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, Claims 1-8 in the reply filed on 08/05/2026 is acknowledged. The amendment of claims in Group II filed on 08/05/2026 have not changed the election/restrictions requirement as mailed in office action on 06/10/2026.
Claims 9-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/05/2026.
Status of Claims
Claims 1-17 are pending and claims 9-17 are withdrawn without traverse due to being drawn to nonelected group. Claims 1 and 9-17 are amended.
Claims 1-8 are being examined on the merits herein.
Priority
This instant application 18893773, filed on 09/23/2024, claims domestic benefit of 63/539793, filed on 09/21/2023.
Information Disclosure Statement
The information disclosure statement (IDS), filed on 05/09/2025, is in compliance with the
provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the
Examiner.
Claim Objections
Claims 1, 6 and 8 are objected to because of the following informalities:
Claim 1 recites “ emit energy at a first wavelength, the energy at a first wavelength”. The second appearance of the phrase should refer to “the first wavelength”.
Claim 6 recites “CrONO” and “Ruthenium(phen)(NO)(Cl)” without full definitions of the chemical names.
Claim 8 recites “radiation does”, which should be “radiation dose”.
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 1-8 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 “a matrix comprising … and a nitric oxide release agent at least partially surrounded by a functional material”. It is unclear whether the matrix or only the nitric oxide release agent is “at least partially surrounded” by a functional material. For the purpose of compact prosecution, based on broadest reasonable interpretation, any material in contact with the matrix or NO release agent for any designated function is considered as “at least partially surrounded by a functional material”.
Claim 1 recites the limitation “providing treatment packages” in line 5. There is insufficient antecedent basis for this limitation in the claim, because “a treatment package” was mentioned previously in the claim, not “packages”. It is unclear whether it’s meant to have multiple of the same previously mentioned treatment package or include other additional treatment packages.
Claim 6 recites “maximized production”. The concept of being maximized is abstract without standardized levels, especially for this instance, there is no specific wavelength or scintillating polymer as reference. For the purpose of compact prosecution, the term is considered as “ensures” production of NO.
Claims 3-5 and 7-8 are rejected accordingly because they are dependent claims of claim 1 and they do not clarify the issues addressed above in claim 1.
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 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 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Evans et al. (Chemical Science, 2018, PTO-892), in view of Mantovani et al. (Nat Rev Drug Discov. 21(11):799-820, 08/16/2022, PTO-892), Philbert et al. (WO0108660, 02/08/2001, PTO-892) and Bourke et al. (WO2013009688, 01/17/2013, PTO-892).
For Claim 1, A method for reducing a number of cancerous cells in a body comprising:
providing a treatment package having a matrix comprising a mixture of scintillating polymer and a nitric oxide (NO) release agent at least partially surrounded by a functional material;
Evans throughout the reference teaches a drug-delivery method for therapeutic treatment at targeted cancer or tumor tissues (e.g., Abstract). Evans teaches a unique package consisting of a manganese-nitrosyl complex, which is a photoactivated NO-releasing moiety (PhotoNORM, corresponding to NO releasing agent), plus Nd3+-doped upconverting nanoparticles (Nd-UCNPs) (e.g., Abstract), corresponding to matrix comprising a mixture of photoactivatable polymer (scintillating polymer) and a nitric oxide release agent, and the NO-releasing agent is at least partially surrounded by the functional material, e.g., Nd3+ or the nanoparticles, with broad reasonable interpretation of claim scope).
providing treatment packages to macrophage for consumption by the macrophage causing
the treatment package to be within the macrophage;
Evans teaches the biodegradable polymer microparticles are taken up by bone-marrow derived murine macrophages (e.g., Abstract). Evans indicates that the goal of experiments is to determine the amount of loaded PLGA (poly(lactic-co-glycolic acid) microparticles that can undergo phagocytosis into the murine bone marrow macrophages and the microparticles are surface modified with a covalently bound layer of IgG to enhance uptake (corresponding to another functional material surrounding the matrix) (Pg. 3731, right Col., 2nd paragraph), indicating the treatment packages containing the matrix are provided to macrophage for consumption and the packages are taken by the macrophage.
