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 1-4, 6-18, and 20-22 are pending in this office action. Claims 5 and 19 are cancelled. All pending claims are under examination in this application.
Priority
The current application was filed on September 27, 2024 is a 371 of PCT/US2023/017586 filed on April 5, 2023, which in turn claims domestic priority to provisional patent application 63/327,554 filed on April 5, 2022.
Information Disclosure Statement
Receipt of the Information Disclosure Statement filed on September 27, 2024 is acknowledged. A signed copy of the document is attached to this office action.
Objection to the Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because the graphs of Figures 7A-7D have axis labels that are unclear to the reader. 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 2, 4, 6-8, 16, 18 and 21 are objected to because of the following informalities:
Claim 2: Please amend the text to address “…10 of more…”.
Claims 4 and 18: Please amend the text within the claims to be completely clear to the skilled artisan, “after coupling of the appropriate amine with the carboxylic acid of the HMCD.”
Claims 6-8, 16, and 21: Please amend the word “radio isotope” to be one word, “radioisotope.”
Appropriate correction is required.
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 1-4, 6-18, and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Chung et al. (US2021/0008217A1, published in January 2021) in view of Wang et al. (EP3473630B1, published in January 2021), Hawthorne et al. (US5,888,473A), Yoo et al. (Bioconjugate Chemistry, 2007), and Ricciardi et al. (Applied Sciences, published in December 2021).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims.]
1. Chung et al.
Chung et al. is the closest prior art to the present invention as it teaches tumor homing statin derivatives (see title). Additionally, Chung et al. disclose that the present invention generally relates to tumor homing statin derivatives (THSD) and their use for therapy, in particular cancer therapy. These THSD comprise three moieties: a statin moiety which comprises a dihydroxyheptanoic acid unit (DHHA) fixated by linkage into its open chain form, a heptamethine carbocyanine dye (HMCD) moiety, and a linker that conjugates the DHHA of the statin to the dye moiety. The linker is linked to the DHHA via an ester bond (ester-linked statin derivative or ELSD), or via an amide bond (amide-linked statin derivative or ALSD). Thus, linked to the DHHA, the linker provides a relatively stable link either for essentially no hydrolysis/statin release after
administration, or preferably for very slow hydrolysis and statin release, as is the case for the ELSD. Embodiments include methods to provide the desired THSD, in particular
the ELSD, with the DHHA in its open chain form. The invention also relates to methods wherein one or more ELSD is administered to a patient in a therapeutically effective amount, and methods wherein an ELSD and an ALSD are co-administered in a coordinated administration schedule. Advantages of the THSD and their use include,
among others, improved efficacy and dose-response, and decreased statin-associated side effects (see abstract).
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2. Wang et al.
Wang et al. teach boron-based prodrug strategy for increased bioavailability and
lower-dosage requirements for drug molecules containing at least one phenol (or aromatic hydroxyl) group (see title). In addition, Wang et al. disclose that the present disclosure relates to boron-based prodrugs, methods for making the same, methods for increased bioavailability and lowered dosage requirements for drug molecules that contain one or more phenol groups, and the synthesis and use of the same. Further, the present disclosure teaches the utilization of said prodrugs as improved medications with lower-dose and longer-lasting efficacy (see paragraph [0001] within Wang et al.).
3. Hawthorne et al.
Hawthorne et al. teach liposome compositions for boron neutron capture therapy and methods thereof (see title). Also, Hawthorne et al. disclose boron neutron capture therapy can utilize XyB20H17L where X is an alkali metal, y is 1 to 4, and L is a two-electron donor such as NH3, Na2B10H9NCO, among others. These borane salts may be used free or encapsulated in liposomes. Liposomes may have embedded within their bilayers carboranes to increase the amount of delivered 10B and/or to increase the tumor specificity of the liposome (see abstract).
