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 .
Summary
Claims 1-5, 8-9, 14-23, 25, 27-28, 31-33 are pending in this office action. Claims 6-7, 10-13, 24, 26, 29-30, and 34-51 are cancelled. All pending claims are under examination in this application.
Priority
The current application was filed on December 12, 2023 is a 371 of PCT/US2022/034086 filed on June 17, 2022, which in turn claims domestic priority to provisional patent application 63/211,919 filed on June 17, 2021.
Information Disclosure Statement
Receipt of the Information Disclosure Statements filed on January 16, 2025 and September 12, 2025 are acknowledged. A signed copy of both documents are attached to this office action.
Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because:
Figures 3, 4, 7-9, 82-83, and 90 are blurry and a reader cannot make out the substituents on the chemical structures.
Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Claim Objections
Claims 8 and 32 are objected to because of the following informalities:
Claim 8: Please insert the full chemical name of DOTA.
Claim 32: Please identify and describe the acronyms in full that have not been previously expanded in claim 8 (NTA, BisTris, EGTA, EDTA, BAPTA, DO2A, DO3A, and MACROPA). Furthermore, DTPA is listed twice within claim 32. Please delete one.
Appropriate correction is required.
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 1-5, 8-9, 14-20, 23, 27-28, 31-33 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 fails to completely define L1, L2, L3, and L4. For example, L1, L2, L3, and L4 can be -C1-3 alkylene-, yet this fails to define examples of functional groups beyond the -C1-3 alkylene- as shown below within Figure I prior to the attachment of the chelators or binding moiety [the arrows point to additional functional groups (thioamide or thiourea) not listed within claim 1].
[AltContent: arrow]Figure I
[AltContent: arrow][AltContent: arrow]
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Dependent claims 2-5, 8-9, 14-20, 23, 27-28, 31-33 fail to cure the deficiency of claim 1.
In a similar manner, claim 18 fails to define L1, L2, L3, and L4 fully as described above.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 4, 8-9, 14-16, and 31-32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kumar et al. (Bioconjugate Chemistry, 2015).
Kumar et al. is considered the closest prior art to the present invention as it teaches molecular platform for design and synthesis of targeted dual-
modality imaging probes (see title). Furthermore, Kumar et al. disclose that we report a versatile dendritic structure-based platform for construction of targeted dual-modality imaging probes. The platform contains multiple copies of 1,4,7,10-tetraazacyclodo- decane-1,4,7,10-tetraacetic acid (DOTA) branching out from a 1,4,7-triazacyclononane- N,N’,N’’-triacetic acid (NOTA) core. The specific coordination chemistries of the NOTA and DOTA moieties offer specific loading of 68/67Ga3+ and Gd3+, respectively, into a common molecular scaffold. The platform also contains three amino groups which can potentiate targeted dual-modality imaging of PET/MRI or SPECT/MRI (PET: positron emission tomography; SPECT: single photon emission computed tomography; MRI: magnetic resonance imaging) when further functionalized by targeting vectors of interest. To validate this design concept, a bimetallic complex was synthesized with six peripheral Gd-DOTA units and one Ga-NOTA core at the center, whose ion T1 relaxivity per gadolinium atom was measured to be 15.99 mM-1 s-1 at 20 MHz. Further, the bimetallic agent demonstrated its anticipated in vivo stability, tissue distribution, and pharmacokinetic profile when labeled with 67Ga. When conjugated with a model targeting peptide sequence, the trivalent construct was able to visualize tumors in a mouse xenograft model by both PET and MRI via a single dose injection (see abstract).
Regarding instant claim 1, Kumar et al. teach a conjugate comprising two or more chelators and a binding moiety. The necessary citations of Kumar et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Kumar et al. Citations
A conjugate comprising two or more chelators and a binding moiety, wherein one of said chelators is a chelator of an imaging isotope and one of said chelators is a chelator of a radiotherapy isotope, and wherein said chelators and said binding moiety are linked via a moiety of Formula (I):
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Kumar et al. disclose molecular platform for design and synthesis of targeted dual-
modality imaging probes (see title and abstract).
Kumar et al. disclose the following molecule that meets all the instant claim 1 limitations within Figure II (see page 551, Scheme 2).
Figure II
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wherein each X is independently selected from N, P, P(=O), CR N, and a moiety of formula (i):
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Regarding instant claim 4, Kumar et al. teach wherein said imaging isotope is 68Ga (see abstract).
