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 .
Acknowledgment and Claim Status
The Examiner acknowledges receipt of the amendment filed 12/1/2025 wherein claims 1-4, 15, and 16 were amended; claim 14 was canceled; and claim 21 was added.
Note(s): Claims 1-13 and 15-21 are pending.
Applicant’s Election
Once again, the Examiner acknowledges receipt of the elected species filed 3/24/2025. Applicant elected the species wherein: biorthogonal ligation moiety is trans-cyclooctene; active agent is cetuximab; polymer spacer is polyethylene glycol (PEG); biomarker is EGFR; detectable label is 64Cu, and targeting moiety is an antibody. Claims 1-3, 5-8, 10-13, and 15-21 read on the elected species.
Note(s): Claims 1-13 and 15-21 are pending.
Initially, Applicant’s elected species was searched. However, since no prior art was found to reject the claims, the search was expanded to the species disclosed in the cited prior art below. The search was not further extended because prior art was found which could be used to reject the claims. The full scope of the pending claims was not searched.
Withdrawn Claims
Claims 4 and 9 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected species.
Priority
This application is a DIV of 16/179,785 filed 11/2/2018 (now US Patent No. 12,029,798);
16/179,785 is a CON of PCT/US2017/030652 filed 5/2/2017;
PCT/US2017/030652 claims benefit to PRO 62/373,036 filed 8/10/2016;
PCT/US2017/030652 claims benefit to PRO 62/346,783 filed 6/7/2016; and PCT/US2017/030652 claims benefit to PRO 62/330,622 filed 5/2/2016.
Note(s): The earliest effective filing date of the pending invention is 5/22016.
Claim Interpretation
Independent claim 1 is directed to a therapeutic probe comprising:
(i) at least one biorthogonal ligation moiety selected from the group consisting of trans-cyclooctene, cyclooctyne, alkyne, alkene, photo-DIBO, cyclopropenone, tetrazine, azide, tetrazole, and photo-tetrazole;
(ii) at least one active agent, wherein the at least one active agent is selected from the group consisting of cetuximab, pertuzumab, trastuzumab, bevacizumab, mAb 8G7, 1116NS19-9, CP-870,893, atezolizumab, UMB2, etaracizumab, E398P, LLP2A, AE105, BBN(7-14), tyr(3)-octreotate, DAPTA, T140, CPCR4-2, RGD, cyclo(RGDyK), and PTP;
(iii) a polymer spacer comprising about 2 to about 30 monomers; and
(iv) a radionuclide.
Information Disclosure Statements
The information disclosure statements filed 3/3/2026 and 9/15/2025 were considered.
Response to Applicant’s Amendment and/or Arguments
The Applicant's arguments and/or amendment filed 12/1/2025 to the rejection of claims 1-3, 5-8, and 10-20 made by the Examiner under 35 USC 103, 112, and/or double patenting have been fully considered and deemed persuasive-in-part for the reasons set forth below.
Written Description Rejection
The 112 first paragraph rejection is WITHDRAWN because Applicant amended the claims to overcome the rejection.
112 Second Paragraph Rejections
All outstanding 112 second paragraph rejections are WITHDRAWN.
Double Patenting Rejections
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.
(I) Claims 1-3, 5-8, and 10-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14, 69, 70, 75-79, 81-84, 87 of copending Application No. 18/515,076 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to at least one biorthogonal ligation moieties, at least one active agent, a polymer spacer, and a radionuclide as set forth in pending independent claim 1. The claims differ in that the copending claims (see independent claim 14) is not limited to a polymer spacer or any particular biorthogonal ligation or active agent. Thus, the claims of the copending application are encompassed by the instant invention. Copending claim 69 discloses a biorthogonal ligation moiety. Copending claim 70 discloses active agents. Copending claim 77 discloses radionuclides. Copending claim 82 disclose a spacer (e.g., polyethylene glycol). Thus, the inventions disclose overlapping subject matter.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
APPLICANT’S ASSERTION
Applicant has requested that the double patenting rejection be held in abeyance until allowable subject matter is identified.
EXAMINER’S RESPONSE
The Examiner acknowledges the request that the double patenting rejection be held in abeyance. The double patenting rejection is still deemed proper.
(II) Claims 1, 3, 5, 7, and 10-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,857,648. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to a compound comprising at least one biorthogonal ligation moiety, at least one active agent, a polymer spacer, and a radionuclide. The claims differ in that the patented invention (see claims 1, 2, and 6) does not disclose all of the biorthogonal moieties in pending claim 1. However, the specific structure disclosed in patented claim 1 is a biorthogonal litigation moiety like the pending invention. Thus, the inventions disclose overlapping subject matter.