4. Yoo et al.
Yoo et al. teach peptidyl molecular imaging contrast agents using a new solid
phase peptide synthesis approach (see title). Furthermore, Yoo et al. disclose a versatile method is disclosed for solid phase peptide synthesis (SPPS) of molecular imaging contrast agents. A DO3A moiety was derivatized to introduce a CBZ-protected amino group and then coupled to a polymeric support. CBZ cleavage with Et2AlCl/thioanisole was optimized for SPPS. Amino acids were then coupled to the aminoDOTA loaded resin using conventional step-wise Fmoc SPPS to create a product with DOT A coupled to the C-terminus of the peptide. In a second study, the DO3A moiety was coupled to a glycine-loaded polymeric support, and amino acids were then coupled to the amino-DOTA-peptide loaded resin using SPPS, to incorporate DOTA within the peptide sequence. The peptide-(Tm3+-DOTA) amide showed a PARA- magnetic Chemical Exchange Saturation Transfer (PARACEST) effect, which demonstrated the utility of this contrast agent for molecular imaging. These results demonstrate the advantages of exploiting SPPS methodologies through the development of unique DOTA derivatives to create peptide-based molecular imaging contrast agents (see abstract).
5. Ricciardi et al.
Ricciardi et al. teach a new low-energy proton irradiation facility to unveil the
mechanistic basis of the proton-boron capture therapy approach (see title). Additionally, Ricciardi et al. disclose that proton therapy (PT) is a fast-growing cancer therapy modality thanks to much-improved normal tissue sparing granted by the charged particles' inverted dose-depth profile. Protons, however, exhibit a low biological effectiveness at clinically relevant energies. To enhance PT efficacy and counteract cancer radioresistance, Proton-Boron Capture Therapy (PBCT) was recently proposed. PBCT exploits the highly DNA-damaging ex-particles generated by the p + 11 B➔3a (pB) nuclear reaction, whose cross-section peaks for proton energies of 675 keV. Although a significant enhancement of proton biological effectiveness by PBCT has been demonstrated for high-energy proton beams, validation of the PBCT rationale using monochromatic proton beams having energy close to the reaction cross-section maximum is still lacking. To this end, we implemented a novel setup for radiobiology experiments at a 3-MV tandem accelerator; using a scattering chamber equipped with an Au foil scatterer for beam diffusion on the biological sample, uniformity in energy and fluence with uncertainties of 2% and 5%, respectively, was achieved. Human cancer cells were irradiated at this beamline for the first time with 685-keV protons. The measured enhancement in cancer cell killing due to the 11B carrier BSH was the highest among those thus far observed, thereby corroborating the mechanistic bases of PBCT (see abstract).
Combination of Chung et al., Wang et al., and Hawthorne et al.
Regarding instant claim 1, Chung et al., Wang et al., and Hawthorne et al. teach a heptamethine carbocyanine dye (HMCD) moiety linked to a carborane for administration in cancer therapy. The necessary citations within Chung et al., Wang et al., and Hawthorne et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Chung et al., Wang et al., and Hawthorne et al. Citations
A compound according to Formula III:
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Chung et al. disclose a HMCD moiety linked to a statin for use in oncology therapy (see title and abstract within Chung et al.).
Figure I
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[where R1=(CH2)3SO3-; a hydrocarbyl group]
Furthermore, Chung et al. disclose HMCDs are known for imaging e.g. of the human body for various diagnostic purposes; some of these dyes have been described for use in both cancer imaging as well as cancer therapy (see paragraph [0005] within Chung et al.).
Chung et al. fails to disclose the use of a plurality of 10B isotopes, 11B isotopes, or combinations thereof. However, Hawthorne et al. disclose the use of carboranes [plurality of 10B isotopes, 11B isotopes, or combinations thereof].
Hawthorne et al. disclose that it is an object of the invention to provide compositions and methods for delivering therapeutically useful concentrations of boron containing compounds to tumors for use in neutron capture tumor therapy (see column 2, lines 21-25 within Hawthorne et al.). [Additionally, natural boron consists of two stable isotopes: Boron-10 (~20%) and Boron-11 (80%) (see PTO NPL X)]. Of particular interest, is the commercial availability of 1-amino-1-carbadodecaborate (CAS #749831-19-4), which could be substituted for the statin within Chung et al. to afford the following analogue after amide coupling:
Figure II
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Wang et al. supports the use of boron-based prodrugs (see title; abstract; and paragraphs [0012-0013] all within Wang et al.).
Despite the analogues not being present within the prior art, all the synthetic pieces were known making the instant application obvious to a skilled artisan.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Chung et al. with the teachings of Hawthorne et al. to insert by simple substitution the carborane of choice instead of the statin portion of the HMCD derivative disclosed by Chung et al. In addition, Wang et al. supports the prodrug approach within boron therapy. The motivation for doing so would have been to create a HMCD linked carborane for boron therapy (PBCT; proton-boron capture therapy or BNCT; boron neutron capture therapy) in cancer patients.