Regarding instant claim 8, Kumar et al. teach wherein each of said chelators independently comprises dodecane tetracetic acid (DOTA) (see abstract and Figure II).
Regarding instant claim 9, Kumar et al. teach wherein said binding moiety is a polypeptide. Kumar et al. disclose the use of the model targeting (poly)peptide, c(RGDyK) (see page 551, left column, paragraphs 2 and 3; also see Figure II).
Regarding instant claim 14, Kumar et al. teach wherein said chelators are covalently attached to said binding moiety (see Figure II).
Regarding instant claim 15, Kumar et al. teach wherein said chelators and said binding moiety are covalently attached via a linker (see Figure II).
Regarding instant claim 16, Kumar et al. teach wherein said compound of Formula (I) has formula:
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Kumar et al. disclose the analogue presented within Figure II which matches the amine illustrated within instant claim 16.
Regarding instant claims 31 and 32, Kumar et al. teach wherein said conjugate comprises three or more chelators. Kumar et al. disclose the structure within Figure II which has six DOTA groups (chelators).
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 non-obviousness.
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, 9, 18-23, 25, and 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over Kumar et al. over Chang et al. (WO2016/112870A1), Wurzer et al. (Chemistry – A European Journal Communication, 2018), Yamane et al. (Bioconjugate Chemistry, 2011), and Burak (WO2018/204869A1).
[The Examiner is going to introduce each new reference and then combine them where appropriate to reject the instant claims.]
1. Chang et al.
Chang et al. teach molecular constructs with targeting and effector elements
(see title). Additionally, Chang et al. disclose that the present invention provides various molecular constructs having a targeting element and an effector element. Methods for treating various diseases using such molecular constructs are also disclosed (see abstract).
2. Wurzer et al.
Wurzer et al. teach dual-nuclide radiopharmaceuticals for positron emission
tomography based dosimetry in radiotherapy (see title). In addition, Wurzer et al. disclose that the improvement of the accuracy of dosimetry in radionuclide therapy has the potential to increase patient safety and therapeutic outcomes. Although positron emission tomography (PET) is ideally suited for acquisition of dosimetric data because PET is inherently quantitative and offers high sensitivity and spatial resolution, it is not directly applicable for this purpose because common therapeutic radionuclides lack the necessary positron emission. This work reports on the synthesis of dual-nuclide labeled
radiopharmaceuticals with therapeutic and PET functionality, which are based on common and widely available metal radionuclides. Dual-chelator conjugates, featuring
interlinked cyclen- and triazacyclononane-based polyphosphinates DOTPI and TRAP, allow for strictly regioselective complexation of therapeutic (e.g., 177Lu, 90Y, or 213Bi) and
PET (e.g. , 68Ga) radiometals in the same molecular framework by exploiting the orthogonal metal ion selectivity of these chelators (DOTPI: large cations, such as lanthanide(III) ions; TRAP: small trivalent ions, such as GaIII). Such DOTPI–TRAP conjugates were decorated with 3Gly-urea-Lys (KuE) motifs for targeting prostate-specific membrane antigen (PSMA), employing Cu-catalyzed (CuAAC) as well
as strain-promoted (SPAAC) click chemistry. These were labeled with 177Lu or 213Bi and 68Ga and used for in vivo imaging of LNCaP (human prostate carcinoma) tumor xenografts in SCID mice by PET, thus proving practical applicability of the concept (see abstract).
3. Yamane et al.
Yamane et al. teach method for enhancing cell penetration of Gd3+ -based MRI contrast agents by conjugation with hydrophobic fluorescent dyes (see title). Furthermore, Yamane et al. disclose gadolinium ion (Gd3+) complexes are commonly used as magnetic resonance imaging (MRI) contrast agents to enhance signals in T1 -weighted MR images. Recently, several methods to achieve cell-permeation of Gd3+ complexes have been reported, but more general and efficient methodology is needed. In this report, we describe a novel method to achieve cell permeation of Gd3+ complexes by using hydrophobic fluorescent dyes as a cell-permeability-enhancing unit. We synthesized Gd3+ complexes conjugated with boron dipyrromethene (BDP-Gd) and Cy7 dye (Cy7-Gd), and showed that these conjugates can be introduced efficiently into cells. To examine the relationship between cell permeability and dye structure, we further synthesized a series of Cy7-Gd derivatives. On the basis of MR imaging, flow cytometry, and ICP-MS analysis of cells loaded with Cy7-Gd derivatives, highly hydrophobic and nonanionic dyes were effective for enhancing cell permeation of Gd3+ complexes. Furthermore, the behavior of these Cy7-Gd derivatives was examined in mice. Thus, conjugation of hydrophobic fluorescent dyes appears to be an effective approach to improve the cell permeability of Gd3+ complexes, and should be applicable for further development of Gd3+ -based MRI contrast agents (see abstract).