APPLICANT’S ASSERTION
Applicant has requested that the double patenting rejection be held in abeyance until allowable subject matter is identified.
EXAMINER’S RESPONSE
The Examiner acknowledges the request that the double patenting rejection be held in abeyance. The double patenting rejection is still deemed proper.
103 Rejection
Note(s): The 103 rejection is modified to address the additional claim limitations found in the amended claims filed 12/1/2025.
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.
Claims 1-3, 5-8, 10-13, and 15-21 are rejected under 35 U.S.C. 103 as being unpatentable over Rahim et al (Bioconjugate Chem., 2015, vol. 26, pages 352-360) in view of Pirker (Trans. Lung Cancer Res., 2012, Vol. 1, No. 4, pages 269-275), Zeng et al (J. Nucl. Med., 2013, Vol. 54, pages 829-832), and Li et al (Nature Chemical Biology, online February 2016, pages 129-137).
Independent claim 1 is directed to a therapeutic probe comprising:
(i) at least one biorthogonal ligation moiety selected from the group consisting of trans-cyclooctene, cyclooctyne, alkyne, alkene, photo-DIBO, cyclopropenone, tetrazine, azide, tetrazole, and photo-tetrazole;
(ii) at least one active agent, wherein the at least one active agent is selected from the group consisting of cetuximab, pertuzumab, trastuzumab, bevacizumab, mAb 8G7, 1116NS19-9, CP-870,893, atezolizumab, UMB2, etaracizumab, E398P, LLP2A, AE105, BBN(7-14), tyr(3)-octreotate, DAPTA, T140, CPCR4-2, RGD, cyclo(RGDyK), and PTP;
(iii) a polymer spacer comprising about 2 to about 30 monomers; and
(iv) a radionuclide.
Rahim et al disclose biorthogonal targeting antibody-conjugated trans-cyclooctenes (TCO). The TCO is linked to the monoclonal antibody via polyethylene glycol (PEG) linkers. In addition, Rahim et al disclose a dual biorthogonal conjugated in which dibenzylcyclooctyne (DBCO) is conjugated to TCO via PEG (see entire document, especially, abstract; page 355, right and left columns, bridging paragraph). Figure 1 (page 353) discloses the conjugation of TCO to antibodies via amine reaction (see excerpt below) and Figure 2 (page 354) discloses the conjugation of TCO and azide to an antibody.
Rahim et al, Figure 1, page 353
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While Rahim et al disclose that the antibody binds EGFR, the reference does not list specific antibodies, but reads on any general EGFR binding antibody.
Pirker is made of record for its disclosure various monoclonal antibodies that bind EGFR. In particular, cetuximab as well as matuzumab, panitumumab, and necitumumab bind EGFR (see entire document, especially, abstract; page 270, Table 1).
Zeng et al is made of record because it illustrate that bioorthogonal ligations have a significant impact on the synthesis and development of radiopharmaceuticals. In addition, it is disclosed that applications of chemistry ligations enables one to generate imaging agents for SPECT and PET, including small molecules, peptides, and proteins labeled with radionuclides such as 18F, 64Cu, 111In, and 99mTc (see entire document, especially, abstract; page 830, Figure 1). Hence, the skilled artisan would be motivated to incorporate radionuclides bioorthogonal ligations based on well-known information in the art regarding the impact of the combination in the development of radiopharmaceuticals.
Li et al is made of record for its teachings regarding biorthogonal. The continual growth of biorthogonal reactions has afforded opportunities for the study and manipulation of biological processes within living systems. Li et al disclose that even though fluorescent protein (probes) represent powerful tools for labeling and visualization of intracellular proteins, bioorthogonal reactions have provided alternative, and in many cases superior, approaches to protein labeling, particular when site specific labeling is desired (page 129, left column, first paragraph).
