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 of the species of compound 15 (Et-NOTA) in the reply filed on June 12, 2026 is acknowledged. While the associated remarks does not provide an explicit traversal, the examiner interprets the request for the withdrawal of the Restriction Requirement as it is submitted that searching all of elected species does not induce further search burden on the examiner to amount to an implicit traversal of the species election requirement. As stated, such traversal is on the ground that there is no undue search burden on the examiner. This is not found persuasive because: (i) this application is a 371 of PCT/CN2022/081959 and for applications filed under 371, PCT rules for lack of unity apply, (ii) search burden is not required to show a lack of unity, and (iii) Vaughn (Vaughn, B. A.; et al., Chem. Sci., 2020) indicates a lack of unity in the claims to which the election requirement mailed April 13, 2026 was applied (see Restriction Requirement mailed that date). Thus, the conclusion of a lack of unity is deemed proper and the species election is also deemed proper.
Status of Claims
Claims 1-22 are pending.
Claims 7-13 have been withdrawn from consideration.
Claims 1-6 and 14-22 are under examination.
Information Disclosure Statement
The information disclosures statements filed March 8, 2024 and January 14, 2025 are acknowledged and have been considered by the examiner.
Drawings
The drawings are objected to for the following informalities:
Both Figures 31 and 32 contain line graphs comparing properties between compositions. However, the colors and markings on the curves on these graphs are not sufficiently different so as a reader can readily assign the appropriate curve to the correct composition. While Figure 32 provides arrows, these arrows only point to a portion of the provided curves in a region where separation is present. The arrow does not enable a reader to distinguish the curves throughout the rest of the plot.
Appropriate correction is required.
Specification
The abstract of the disclosure is objected to because it is too short (38 words). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because of the following informality:
In [75], the specification states “From the table shown below, it is supposed that the manganese complexes of NOTA and Et-NOTA without water molecule coordinated on the first-sphere of the metal ions…” However, no table is provided after this statement. Furthermore, it is not clear to the examiner if “from the table show below” is a necessary phrase to include in the sentence. The examiner suggests removing this phrase.
Appropriate correction is required.
Claim Interpretation
The examiner interprets claims 19-22 to contain functional language. As written, the claims are drawn to chiral NOTA complexes, which are compositions of matter. The phrases “for use in imaging a sample” in claim 19 and “for use in imaging a subject” in claim 21 recite intended uses of the NOTA complex and do not provide additional structural restrictions on the composition. Additionally, claims 20 and 22 only narrow the scope of the imaging intended use by listing specific imaging methods. Please note that a recitation of an intended use does not distinguish over the prior art since a composition claim covers what the composition is and not what it is used for. A chemical composition and its properties are inseparable (MPEP § 2112.01). Therefore, as long as the prior art teaches the claimed structural features of the composition and the composition is capable of these functions, it reads on the claim.
Claim Rejections - 35 USC § 112(b)
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 1-6 and 14-22 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.
Claim 1 recites at the top of pg. 2 of the amended claims that “Z is a moiety of Formula 2 or a pharmaceutically acceptable salt or zwitterion thereof” and that “R2 is a moiety of Formula 3 or a pharmaceutically acceptable salt or zwitterion thereof.” However, this language is unclear. It is not clear how a moiety (partial chemical structure) can exist as a pharmaceutically acceptable salt when it is not a complete chemical structure. As it is unclear how a moiety would fit the provided description, these limitations render the claim indefinite. Furthermore, claims 2-6 and 14-22 are rejected due to their dependence on claim 1. The examiner notes that the second line of text of claim 1 allows for pharmaceutically acceptable salts or zwitterions of the full molecule of Formula 1, thus repeating the phrase in the context of moieties Z and R2 is unnecessary duplication within the scope of the claim.
Claim 16 recites the limitation "the at least one metal" in line 1. There is insufficient antecedent basis for this limitation in the claim. As it is currently written, claim 16 depends upon claim 14, which does not require a metal. However, claim 15 recites the phrase “at least one metal.” For the purpose of examination, the examiner will interpret claim 16 to depend upon claim 15.
Claim 17 recites the limitation "the at least one metal" in line 1. There is insufficient antecedent basis for this limitation in the claim. As it is currently written, claim 17 depends upon claim 14, which does not require a metal. However, claim 15 recites the phrase “at least one metal.” For the purpose of examination, the examiner will interpret claim 17 to depend upon claim 15.