4. Burak
Burak teach pharmacokinetic enhancements of bifunctional chelates and uses thereof (see title). Also, Burak disclose that the present invention relates to conjugates including a chelating moiety of a metal complex thereof and a therapeutic or targeting moiety, methods for their production, and uses thereof. (see abstract).
The teachings of Kumar et al. are presented above within the 35 U.S.C §102 section. Kumar et al. teach all the elements of instant claim 1.
Ascertaining the Difference
Kumar et al. does not teach numerous aspects of the present invention. The combination of Kumar et al. with various references makes the instant application obvious to the skilled artisan (POSITA; person of ordinary skill in the art). The motivation being to incorporate the additional and alternative elements supplied by Chang et al., Wurzer et al., Yamane et al., and Burak to synthesize an enhanced dual prong therapeutic using the Kumar et al. reference as the base.
Combination of Kumar et al. and Wurzer et al.
Regarding instant claims 2 and 3, Kumar et al. and Wurzer et al. teach wherein said isotope used for radiotherapy is an a-emitter. Wurzer et al. disclose the use of the a-emitter, 213Bi (see page 548, paragraph 4 within Wurzer et al.; also see PTO-892 NPL X).
Combination of Kumar et al. and Burak
Regarding instant claim 5, Kumar et al. and Burak teach wherein said imaging isotope is 64Cu and wherein said radiotherapy isotope is 212Pb. Burak discloses that the metal can be selected from …64Cu and 212Pb (see page 3, lines 13-18 within Burak).
Combination of Kumar et al. and Yamane et al.
Regarding instant claims 18 and 19, Kumar et al. and Yamane et al. teach wherein said chelators and said binding moiety are linked via a moiety of Formula (II):
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Yamane et al. disclose a thiourea structure each nitrogen being substituted with a phenyl group with an alkyl group in the 4-position (see Figure 1 within Yamane et al.).
Figure III
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In this case, Yamane et al. links a chelator and a hydrophobic fluorescent dye (see title and abstract within Yamane et al.). The dye could easily be substituted under routine experimental conditions based on the Kumar et al. reference. A skilled artisan (POSITA) would be motivated to exploit the thiourea-phenyl moiety linker (see page 2232, right column, paragraph 1 within Yamane et al.) to incorporate a binding moiety or a chelator depending upon the therapeutic application.
Combination of Kumar et al. and Chang et al.
Regarding instant claim 20, Kumar et al. and Chang et al. teach a method of treating cancer in a mammal in need thereof, wherein said method comprises administering a conjugate of instant claim 1 to said mammal, wherein said conjugate comprises said imaging isotope complexed to said chelator of said imaging isotope and wherein said conjugate comprises said radiotherapy isotope complexed to said chelator of said radiotherapy isotope.
Please see the discussion and citations within instant claim 1 for the necessary rejection text. Kumar et al. disclose the visualization of tumors using the targeting peptide sequence (see abstract within Kumar et al.). Additionally, Chang et al. disclose a method of treating cancer (see claim 40 and 41 within Chang et al.). Moreover, Chang et al. disclose that a subject or patient comprises any mammal (see paragraph [231] within Chang et al.). [Chang et al. disclose similar molecular scaffolds as disclosed by Kumar et al.).
Regarding instant claims 21-23 and 25, Kumar et al. and Chang et al. teach a method of treating cancer in a mammal, wherein said method comprises: a) administering, to said mammal, a first conjugate comprising two or more chelators and a binding moiety, wherein one of said chelators is a chelator of an imaging isotope and one of said chelators is a chelator of a radiotherapy isotope, wherein said first conjugate comprises said imaging isotope complexed to said chelator of said imaging isotope; b) determining, in said mammal, the biodistribution of said first conjugate; and c) administering, to said mammal, an amount of a second conjugate that is identical to said first conjugate except that said second conjugate comprises said radiotherapy isotope complexed to said chelator of said radiotherapy isotope.
