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 in the reply filed on June 9, 2026 is acknowledged.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in PEOPLE'S REPUBLIC OF CHINA on March 24, 2023. It is noted, however, that applicant has not filed a certified copy of the CN202310295680.3 application as required by 37 CFR 1.55.
Specification
The abstract of the disclosure is objected to because it is too long in length (152 words). Applicant is reminded of the proper language and format for an abstract of the disclosure. The abstract should be in narrative form and generally be limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details. 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).
Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following informalities:
Inconsistent terms are used to refer to the same PECAM-1 (platelet-endothelial cell adhesion molecule-1) targeted monoclonal antibody (mAb). The terms are written alternately with a hyphen (“-“) and an underscore (“_”). For example, claim 1 recites “…preparation of radionuclide-labeled PECAM-1_4G6 mAb…”, “…subjecting hydrazinonicotinamide (HYNIC) and PECAM-1-4G6…”, and “…radionuclide-labeled PECAM-1_4G6 mAb….” Claim 3 recites “177Lu-labeled PECAM-1_4G6 mAb.” It is suggested to use one consistent term throughout the claims.
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 2 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.
Claim 2 recites “the reducing agent comprises 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) and N-hydroxysuccinimide (NHS).” One of ordinary skill in the art would recognize that EDC·HCl and NHS are not reducing agents. Rather, they are well-known coupling/conjugating agents. Because EDC·HCl and NHS do not chemically function as a “reducing agent”, the phrase “the reducing agent comprises 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) and N-hydroxysuccinimide (NHS)” is technically contradictory and renders the scope of the “reducing agent” indefinite. Because the specification does not provide a specific definition of the “reducing agent”, it is unclear whether the ”reducing agent” comprises a true reducing agent in addition to EDC·HCl and NHS or if it intends to refer to a coupling agent system.
Clarification and/or amendment is required.
For the purposes of applying art, EDC·HCl and NHS are interpreted as a coupling agent system rather than a functional reducing agent for radionuclides.
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 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Mei (梅) et al. (CN 114939171A, 2022; cited on PTO-892; all citations from the machine translation) in view of Wang et al. (EP 3 906 947, 2021; cited on PTO-892), Rajopadhye et al. (Bioorganic & Medicinal Chemistry Letters, 1997; cited on PTO-892), Bentivoglio et al. (Biomolecules, 2022, cited on PTO-892), Chen et al. (American Journal of Physiology-Renal Physiology, 2015; cited on PTO-892), and Yang et al. (Advanced Healthcare Materials, 2021; cited on PTO-892).
Regarding claim 1, Mei discloses a method of preparing a nanometer drug-carrying system comprising PECAM-1_4G6 mAb as a targeting moiety, HES (hydroxyethyl starch)-CH (cholesterol) nanoparticles (HCNPs) as a nanocarrier, and TPCA-1 ([5-(p-fluorophenyl)-2-ureido]thiophene-3-carboxamide) as a drug for targeted therapy (abstract). Mei discloses that an aqueous solution of the mAb-TPCA-1@HCNPs can be obtained by adding N,N’-disuccinimidyl carbonate (DSC) to HCNPs aqueous solution, stirring, dialyzing, adding PECAM-1_4G6 mAb, and stirring at room temperature (page 14, ¶ 8). Regarding claim 6, Mei discloses a method of assembling TPCA-1@HCNPs (Pickering emulsion evaporation method) comprising dissolving HES-CH in deionized water, utilizing ultrasonic solubilization to obtain an aqueous solution, slowly adding dropwise an oil phase solution containing chloroform into the solution, ultrasonically sonicating the mixture during the dropwise addition, evaporating the chloroform with a rotary evaporator, centrifuging the aqueous solution to discard the precipitate, and lyophilizing the remaining solution to obtain a nanoparticle powder (page 11, ¶ 7; page 14, ¶ 7).
Mei does not disclose a radionuclide-labeled PECAM-1_4G6 mAb using HYNIC (hydrazino nicotinamide) prepared by step S1 of instant claim 1.
