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 .
Election/Restrictions
Applicant’s election without traverse of Group I and species of 4,4'-[7,11-bis(2-{3-[2-carboxy-6-({16-[(6- carboxypyridin-2-yl)methyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7- yl}methyl)pyridin-4-yl]propanamido}ethyl)-3,15-dioxo-4,7,11,14-tetraazaheptadecane-1,17- diyl]bis[6-({16-[(6-carboxypyridin-2-yl)methyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7- yl}methyl)pyridine-2-carboxylic acid] (Tet5) in the reply filed on March 20, 2026 is acknowledged.
Drawings
The drawings are objected to because:
Figures 1a, 2a, and 2b show black and gray lines, but it is unclear what each line represents.
Figure 1a displays dual Y-axis scales (left and right), but it is unclear which data trace corresponds to which scale.
Figures 3 and 5 lack descriptive labels and units for the Y-axes.
Figure 6 contains an unlabeled legend entry (a small gray square) located to the right of the “TL-209” label. It is unclear if this extra symbol corresponds to any data series.
Figure 12 contains symbols (* and **) without definitions. It should be clarified if these symbols indicate statistical significance levels.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities:
The use of the terms Kryptofix®, CHIRALCEL®, MestReC™, ACQUITY UPLC®, Xevo®, BEH™, LCMS-2020™, Chromolith®, Luna®, Chromolith®, HiLoad®, Superdex®, 1260 Infinity™, Eppendorf Tubes®, Vanquish™, FlowStar² LB 514™, 1290 Infinity II™ which are a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Objections
Claims 1 and 24 are objected to because of the following informalities:
In claim 1, “C represents the macrocyclic chelating agent…” should read “C represents a macrocyclic chelating agent….”
In claim 24, “…active ingredients comprises…” should read “…active ingredients comprise.…”
Appropriate correction is required.
Claim Rejections - 35 USC § 112 Indefiniteness
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.
Claim 5 is 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.
Regarding claim 5, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Clarification and/or amendment is required.
Claim Rejections - 35 USC § 112 Improper dependency
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.
Claim 15 is 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.
Claim 15 recites multimeric chelating ligands (“[(C)n-L]” of instant claim 1). However, these compounds do not comprise a tissue-targeting moiety (“(V)m” of instant claim 1), which is required by independent claim 1. Because the dependent claim 15 fails to include all limitations of its parent claim, it does not properly further limit claim 1.
Clarification and/or amendment is required.
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.
Claims 1-5, 18, 19, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Wilson and Thiele (WO 2018 183906; cited on IDS filed August 1, 2023) in view of Wängler et al. (Bioconjugate Chemistry, 2008; cited on IDS filed August 1, 2023).
Regarding claims 1 and 4, Wilson discloses compounds comprising macrocyclic chelating agent macropa, a reactive isothiocyanate functional group (NCS) which acts as a linker moiety for covalent bonds, and trastuzumab (Tmab) which is a monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2) in breast and other cancers (¶ 173). Regarding claims 2 and 3, Wilson discloses that the complexes can comprise alpha-emitting radionuclide such as actinium-225 (225AC) for the treatment of cancers (abstract; claim 1; ¶ 134). Regarding claim 18, Wilson discloses pharmaceutical compositions comprising the macropa compound and pharmaceutically acceptable carrier (¶ 8). Regarding claims 19 and 24, Wilson discloses that the compound can comprise one or more cancer cell targeting agent such as Tmab (¶ 95). Wilson discloses that macropa can act as an exceptional chelator for 225AC, showing more efficient complexation with 225AC compared with DOTA (¶ 164; ¶ 168).
Regarding claims 1 and 5, Wängler does not disclose the compound comprising multiple macrocyclic chelating agents and a multi-functional linker moiety comprising multiple functional groups.
Wängler discloses antibody-dendrimer conjugates comprising macrocyclic chelating agent DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) multimers linked to the antibody hMAb425 (humanized monoclonal antibody designed to target the epidermal growth factor receptor) via heterobifunctional cross-linker Sulfo-SMCC (sulfosuccinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate), which reads on multiple macrocyclic chelating agents and multi-functional linker moiety comprising multiple functional groups for the covalent attachment of instant claims 1 and 5 (Abstract; page 817, Figure 6; page 818, Formation of DOTA-Multimers; page 818, Conjugation of DOTA-Multimers to hMAb425). Wängler discloses that the conjugates can comprise multiple chelators such as 4 chelators and the size of the dendrimer does not significantly impact the antibody's ability to bind its target, providing insights for improved radioimmunotherapy and diagnostic imaging (Abstract; page 813, Introduction; page 817, Table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the compounds of Wilson by incorporating multimers of macropa with a multi-functional linker to improve radioimmunotherapy. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Wängler teaches that the compound can comprise multiple chelators and a multi-functional linker and using smaller, more numerous dendrimers can allow for high-capacity, targeted delivery of radionuclides or drugs. Further, a person of ordinary skill in the art would have been motivated to use multimers of macropa in order to create a stable and efficient compound for targeted alpha therapy (TAT). Accordingly, applying the teachings of Wängler to the compound of Wilson constitutes no more than the predictable use of prior art elements according to their established functions, thus rendering claims 1 and 5 obvious.
Claims 6, 13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Wilson and Thiele (WO 2018 183906; cited on IDS filed August 1, 2023) and Wängler et al. (Bioconjugate Chemistry, 2008; cited on IDS filed August 1, 2023) as applied to claims 1-5, 18, 19, and 24 above, and further in view of Chang et al. (WO 2006 043984; cited on PTO-892).
In addition to the teachings of Wilson discussed above, Wilson discloses that the structure of macropa can be formula I, wherein A1 and A10 are N, R2 and R9 are COOH, and R4 is CH2CH2COOH (claim 1), which reads on the structure of formula (B) of instant claim 13.
Wängler is discussed above.
Neither Wilson nor Wängler discloses that the linker is the first structure shown in instant claim 6, nor that amide bonds are formed between the carboxylic acid groups and L or V.
Chang discloses the structure of amine formula (V’) (claim 1), which reads on the linker structure of instant claims except for the linker length between the central nitrogen (N) and the terminal amino group (NH2). The side chains of Chang consist of propylene bridges (CH2CH2CH2) connecting the central N to the terminal NH2 groups, whereas the side chains of instant claims consist of ethylene bridges (CH2CH2). Chang discloses that the amine can be crosslinked with a crosslinking agent for therapeutic and/or prophylactic applications (claim 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the compounds of Wilson and Wängler by using the amine formula (V’) of Chang as a linker to connect the four macropa moieties via amide bonds between carboxylic groups of macropa and NH2 groups of the linker. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Chang teaches that the formula (V’) can be used to link various agents for pharmaceutical use. Further, a person of ordinary skill in the art would have been motivated to use the amine formula (V’) of Chang as a linker in order to achieve enhanced chelating properties and improved bioavailability as a radiotherapy agent. The length of the alkyl spacer between the core N and the peripheral NH2 group of the linker can be variable depending on the desired flexibility and chelating properties of the molecule. Compounds which are positional isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties (MPEP § 2144.09). Accordingly, applying the teachings of Chang to the compounds of Wilson and Wängler constitutes no more than the predictable use of prior art elements according to their established functions, thus rendering claims 6, 13, and 15 obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JONG HWAN BAEK whose telephone number is (571)272-0670. The examiner can normally be reached Mon - Thu, 9 am - 3 pm ET.
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/JONG HWAN BAEK/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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