effective amount of the formula I wherein B is a human or humanized IgG antibody that does not specifically bind to IGF-1R optionally wherein the method comprises administering to a subject a first dose of formula I followed by a second dose of formula I optionally wherein the first and second dose are the same or different and effective for radiation treatment and wherein the cancer is a solid tumor such as a breast cancer and optionally the method further comprising administering an antiproliferative agent within 28 d of each other or an immunomodulatory agent within 90 d of each other and optionally wherein the first dose is 111In or 225Ac and the second dose is 225Ac.
Valliant et al. teach as discussed above.
Fleuren et al. teach as discussed above.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify claims 1-16 of U.S. Patent No. 11,191,854 B2 so that B is a human or humanized antibody not binding specifically to IGF-1R as taught by Valliant et al. and Fleuren et al. because the antibody that does not bind specifically to IGF-1R would have been expected to provide an equivalent antibody conjugate suitable for use in radiation treatment planning/radiation treatment of cancers such as HER2 expressing cancers. There would have been a reasonable expectation of success since Valliant et al. teach that the antibody may be a human or humanized IgG antibody of any type (IgG1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify claims 1-16 of U.S. Patent No. 11,191,854 B2 by administering a first dose of the obvious compound and a second dose of the obvious compound which is the same or different from dose optionally wherein the first dose is effective for treatment planning and the second dose is effective for radiation treatment and optionally wherein the first dose comprises 111In or 225Ac and the second dose comprises 225Ac as taught by Valliant et al. and Fleuren et al. because it would have been expected to advantageously enable treatment over time by repeated administration and/or treatment planning by imaging prior to radiation treatment. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify claims 1-16 of U.S. Patent No. 11,191,854 B2 so that the compound and the antiproliferative agent are administered within 28 d of each other or so that the compound and the immunomodulator agent are administered within 90 d of each other as taught by Valliant et al. because it would have been expected to provide an equivalent method of treatment and/or advantageously enhanced treatment by a combinatorial effect.
Conclusion
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618