Wang discloses a method of preparing a pharmaceutical composition comprising an immunotherapeutic medicament and a nanoantibody molecular imaging probe for targeted radiotherapy and immunotherapy under the guidance of images (integrated diagnosis and treatment) (title, abstract). Wang discloses that a complex of the composition can comprise a radionuclide, a bifunctional chelator such as HYNIC (hydrazino nicotinamide), and an RGD (Arg-Gly-Asp) polypeptide as a targeting moiety (claim 2). Regarding claims 2 and 3, Wang discloses that the radionuclide can be 177Lu (claim 2).
Rajopadhye discloses a method of preparing peptide-HYNIC conjugate comprising deprotection under acidic condition and purification steps (page 956, ¶ 2).
Bentivoglio discloses a radiolabeling method using reducing agent to increase radiochemical yield (page 3, ¶ 8).
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 method of Mei by labeling the PECAM-1_4G6 mAb with a radionuclide (such as 177Lu) by preparing the PECAM-1 and HYNIC reaction under acidic conditions, and radiolabeling the conjugate in the presence of a reducing agent for targeted theranostics. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Wang teaches a composition comprising a radionuclide such as 177Lu, HYNIC, and a targeting moiety for integrated diagnosis and treatment; Rajopadhye teaches acidic conditions for the peptide-HYNIC conjugation; and Bentivoglio teaches the use of a reducing agent for radiolabeling. Further, a person of ordinary skill in the art would have been motivated to utilize a radionuclide-labeled PECAM-1_4G6 mAb as a targeting moiety with a radionuclide for diagnosis and/or treatment in order to achieve higher endothelial and inflammation specificity and superior internalization for the applications of a targeted drug delivery system. A person of ordinary skill in the art would have been motivated to use acidic conditions for HYNIC-peptide conjugation to promote deprotection, prevent unwanted reactions, and dissolve aggregating peptides. A person of ordinary skill in the art would have been motivated to use reducing agent for radiolabeling in order to achieve direct, highly efficient labeling.
Mei does not disclose antithrombin in step S2 of instant claims 1, 4, and 5. Mei does not disclose the use of EDC·HCl and NHS in instant claim 2.
Chen discloses that nanoparticle-based antithrombin therapy can be used for highly localized and safe inhibition of clotting that accompanies vascular damage, coagulation-based renal injury, and thrombin-mediated inflammation (page F765, column 2, ¶ 2). Chen discloses that the nanoparticles can be molecularly targeted and can include molecules for in vivo imaging (page F765, column 2, ¶ 3).
Yang discloses a method of preparing nanoparticles comprising PHSRN (Pro-His-Ser-Arg-Asn) peptides as a targeting moiety, HES as a nanocarrier platform, and smoothened agonist (SAG) as a drug for targeted therapeutics (abstract; page 2, column 1, ¶ 3; page 13, column 2, ¶ 3). Yang discloses that a mixture of targeting moiety and nanocarrier in deionized water can be stirred and dialyzed against deionized water (page 13, column 1, ¶ 8). Yang discloses that the drug can be bound to the nanocarriers by electrostatic adsorption (page 2, ¶ 4). Regarding claim 2, Yang discloses that EDC·HCl and NHS can be used for the synthesis of the targeting moiety-nanocarrier conjugate (page 13, column 1, ¶ 8).
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 method of Mei by replacing the TPCA-1 drug with antithrombin, and utilizing EDC·HCl and NHS for preparing stable conjugates. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Chen teaches antithrombin as a drug for various therapeutic applications, and Yang teaches that EDC·HCl and NHS can be used for the synthesis of the targeting moiety-nanocarrier conjugate. Further, a person of ordinary skill in the art would have been motivated to load antithrombin into a PECAM-1-targeted nanoprobe in order to treat blood clots more effectively for theranostic application. A person of ordinary skill in the art would have been motivated to use electrostatic interaction for loading antithrombin in order to maintain protein activity and enable targeted release. A person of ordinary skill in the art would have been motivated to use ultrapure water to dissolve αPECAM-1-HCNPs and antithrombin in order to prevent unwanted chemical reactions and preserve molecular stability. A person of ordinary skill in the art would have been motivated to conduct a purification step such as ultrafiltration after the synthesis reaction in order to achieve a highly purified product by removing unconjugated molecules. The proportion of αPECAM-1-HCNPs and antithrombin, the selection of solvent such as ultrapure water, and purification steps such as ultrafiltration are clearly result-effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the proportion of the molecule dissolved in the appropriate solvent and the purification steps in order to optimally synthesize the desired composition.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. (Advanced Healthcare Materials, 2021; cited on PTO-892) in view of Wang et al. (EP 3 906 947, 2021; cited on PTO-892), Muzykantov et al. (Proceedings of the National Academy of Sciences, 1999; cited on PTO-892), Rajopadhye et al. (Bioorganic & Medicinal Chemistry Letters, 1997; cited on PTO-892), Bentivoglio et al. (Biomolecules, 2022, cited on PTO-892), Xu et al. (Carbohydrate Polymers, 2022; cited on PTO-892), Battogtokh et al. (European Journal of Pharmaceutics and Biopharmaceutics, 2015; cited on PTO-892), and Chen et al. (American Journal of Physiology-Renal Physiology, 2015; cited on PTO-892).