Claim Rejections - 35 USC § 112(d)
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 22 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 22 recites “the chiral NOTA complex for use of claim 20,” indicating that claim 22 depends from claim 20. Claim 20 recites that the imaging comprises PET, MRI, CT, or optical imaging. Claim 22 additionally recites that the imaging “comprises PET, MRI, CT, or optical imaging.” This is identical in scope to claim 20, as the scope of the imaging method is not narrowed. Thus, claim 22 depends from claim 20 but fails to further limit the subject matter of the claim upon which it depends.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
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.
Claims 1-6 and 14-22 are rejected under 35 U.S.C. 103 as being unpatentable over Drahos (Drahos, B.; et al., Dalton Trans., 2011) in view of Law (WO 2018/051197 A1) and Evans (Evans, N. H.; et al., Dalton Trans., 2013).
Drahos teaches complexes of NOTA and DOTA chelators with Mn2+ (pg. 1945, Abstract). Drahos describes both NOTA and DOTA as “common polydentate macrocyclic ligands” (pg. 1946, left column, second paragraph). Drahos teaches the formation of a Mn2+ complex with NOTA (pg. 1946, Experimental, first paragraph). Drahos concludes from complex dissociation kinetics data (pg. 1949, Table 2) that the complex of NOTA and Mn2+ is unexpectedly kinetically inert and possesses high thermodynamic stability (pg. 1950, Conclusion, first two sentences). Drahos also describes that chelates of Mn2+ and Gd3+ are widely applied in magnetic resonance imaging (MRI) (pg. 1945, Introduction, first sentence).
Drahos does not teach chiral ethyl modifications on the carbon atoms of the TACN ring of NOTA in a symmetric manner wherein each modified carbon possesses the same stereochemistry.
Law teaches chiral cyclen chelators (pg. 4, [0015]). Among the embodiments of Law’s invention are chiral forms of DOTA (pg. 9, [0111]). More specific forms of this embodiment are 2,2′,2″,2′″-((2S,5S,8S,11S)-2,5,8,11-tetraethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid and 2,2′,2″,2′″-((2R,5R,8R,11R)-2,5,8,11-tetraethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (pg. 18, [0148], compounds 9 and 10 in the recited list), which can be described as DOTA derivatives in which ethyl groups modify one carbon per repeat unit of the ring structure with an ethyl group in a symmetric manner, all ethyl-modified carbons possessing the same stereochemistry. The all S form is depicted as structure L2 in Figure 1A and referred to by this name throughout the disclosure. Law also teaches the synthesis of L2 (pg. 31, [0169]). Law teaches analysis of complexes of L2 with Yb and Eu to study twisted square antiprismatic to square antiprismatic (TSA/SA) conformation ratios of these molecules (Example 1, part 10; and Figures 3, 4, and 10). Law also teaches measures of kinetic inertness and relaxivity of complexes of L2 with Gd (Example 1, parts 11 and 12) and biodistribution of the same complexes (Example 5). Law teaches that the chiral DOTA derivatives may be prepared as compositions for imaging, comprising the chiral DOTA derivative, one or more metals, and pharmaceutically acceptable excipients (pg. 28, [0149]). Law also teaches methods of using the composition for imaging comprising administering the composition to a subject in need thereof, detecting radiation, and forming an image (pg. 28, [0151]). Law teaches that the chiral DOTA derivatives may be used for biological imaging techniques including MRI and PET (pg. 14, [0142]). Law teaches that the advantages of the chiral modifications to the DOTA chelator include “(a) enhanced dominance of the favored isomer for MRI imaging -TSA/SA; (b) ease of labeling with metal used for radioimaging (Lu and Ga), such as SPECT and PET, at mild conditions; (c) highly stable complexes” (pg. 14, [0143]).
Evans teaches stereoisomer control of 1,4,7-triazacyclononane (TACN) derivatives through chiral modification of a carbon in the ring (pg. 15610, Abstract). Evans describes that TACN derivatives can produce thermodynamically and kinetically stable metal complexes and can be used for circularly polarized luminescence (CPL) if enantiomerically pure (pg. 15610, Introduction). Evans teaches the synthesis of several TACN derivatives with different alkyl modifications creating a chiral center on one carbon of the TACN ring (pg. 15611, Scheme 1). Evans teaches that chiral carbon modification results in production of a chiral product with >96% isomeric purity (pg. 15611, Stereochemistry and CPL of complexes). Evans also teaches preparation of complexes of these chiral products with Eu (pg. 15614-15616, Synthesis of complexes). Evans discloses the CPL spectra of the enantiomers of one of the products (pg. 15612, Fig. 4), indicating such complexes could be used in luminescence experiments.