Traditionally, biorthogonal chemistry has largely been viewed as consisting of two component ‘ligation’ reaction in which the inert stable and biocompatible reaction pairs react under physiological conditions (page 130, Figure 1a). Building upon a pool of bioorthogonal ligation reactions created in the chemical biology community, the repertoire of bioorthogonal reactions are further expanded to encompass a broader scope of orthogonal chemical transformations (page 129, left column, second complete paragraph). Hence, the skilled artisan would be motivated to replace the fluorescent moiety of the probe of Rahim et al with another labeling moiety since Li et al recognizes the labeling qualities of using biorthogonal reaction ligation components.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the pending invention to combine the teachings of Rahim et al and Pirker and arrive at the pending invention. Specifically, Rahim et al disclose that their targeting antibody binds EGFR. The document does not limit the antibody to any particular antibody, but reads on EGFR binding antibodies in general. Pirker discloses that it is well known in the art that cetuximab binds EGFR and is an antibody often associated with cancer subjects.
The combined teachings of Zeng et al in combination with Li et al provide the necessary motivation to generate a probe comprising both a bioorthogonal litigation component and a radionuclide based on the superior results of radionuclides compared to the fluorescent component that is used in Rahim et al.
Furthermore, since both Rahim et al and Pirker are directed to antibodies that bind EGFR, the references may be considered to be within the same field of endeavor. Also, since Rahim et al Zeng et al, and Li et al are all directed to bioorthogonal litigation containing moieties that may be used to generate probes, the references may be considered to be within the same field of endeavor. Thus, the reference teachings are combinable. Hence, the limitations of independent claim 1 are met.
Pending claim 2 is directed to at least one bioorthogonal ligation moiety comprises a first and a second biorthogonal ligation moiety. Pending claim 3 is directed to the biorthogonal ligation moiety is cyclooctyne.
In Figure 1 (page 353), Rahim et al disclose three biorthogonal ligation moieties: tetrazine, trans-cyclooctene, and dibenzylcyclooctyne which are both cyclooctynes. Thus, the limitations of claims 2 and 3 are met.
Pending claim 5 is directed to at least one active agent binds to at least one biomarker of a cell, tissue or structure in a biological subject. Pending claim 6 is directed to at least one biomarker in a tumor or a cancer cell. Pending claim 7 is directed to at least one biomarker is selected from the group consisting of integrin, urokinase receptor (uPAR), gastrin-releasing peptide (GRP), somatostatin receptor 2 (SSTR2), folate receptor, C-C chemokine receptor type 5 (CCR5), C-X-C chemokine receptor type 4 (CXCR4), plectin-1, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), mucin-4 (MUC4), carbohydrate antigen 19-9 (CA19-9), cluster of differentiation 40 (CD40), programmed death-ligand 1 (PD-L1), and combination thereof.
Rahim et al disclose that the antibody binds to EGFR (biomarker) using TCO-PEG (Figure 2, page 354; page 355, left and right columns, bridging paragraph). In addition, it is disclosed that that the use of biorthogonal antibody conjugates result in improved imaging capabilities for different cancer biomarkers. Thus, the limitations of claims 5-7 are met.
Pending claim 8 is directed to at least one active agent is cetuximab.
While Rahim et al disclose that their antibody binds EGFR, the document does not specially list cetuximab. However, Pirker discloses that cetuximab is well known in the art for binding EGFR. In addition, it is disclosed that cetuximab is an antibody associated with cancer (page 269, abstract).
According to MPEP 2144.06, it is prima facie obvious to combine tow compositions each of which is taught by the prior art to be useful for the same purpose in order to form a third composition to be used for the same purpose (In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Thus, for the reasons herein, the limitation of claim 8 is rendered obvious.
Pending claim 10 is directed an active agent is internalizable or non internalizable.
Rahim et al disclose that the conjugate binds cells and become activated. Thus, the limitation of the claim is made.
Pending claim 11 is directed to the first bioorthogonal ligation moiety and the at least one targeting agent linked together via the polymer spacer. Claim 12 is directed to a polymer comprising at least one subunit of the polymer. Claim 13 is directed to the polymer polyethylene glycol (PEG).
Rahim et al disclose DBCO-PEG-TCO (see page 352, abstract; page 355, left and right columns, bridging paragraph). Thus, the limitations of claims 11, 12, and 13 are met.
Claim 14 is directed to the probe further comprising a detectable label.
Rahim et al disclose that one may have a fluorophore (e.g., Oregon Green 488 and Alexa Fluor 488) present (page 354, Figure 2; page 355, Figure 3). Thus, the limitation of claim 14 is met.
Claim 17 is directed to the probe further comprising a targeting moiety. Claim 18 is directed to a targeting moiety selected from a protein, antibody, peptide, small molecule, nanoparticle, polysaccharide, or polynucleotide.