Regarding instant claims 2-4 and 18, Chung et al., Wang et al., and Hawthorne et al. teach the wherein S1 includes 10 or more 10B isotopes, 11B isotopes, or combinations thereof, and wherein S1 includes one or more carboranes, and wherein S1 includes at least one of 1-amido-1-carbadodecaborate and 1-(2-amidoethyl)-3-(dodecaborate-1- thio)pyrrolidine-2,5-dione.
Please see the discussion and citations within instant claim 1 for the necessary rejection text. All claim limitations are present based on the presented references.
Combination of Chung et al., Wang et al., Hawthorne et al., and Yoo et al.
Regarding instant claims 6-8, 16, and 21, Chung et al., Wang et al., Hawthorne et al., and Yoo et al. teach the insertion of a chelating moiety, a radioisotope, and 64Cu and/or 67Cu.
The S1 portion of Formula III can include all of the above limitations.
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If a skilled artisan (POSITA; person of ordinary skill in the art) covalently bonds a chelating group, such as a derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), to the carboxylic acid moiety of HMCD with an amine of DOTA, then the reaction will afford an amide. DOTA chelating groups are known to bind copper radioisotopes (see PTO-892 NPL V and 2U). Furthermore, if the DOTA moiety has a carboxylic acid group that could be free to react and form another amide through an amine coupling the 1-amino-1-carbadodecaborate (sensitive portion) could be synthetically incorporated into the molecule.
Yoo et al. is in the art of developing a DOTA derived chelating group (see title and abstract within Yoo et al.). In addition, Yoo et al. disclose working on the solid-phase platform (see title and abstract within Yoo et al.). The following intermediate (3; see Scheme 1 within Yoo et al.) illustrates the “synthetic handles” that could be used to carry out the synthesis outlined in the above paragraph:
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Removal of the Fmoc protecting group would afford a free amine available for amide coupling with the HMCD.
A skilled artisan (POSITA) would have at least three options here: (a) direct coupling with 1 equivalent of 1-amino-1-carbadodecaborate; (b) protection using 2 equivalents of t-BuOH or suitable protecting groups, followed by isolation, and then coupling with 1 equivalent of 1-amino-1-carbadodecaborate; (c) direct coupling with 1 equivalent of 1-amino-1-carbadodecaborate.
Introduction of the 1-amino-1-carbadodecaborate group (sensitive portion) would occur in the last synthetic step.
In this manner, a skilled artisan (POSITA; person of ordinary skill in the art) could synthesize a HMCD moiety linked through an amide coupling reaction to a DOTA derivative. In addition, the DOTA derivative could then be coupled through another amide bond to 1-amino-1-carbadodecaborate. The DOTA chelating group is adapt at binding copper radioisotopes (64Cu or 67Cu; see PTO-892 NPL V and 2U).
Combination of Chung et al., Wang et al., and Hawthorne et al.
Regarding instant claims 9, 13, and 20, Chung et al., Wang et al., and Hawthorne et al. teach wherein R1 includes a hydrocarbyl group substituted with a carboxylate group, a sulfonate group, or combinations thereof.
Please see the discussion and citations within instant claim 1 for the necessary rejection text (hydrocarbyl group substituted with a sulfonate group).
Regarding instant claim 10, Chung et al., Wang et al., and Hawthorne et al. teach wherein the compound has a chemical structure according to Formula IV:
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Please see the discussion and citations within instant claim 1 for the necessary rejection text.
Regarding instant claim 11, Chung et al., Wang et al., and Hawthorne et al. teach a method of making a theranostic compound, comprising: providing a concentration of a tumor-targeting compound, the tumor-targeting compound including a heptamethine cyanine dye (HMCD) having an available carboxyl group; reacting the available carboxyl group with ethyl chloroformate and triethylamine to form an intermediate; and reacting the intermediate with a sensitive compound including an amine and a sensitive portion to form a theranostic compound having a sensitive portion connected to a tumor targeting portion via a secondary amide, wherein the sensitive portion includes a plurality of 10B isotopes, 11B isotopes, or combinations thereof.
Please see the discussion and citations within instant claim 1 for the necessary rejection text. In the second step of the method, using a mixed anhydride to form an amide is common within synthetic organic chemistry and peptide synthesis. All method steps are addressed within Table I.