presenting the macrophage to a human body, the human body having cancer cells living
within the human body; waiting a period of time for the macrophage to travel to the cancer cells;
Evans teaches 50 ul aliquot of a solution of the macrophages, blank or NO-donor loaded particles at 4 x10 5 cells per mL is added to tumor spheroids and put in a cell incubator for 3 days to assure optimal interaction between macrophages and spheroids to allow the macrophage to travel or to be incorporated into the tumor spheroids (pg. 3736, right Col., 3rd paragraph). As known in field, tumor spheroid models mimic the architecture and microenvironment of solid tumors and are widely used to replicate human tumor microenvironment in cancer biology and drug delivery. Evans points out that such macrophages have the potential to act as “cellular Trojan Horses” to carry a therapeutic payload into tumors (Pg. 3730, Left Col. 2nd paragraph).
directing X-ray radiation to locations of the cancer cells, such that the X-ray radiation cause the scintillating polymer to emit energy at a first wavelength, the energy at a first wavelength causing the NO release agent to release nitric oxide, which reduces a number of cancer cells, wherein the scintillating polymer is an organic silicon-based polymer.
Evans teaches both the photoNORM and Nd-UCNPs are activated by tissue-penetrating near-infrared (NIR) light at ~800 nm (Abstract) (corresponding to emit energy at a first wavelength). Evans illustrates the radiation scheme (Scheme 1 Figure, Pg. 3730, top left), showing that macrophages which contain the photoNORMs and UCNPs at the tumor site upon NIR laser are activated to release NO, resulting in NO mediated cancer therapeutics. Evans investigates the irradiation energy transfer from UCNPs to photoNORMs using photosensitive Mn photoNORM I or Nd-UCNPs toward NO release via direct single-photon excitation with 794 nm light (Pg. 3731, left Col. bottom), indicating the first wave length causing the NO release agent to release nitric oxide). Evans concludes that once carried inside the spheroid by the macrophage, the photoNORM in the microparticles can be activated with NIR light to release NO that can cause direct tumor cell cytotoxicity or significant drop in the expression of hypoxia inducible factor HIF-1a in the tumor microenvironment (Pg. 3730, Left Col. 2nd paragraph) (reducing numbers of cancer cells).
For Claim 2, Evans teaches the unique treatment package contains a manganese-nitrosyl complex as photoactivated photoNORM with Nd-UCNPs nanoparticles incorporated into biodegradable polymer microparticles (e.g., Abstract), showing in drawing as microsphere form in Scheme 1 (Pg. 3730, top left).
For Claim 3, Evans throughout the reference teaches using macrophages carrying NO-donor loaded microparticles with a NIR photo-activated theranostic payload into a tumor as treatment for cancer hypoxia (e.g., Abstract).
For Claims 6-7, Evans tests NO release from photoNORM loaded polymer microparticles with excitation 794 nm light, to compare Nd-UCNPs (PLGA-1) and Mn photoNORM I (PLGA-2) to carefully select the first wavelength of the energy emitted corresponding to an energy wavelength that maximize the NO release, e.g., NO release efficiencies for PLGA-1 and PLGA-2 are 1.63 pmol W-1 cm2s-1 and 2.06 pmol W-1 cm 2 s-1 respectively (Pg. 3730-3731, e.g., Pg. 3731, right Col. 1st paragraph). Apparently, the scintillating polymer is selected as such that the first wavelength emitted corresponds to activation wavelength of the NO release agent and to ensure NO production from the NO release agent for effective tumor treatment.
Evans does not explicitly teach presenting the macrophage to a human body having cancer cells as recited in instant claim 1. Evans does not teach using X-ray as radiation source or the scintillating polymer being silicon-based polymer in instant claim 1, NO release agent species as recited in instant claim 5, X-ray radiation dose less than 5 MeV in instant claim 8.