Rahim et al disclose that monoclonal antibodies bind to EGFR in their invention (see entire document, especially, abstract; page 353, Figure 1; page 354, Figure 2; page 355, left and right columns, bridging paragraph; page 355, Figure 3; page 356, Figure 5). Thus, the limitation of claims 17 and 18 are met.
Claim 19 is directed to the targeting moiety being the same as the at least one active agent.
Rahim et al disclose that the targeting agent may be modified antibodies of the same type as in Figure 1, page 353 that are introduced by azides. Thus, the limitation of claim 19 is met.
Claim 20 is directed to the targeting moiety being different from the at least one active agent.
Rahim et al, Figure 5 (page 356) is directed to dual orthogonal coupling to different antibodies. Also, in Figure 1 (page 353), Rahim et al disclose three bioorthogonal ligation moieties: tetrazine, trans-cyclooctene, and dibenzylcyclooctyne. Thus, the claim limitation of claim 20 is met.
APPLICANT’S ASSERTIONS
In summary, Applicant asserts the following. (1) The claims were amended to recite that the therapeutic probe comprises a radionuclide. It is asserted that Rahim et al fail to render the invention obvious because the reference is silent on a radionuclide and a bioorthogonal ligation moiety couple with and active agent such as an EGFR antibody. (2) It is asserted that Rahim et al disclose a probe comprising an antibody which uses a biorthogonal ligation moiety to link a fluorescent molecule to the antibody which results in the reactive biorthogonal ligation moiety into a non-reactive linkage unit incapable of further litigation reactions. (3) It is asserted that the incorporation of a radionuclide is a significant improvement over Rahim et al because a radionuclide provides radiation in the tumor that facilitates both molecular imaging of the tumor and localized radiotherapy with the tumor. In addition, some of the enhances features of using a radionuclide are discussed by Applicant.
EXAMINER’S RESPONSE
The Examiner has reviewed Applicant’s amendment and arguments. The amended rejection addresses the amendment and arguments. Applicant’s arguments were not found persuasive for the following reasons.
In regards to (1) above, it is duly noted that the claims were amended to encompass a radionuclide. While Rahim et al disclose that one may have a fluorescent component attached in the probe, Li et al is made of record to illustrate that for bioorthogonal ligation even though fluorescent probes (probes having a fluorescent component) are powerful for labeling and visualizing of intracellular proteins of interest, biorthogonal reactions have provided an alternative, and in many cases superior, approaches to protein labeling, particularly when site-specific labeling is desired. Thus, the skilled artisan would be motivated to replace the fluorescent moiety of Rahim et al with another labeling moiety (e.g., radionuclide). As a result, Zeng et al was made of record because it is directed to the growing impact of biorthogonal litigation on radiopharmaceuticals. In particular, it sets forth the teachings that biorthogonal ligations have a significant impact of radiopharmaceuticals in the preparation of imaging agents for SPECT and PET, including small molecules, peptides, and proteins labeled with radionuclides such as 18F, 64Cu, 111In, and 99mTc. Thus, the teachings of Rahim et al and Zeng et al are consistent with the modification of probe comprising a radionuclide and biorthogonal ligation moiety component.
In regards to (2), the components present in Applicant’s probe are rendered obvious by the combination of references as detailed supra. According to MPEP 2112.01, products of identical chemical composition cannot have mutually exclusive properties. In other words, a chemical composition and its properties are inseparable. Thus, if the prior art teaches (renders obvious) the identical chemical structure, the properties Applicant discloses and/or claims are necessarily present would also be possessed by the prior art composition.
In regards to (3), as detailed supra, the teaching of Zeng et al and combined teachings of Zeng et al and Li et al are consistent with the incorporation of a radionuclide into the probe. Li et al disclose why one would replace the fluorescence moiety of the probe with a moiety having a biorthogonal litigation component and labeling and visualization moiety that allows for results superior to that of using a fluorescence moiety. Zeng et al also addresses the significance of having a bioorthogonal litigation component, but specifically in combination with radionuclides encompassed by the pending invention. Hence, the impact of the radionuclide and bioorthogonal ligation moiety is consistent with the teachings in the prior art.
For the reasons set forth herein, the 103 combination rejection is still deemed proper.
Conclusion
Claims 4 and 9 are withdrawn. Claims 1-3, 5-8, 10-13, and 15-21 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Future Correspondences
Any inquiry concerning this communication or earlier communications from the examiner should be directed to D L Jones whose telephone number is (571)272-0617. The examiner can normally be reached M-F.
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/D. L. Jones/
Primary Patent Examiner
Art Unit 1618
March 12, 2026