Please see the discussion and citations within instant claim 20 for the necessary rejection text. The methods disclosed by Chang et al. to treat cancer (see claim 40 and 41 within Chang et al.) would employ the known techniques of a skilled artisan. Also, the methods of instant claims 21-22 and 25 are not unique and a skilled artisan (POSITA) would follow a similar protocol using both the Kumar et al. and Chang et al. references. These citations give a blueprint for the treatment of cancer using the compositions of instant claim 1. [A skilled artisan (POSITA) would collect imaging data or employ a radiotherapy protocol depending upon the patient disease scenario.]
Regarding instant claim 27, Kumar et al. and Chang et al. teach wherein said polypeptide binds prostate specific membrane antigen, a somatostatin receptor, a fibroblast activation protein, or a melanocortin-1 receptor (see claim 48 within Chang et al.).
Combination of Kumar et al. and Wurzer et al.
Regarding instant claim 28, Kumar et al. and Wurzer et al. teach wherein said conjugate comprises two or more binding moieties. Wurzer et al. disclose wherein said conjugate comprises three binding moieties (see Scheme 1 within Wurzer et al.).
Analogous Art
The Kumar et al., Chang et al., Wurzer et al., Yamane et al., and Burak references are directed to the same field of endeavor as the instant claims, that is, a conjugate comprising two or more chelators and a binding moiety, as disclosed within instant claim 1.
Obviousness Analysis
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the radiotherapy composition disclosed by Kumar et al., using the teachings of Chang et al., Wurzer et al., Yamane et al., and Burak in order to arrive at the subject matter of the instant claims.
The Kumar et al., Chang et al., Wurzer et al., Yamane et al., and Burak references all have considerable overlap in the radioimmunoconjugate arts. In this instance, Kumar et al. supplies the molecular platform for design and synthesis of targeted dual-modality imaging probes, Chang et al. supplies the method for treating cancer using these compositions, Wurzer et al. and Yamane et al. supply alternative chemistries (linkers, binding moieties, and radioisotopes), while Burak supplies the additional elements used for imaging and radiotherapy techniques. All references are directed to the radioimmunoconjugates and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the five references when seeking to develop an enhanced conjugate comprising two or more chelators and a binding moiety for treating cancer incorporating the limitations supplied by the citations above.
Given these teachings, a POSITA would have been motivated to combine the molecular platform for design and synthesis of targeted dual-modality imaging probes of Kumar et al., the method of treating cancer disclosed by Chang et al., and the alternative synthetic elements supplied by Wurzer et al., Yamane et al., and Burak.
The modification constitutes a simple substitution of one known element for another to obtain a predictable results [MPEP §2143(I)(B)].
The combination represents the use of a known technique to improve a similar device in the same way [MPEP §2143(I)(C)].
The art provides a finite number of identified, predictable solutions, and the POSITA would have pursued the claimed configuration with a reasonable expectation of success [MPEP §2143(I)(E); KSR].
The combination of the imaging and radiotherapy composition taught by Kumar et al. along with the use of the necessary claim limitations taught by Chang et al., Wurzer et al., Yamane et al., and Burak would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
Furthermore, the additional claim limitations taught by Chang et al., Wurzer et al., Yamane et al., and Burak would have been viewed by a POSITA as routine design optimizations or known modifications for administration of dual imaging and radiotherapy agents. The motivation being to incorporate the additional and alternative elements supplied by Chang et al., Wurzer et al., Yamane et al., and Burak to synthesize an enhanced dual prong therapeutic. Implementing these features in Kumar et al.’s molecular platform for the design and synthesis of targeted dual-modality imaging probes would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Kumar et al., Chang et al., Wurzer et al., Yamane et al., and Burak provides all the elements of the claimed invention. The resulting conjugate comprising two or more chelators and a binding moiety for cancer treatment constitutes no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Allowable Subject Matter
Claims 17 and 33 are objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Both claims 17 and 33 have allowable subject matter because the presented structures are absent from the prior art. Motivation is lacking to add these synthetic variations to the closest reference of Kumar et al.
Conclusion
No claims are allowed.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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