Mantovani throughout the reference reviews macrophages as tools and targets in cancer therapy (Title), stating that macrophages can mediate phagocytosis of cancer cells and cytotoxic tumor killing when appropriately activated and engage in effective bidirectional interactions with components of the innate and adaptive immune system (Abstract). Mantovani teaches tumor-associated macrophages (TAMs) in conventional cancer therapies, including some selected chemotherapeutic agents such as doxorubicin induce the release of tumor antigens and adjuvant molecules, a process known as immunogenic cell death, engaging macrophages in a fruitful cancer-immunity cycle (Pg. 803, left Col. 1st paragraph). Mantovani indicates that with drugs that induce DNA damage via the generation of reactive oxygen species (ROS), such as platinum-based chemotherapies, the gut microbiome can prime intratumour mononuclear phagocytes to produce ROS, positively modulating the efficacy of these agents (Pg. 803, right Col. bottom). Mantovani exhibits selected clinical trials of agents targeting TAMs (Pg.806, Table 1), corresponding to presenting macrophage in human body having cancer cells in instant claim 1.
Philbert throughout the reference directs to cancer or tumor cell destruction via fiberless radiative effectors that encapsulate a free radical generator, and the effectors include a polymer matrix, a photodynamic or radiodynamic dye which produces free radicals upon stimulation, cloaking material, and at least one molecular recognition element for targeting to a biological target (including cancer/tumor cells) (e.g., Abstract; Pg. 1, Lines 8-30; Pg. 52, Lines 15-20).
Philbert teaches radiodynamic compounds include but are not limited to polystyrene and scintillating compounds (e.g., Pg. 15, 1st paragraph), radioactive element refers to any material which emits alpha, beta, or gamma particles (Pg. 15, 2nd paragraph), and the fiberless radiative effector is generally spherical form of matrix that can be made of polymeric matrices (e.g., polyacrylamide, polyvinyl chloride, decyl-methacrylate or polylactic acid) or sol-gel matrics, while a variety of toxic agents participating in the production of toxic diffusible molecules upon stimulation or excitation from an energy source (e.g., incandescent light, red light, laser, x-rays, or gamma rays), are incorporated into the matrix (Pg. 22, 1st-2nd paragraphs) (corresponding to the matrix and radiation in method of claim 1).
Philbert teaches that X-rays or gamma-rays can be used for excitation, instead of standard light sources (e.g., lasers), which is demonstrated with x-ray transducing materials (e.g., polystyrene based nano scintillators), that transfer the energy to the photoactive molecule ( one absorbed x-ray photon gives the equivalent of 500 absorbed visible photons). Even the visible photon absorption and quantum efficiency can be much improved by supra- or super-molecular antenna systems, in analogy to the photosynthetic antenna in green plants. The fiberless radiative effector core thus serves as an efficient amplification system. This makes it possible to use significantly reduced doses of irradiation, thus minimizing side effects. Additionally, there is practically no limit on treatable tumor depth with the use of x-rays or gamma rays for photodynamic excitation (Pg. 24 bottom – Pg. 25 top) (corresponding to X-ray as radiation source in claim 1).
Philbert teaches toxic agents directly produce free radicals incorporated into the fiberless radiative effectors during polymerization; such toxic agents include Roussin’s black salt and Roussin’s red salt, serving as sources of NO which is toxic to cells (e.g., Pg. 29, 1st paragraph), and radioactive element or compound that emits gamma rays including Fe (iron), Cu (copper), I, Te, and Cr or elements or compounds that emit beta particles (e.g., Pg. 30, Lines 14-16), corresponding to NO release agent species in instant claim 5.
Bourke throughout the reference methods of use for increasing the effectiveness and/or the efficiency of light emission in a subject or medium being treated by X-ray radiation or a particle beam, as well as methods and structures for assembling nano-particles containing scintillating materials to increase their net light output under excitation (e.g., Pg. 2, top, Field of Invention), which can be photodynamic therapy with the energy modulation agents (phosphors, scintillators, fluorescent materials, and combinations and agglomerations thereof) (e.g., Pg. 44, bottom; Pg. 47, top) for treating cell proliferation disorder including cancer (e.g., Claim 19).