Regarding instant claim 12, Chung et al., Wang et al., and Hawthorne et al. teach the method according to instant claim 11, wherein the HMCD has a chemical structure according to Formula VII:
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Please see the discussion and citations within instant claims 1 and 11 for the necessary rejection text. This intermediate would be obvious en route to the final amide product.
Regarding instant claim 14, Chung et al., Wang et al., and Hawthorne et al. teach wherein the sensitive compound includes 1-amino-1-carbadodecaborate.
Please see the discussion and citations within instant claims 1 and 11 for the necessary rejection text.
Regarding instant claims 15 and 22, Chung et al., Wang et al., and Hawthorne et al. teach wherein the theranostic compound has a chemical structure according to Formula IV:
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Please see the discussion and citations within instant claims 1 and 11 for the necessary rejection text. The analogue is described in detail within Table I.
Combination of Chung et al., Wang et al., Hawthorne et al., and Ricciardi et al.
Regarding instant claim 17, Chung et al., Wang et al., Hawthorne et al., and Ricciardi et al. teach a method of treating cancer in a patient, comprising: identifying cancerous tumor cells in a patient; administering to the patient an effective amount of a composition for selective uptake by the cancerous tumor cells, the composition including a compound according to Formula III:
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and,
contacting the cancerous tumor cells with a beam of protons, neutrons, or combinations thereof, wherein S1 includes a plurality of 10B isotopes, 11B isotopes, or combinations thereof, and R1 is a substituted hydrocarbyl group.
Please see the discussion and citations within instant claims 1 and 11 for the necessary rejection text. Chung et al. disclose methods of treating cancer using the HMCD moiety (see claims 19 and 20; paragraphs [0065], [0089], [0141] and [0144]; all within Chung et al.). Furthermore, the Ricciardi et al. disclosure supports the use of PBCT therapy (see title and abstract within Ricciardi et al.).
Therefore, a skilled artisan (POSITA) could apply the Chung et al. methods to the present instant claim with the PBCT research by Ricciardi et al. (see title and abstract within Ricciardi et al.).
Analogous Art
The Chung et al., Wang et al., Hawthorne et al., Yoo et al., and Ricciardi et al. references are directed to the same field of endeavor as the instant claims, that is, a HMCD moiety linked to a carborane for administration in cancer therapy, 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 HMCD pharmaceutical composition disclosed by Chung et al., using the teachings of Wang et al., Hawthorne et al., Yoo et al., and Ricciardi et al. in order to arrive at the subject matter of the instant claims.
The Chung et al., Wang et al., Hawthorne et al., Yoo et al., and Ricciardi et al. references all have application in the boron-based prodrug arts. In this instance, Chung et al. supplies the template for the HMCD pharmaceutical composition, Wang et al. supplies the support for the boron-based prodrug, Hawthorne et al. supplies support for BNCT utilizing carboranes, Yoo et al. supplies the DOTA derivative for chelating radioisotopes of copper, while Ricciardi et al. supplies the support for the use of PBCT. All references are directed to modifying boron-based prodrugs and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the five references when seeking to develop a HMCD boron-based composition.
Given these teachings, a POSITA would have been motivated to combine the template for the HMCD pharmaceutical composition as disclosed by Chung et al., the support for the boron-based prodrug disclosed by Wang et al., support for the use of BNCT and carboranes as disclosed by Hawthorne, and the support for the DOTA chelating derivative and PBCT disclosed by Yoo et al. and Ricciardi et al., respectively.
The modification constitutes a simple substitution of one known element for another to obtain a predictable result [MPEP §2143(I)(B)].
The combination represents the use of a known technique to improve a similar composition 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 HMCD pharmaceutical composition taught by Chung et al. along with the use of the necessary claim limitations taught by Wang et al., Hawthorne et al., Yoo et al., and Ricciardi et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
Furthermore, the additional claim limitations taught by Wang et al., Hawthorne et al., Yoo et al., and Ricciardi et al. would have been viewed by a POSITA as routine design optimizations or known modifications for boron-based prodrugs. The motivation for doing so would have been to create a HMCD linked carborane for boron therapy (PBCT or BNCT) in cancer patients. Implementing these features in Chung et al.’s HMCD pharmaceutical composition would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Chung et al., Wang et al., Hawthorne et al., Yoo et al., and Ricciardi et al. provides all the elements of the claimed invention. The resulting HMCD boron-based prodrug, 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.
Conclusion
No claims are allowed.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
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