A person of ordinary skill in the art would recognize that DOTA and NOTA are similar polyaza macrocyclic chelator molecules known to bind metals. It would also be recognized that both Law and Evans teach that chiral modifications to carbons in such chelators results in forcing the chelator to adopt certain structural conformations that can be beneficial to the uses of said chelators.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the NOTA chelator of Drahos with the chiral ethyl modifications on carbon atoms of the polyaza ring as taught by Law, as Law and Evans teach and suggest that such a modification can be used to force a desired 3-dimentional conformation, which Law teaches may result in improvements such as improved metal labeling and highly stable complexes (MPEP § 2143(I)(G)). This combination would have yielded the predictable outcome of a chiral ethyl-NOTA chelator.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because NOTA and DOTA are related polyaza chelating groups with very similar chemical structures. Thus, the same chemistry that can be used to modify DOTA with the ethyl groups to produce chiral centers can also be used to modify the core NOTA molecule. Furthermore, Evans demonstrates that chiral modification of NOTA ring carbons is feasible.
The skilled artisan would have been motivated to make this modification because Law teaches that such modifications can enhance the dominance of certain chelator complex isomers, increase ease of labeling with metals, and result in highly stable complexes (pg. 14, [0143]).
Regarding claims 1-6 and 14, Drahos teaches a NOTA chelator (pg. 1946, Chart 1). Law teaches modification of a polyaza chelator (DOTA) ring with ethyl groups in a way that all ethyl groups modify a carbon in the ring in a symmetric manner and is done such that each carbon has the same stereochemistry (compound L2, Figure 1A; and Figure 7). The combination of the chiral ethyl modification of Law with the NOTA chelator of Drahos would result in the following structure.
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This structure reads on claims 1-3 wherein each R1 is alkyl and each R2 is -CH2(C=O)OH. The structure also reads on claims 4-6 wherein each R1 is C2 alkyl (ethyl) and A1 is OH. It is identical to that of the first structure of claim 14 wherein A1 is OH. Therefore, the combined teachings of Drahos, Law, and Evans render claims 1-6 and 14 obvious.
Regarding claims 15-17, Drahos teaches a complex of NOTA and Mn (pg. 1948, Scheme 1; pg. 1949, Table 2; and pg. 1946, Experimental, first paragraph). Mn is a metal and is included in the list of claim 17. Furthermore, Law teaches complexes of an ethyl-modified chiral polyaza chelator with Yb, Eu, and Gd (Example 1, parts 3, 4, and 10-12; and Example 5), which are lanthanide metals. It would be expected that the modified NOTA could also bind these metals due to the similarity in structure with DOTA. Therefore, the combined teachings of Drahos, Law, and Evans render claims 15-17 obvious.
Regarding claim 18, Law teaches that the chiral DOTA derivatives may be prepared as compositions for imaging, comprising the chiral DOTA derivative, one or more metals, and pharmaceutically acceptable excipients (pg. 28, [0149]). As biomedical imaging requires compositions to be administered to a body and to be of pharmaceutical grade purity, stability, and safety; and that the excipients Law teaches are pharmaceutically acceptable; the examiner interprets this composition for imaging to read on the limitation of “pharmaceutical composition.” Therefore, the combined teachings of Drahos, Law, and Evans render claim 18 obvious.
Regarding claims 19-22, as described above, the combination of Drahos, Law, and Evans render the composition of claim 15 obvious. Additionally, as described in the Claim Interpretation section of this action, these claims are understood by the examiner to be claims to a composition of matter with recitations of intended use (MPEP § 2111.02). Furthermore, since Drahos describes metal complexes with polyaza chelators as contrast agents for MRI (pg. 1945, Introduction, first paragraph) and Law teaches that the chiral DOTA derivatives may be used for biological imaging techniques including MRI and PET (pg. 14, [0142]), it is understood by the examiner that the complexes taught by the combination of these references would also be capable of use in imaging by MRI. Therefore, the combined teachings of Drahos, Law, and Evans render claims 19-22 obvious.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric P Mosher whose telephone number is (571)272-3258. The examiner can normally be reached Monday-Friday 9am-5pm.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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