Bourke teaches that Loctite Corporation has designed and developed UV and UV /moisture dual curable silicone compositions, which demonstrate high resistance to flammability and combustibility (corresponding to silicon-based polymer in instant claim 1) where the flame-retardant component comprising a member selected from the group consisting of organo ligand complexes of transition metals (Pg. 87, 2nd paragraph). Bourke specifies that UV photoactivatable silicones, free-radical polymerizable functional silicone polymers, or silicon resins are suitable (Pg. 87, 3rd paragraph), and desirable hydrophobic silicas including polydimethylsiloxane-treated silicas (corresponding to instant claim 4). The resulted in scintillators are complexed with the other X-ray down converting particles or other energy modulation agents permitting for example X-ray irradiation to assist in the process (Pg. 90, bottom).
Bourke species that the reduced-voltage x-ray source configured to generate x-rays from a peak applied cathode voltage at or below 105 kVp (kilovolts peak) (e.g., Abstract; Claim 1; Claim 51), which is the same as at or below 0.105 MeV (megaelectrovolts), corresponding to radiation dose less than 5 MeV in instant claim 8.
Bourke states that a first plurality of energy-emitting particles in the medium which, upon radiation from the x-ray source, radiate at a first lower energy than the x-ray source to interact with the medium or with at least one photoactivatable agent in the medium (Claim 1), a second plurality of energy-emitting particles which, upon radiation from the x-ray source, radiate at a second lower energy than the x-ray source (Claim 2), wherein the first plurality of energy-emitting particles comprising at least one of the components including scintillator particles, fluorescent particles, a metallic shell encapsulating at least a fraction of a surface of the particles, etc. (Claim 11) (corresponding to X-ray radiation in instant claim 1), and the metallic material can comprise at least one of Au, Ag, Cu (copper), Ni, Pt, Pd, Co, Ru, Rh, or a combination thereof (e.g., Claims 15 and 65) (corresponding to No release agent species in instant claim 5).
It would have been prima facie obvious for a person with ordinary skills in the art prior to filing date incorporate the teachings from Mantovani, Philbert and Bourke into the method taught by Evans to arrive at current invention. Evans uses tumor model to investigate the treatment system and strongly suggests to the potential of such treatment package with macrophage as a tumor therapy tool, while Mantovani demonstrates that macrophage cancer therapy has been presented in many clinical trials, artisans would have motivated to combine the teaching and implement the method in human cancer patients for reasonable expectation of success. Philbert specifies that X-ray makes it possible to use significantly reduced doses of irradiation than laser beams, e.g., NIR, thus minimizing side effects, plus, there is practically no limit on treatable tumor depth with the use of x-rays or gamma rays for photodynamic excitation, and Bourke demonstrates using low dose X-ray with high resistance to flammability and combustibility suitable silicon-based photoactivable polymers in the cell proliferation disorder (e.g., cancer or tumor cells), an artisan would have motivated to take the benefits and advantages of using X-ray instead of NIR and select suitable components from the combined prior art for reasonable expectation of success. This renders obviousness as “use of known technique to improve similar devices (methods, or products) in the same way” or as “applying a known technique to a known device (method, or product) ready for improvement to yield predictable results”. See MPEP §2143. (I)(C) and (I)(D). Moreover, It is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use (MPEP §2144.07). See Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP §2144.05(I) states that “A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.” See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). For this instance, the X-ray radiation dose overlaps with that in prior art. Furthermore, “[i]t would have been prima facie obvious for one of ordinary skill in the art to optimize additive amount through nothing more than “routine experimentation,” because of a reasonable expectation of success resulting from the optimization for desirable features of intended use of the composition (MPEP §2144.05 (II)). See Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
MPEP 2144.01 points out "[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom." In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968). At times prior art does not explicitly teach certain terms or does not carry out steps in exact the same manner or same descriptive language as instantly claimed, one skilled in the art would have reasonably been expected to draw therefrom from combined teachings Evans, Philbert and Bourke, of current invention as presented above.
Conclusion
No claims are allowed.
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/DX.Z./ Examiner, Art Unit 1616
/MONICA A SHIN/ Primary Examiner, Art Unit 1616
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