Regarding claim 1, as discussed above, Yang discloses a method of preparing nanoparticles comprising PHSRN peptides as a targeting moiety, HES as a nanocarrier platform, and SAG as a drug for targeted therapeutics (abstract; page 2, column 1, ¶ 3; page 13, column 2, ¶ 3). Yang discloses that the mixture of targeting moiety and nanocarrier in deionized water can be stirred and dialyzed against deionized water (page 13, column 1, ¶ 8). Yang discloses that the drug can be bound to the nanocarriers by electrostatic adsorption (page 2, ¶ 4). Regarding claim 2, Yang discloses EDC·HCl and NHS can be used for the synthesis of targeting moiety-nanocarrier conjugate (page 13, column 1, ¶ 8).
Yang does not discloses a radionuclide-labeled PECAM-1_4G6 mAb prepared by step S1 of instant claim 1.
As discussed above, Wang discloses a method of preparing a pharmaceutical composition comprising an immunotherapeutic medicament and a nanoantibody molecular imaging probe for targeted radiotherapy and immunotherapy under the guidance of images (integrated diagnosis and treatment) (title, abstract). Wang discloses that a complex of the composition can comprise a radionuclide, a bifunctional chelator such as HYNIC, and an RGD polypeptide as a target moiety (claim 2). Regarding claims 2 and 3, Wang discloses that the radionuclide can be 177Lu (claim 2).
Muzykantov discloses that radiolabeled PECAM-1_4G6 mAb can be used for immunotargeting as it can react with the most membrane -proximal, sixth Ig-like loop of human PECAM-1 (abstract; page 2379, column 2, ¶ 5).
As discussed above, Rajopadhye discloses a method of preparing a peptide-HYNIC conjugate comprising deprotection under acidic conditions and purification steps (page 956, ¶ 2).
As discussed above, Bentivoglio discloses a radiolabeling method using a reducing agent to increase radiochemical yield (page 3, ¶ 8).
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 method of Yang by replacing the PHSRN peptides with a radionuclide (such as 177Lu)-labeled PRCAM-1_4G6 mAb, preparing the PECAM-1 and HYNIC reaction under acidic conditions, and radiolabeling the conjugate in the presence of a reducing agent. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Wang teaches a composition comprising a radionuclide such as 177Lu, HYNIC, and a targeting moiety for integrated diagnosis and treatment; Muzykantov teaches PECAM-1_4G6 mAb as a targeting moiety; Rajopadhye teaches acidic conditions for the peptide-HYNIC conjugation; and Bentivoglio teaches the use of reducing agent for radiolabeling. Further, a person of ordinary skill in the art would have been motivated to utilize a radionuclide-labeled PECAM-1_4G6 mAb as a targeting moiety with a radionuclide for diagnosis and/or treatment in order to achieve higher endothelial and inflammation specificity and superior internalization for the applications of a targeted drug delivery system. A person of ordinary skill in the art would have been motivated to use acidic conditions for HYNIC-peptide conjugation to promote deprotection, prevent unwanted reactions, and dissolve aggregating peptides. A person of ordinary skill in the art would have been motivated to use reducing agent for radiolabeling in order to achieve direct, highly efficient labeling.
Yang does not disclose HCNPs in step S2 of instant claim 1.
Xu discloses a method of preparing nanoparticles comprising amphipathic imidazole/cholesterol modified HES (Chol-HES-Imi, IHC) and doxorubicin as a drug for tumor chemotherapy (abstract; page 2, column 2, ¶ 4).
Battogtokh discloses a method of preparing albumin nanoparticles with improved stability and drug loading capacity (abstract). Battogtokh discloses that DSC can be used as a coupling agent and that the synthesis of the conjugate can be performed at room temperature, with the resulting mixture being purified (abstract; page 97, column 1, ¶ 5).
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 method of Yang by replacing the HES nanocarrier with HCNPs, preparing by using DSC. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Xu teaches cholesterol modified HES as an effective drug carrier and Battogtokh teaches DSC as an effective coupling agent for preparing a conjugate comprising cholesterol. Further, a person of ordinary skill in the art would have been motivated to utilize a cholesterol-modified HES in order to make the nanocarrier amphiphilic, allowing it to form nanoparticles that can effectively encapsulate drugs. A person of ordinary skill in the art would have been motivated to utilize DSC as a highly reactive coupling agent in order to create a stable cholesterol-containing nanocarrier-antibody conjugate without toxic byproduct. The reaction temperature and purification steps such as dialysis are clearly result-effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the reaction temperature and purification steps in order to optimally synthesize the desired composition.
Yang does not disclose antithrombin in step S2 of instant claims 1, 4, and 5.
As discussed above, Chen discloses that nanoparticle-based antithrombin therapy can be used for highly localized and safe inhibition of clotting that accompanies vascular damage, coagulation-based renal injury, and thrombin-mediated inflammation (page F765, column 2, ¶ 2). Chen discloses that the nanoparticles can be molecularly targeted and can include molecules for in vivo imaging (page F765, column 2, ¶ 3).
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 method of Yang by replacing the SAG drug with antithrombin. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Chen teaches antithrombin as a drug for various therapeutic applications. Further, a person of ordinary skill in the art would have been motivated to load antithrombin into a PECAM-1-targeted nanoprobe in order to treat blood clots more effectively for theranostic application. A person of ordinary skill in the art would have been motivated to use electrostatic interaction for loading antithrombin in order to maintain protein activity and enable targeted release. A person of ordinary skill in the art would have been motivated to use ultrapure water to dissolve αPECAM-1-HCNPs and antithrombin in order to prevent unwanted chemical reactions and preserve molecular stability. A person of ordinary skill in the art would have been motivated to conduct a purification step such as ultrafiltration after the synthesis reaction in order to achieve a highly purified product by removing unconjugated molecules. The proportion of αPECAM-1-HCNPs and antithrombin, the selection of solvent such as ultrapure water, and purification steps such as ultrafiltration are clearly result-effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the proportion of the molecule dissolved in the appropriate solvent and the purification steps in order to optimally synthesize the desired composition.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Yang, Wang, Muzykantov, Rajopadhye, Bentivoblio, Xu, Battogtokh, and Chen as applied to claims 1-5 above, and further in view of Zhou et al. (Journal of controlled release, 2018; cited on PTO-892).
In addition to the teachings of Xu discussed above, Xu discloses a method of preparing IHC nanoparticles comprising sonication and filtration (page 2, column 2, ¶ 4).
Yang, Wang, Muzykantov, Rajopadhye, Bentivoblio, Battogtokh, and Chen are discussed above.
None of Yang, Wang, Muzykantov, Rajopadhye, Bentivoblio, Xu, Battogtokh, and Chen discloses the method of preparing HCNPs described in instant claim 6.
Zhou discloses a method of preparing nanoparticles comprising HES and polylactide (PLA) (Supporting Information, page 2, ¶2). Zhou discloses that the ultrasonic emulsification method for nanoparticle preparation can comprise dissolving HES-PLA in water, adding a chloroform solution dropwise into the HES-PLA solution during ultrasonic emulsification, utilizing rotary evaporation to remove the chloroform, performing dialysis against ultrapure water for purification, and freeze-drying (Supporting Information, page 2, ¶2).
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 method of Yang, Wang, Muzykantov, Rajopadhye, Bentivoblio, Xu, Battogtokh, and Chen by utilizing the ultrasonic emulsification method of Zhou to prepare HCNPs more efficiently. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Zhou teaches a method for preparing nanoparticles comprising HES. Further, a person of ordinary skill in the art would have been motivated to utilize the ultrasonic emulsification method in order to prepare stable, uniform nanoparticles without using an emulsifier. The purification steps are clearly result-effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine appropriate purification steps in order to optimally achieve the synthesis of the desired composition.
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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