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 July 12, 2026 is acknowledged.
Claim Objections
Claims 32 and 33 are objected to because of the following informalities:
In claims 32 and 33, “centipose” should read “centipoise.”
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.
Claims 32 and 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.
Dependent claims 32 and 33 recite the limitation “the vehicle.” The claims lack an antecedent basis for this limitation. Independent claim 31 recites “an aqueous solution.” It is suggested that claims 32 and 33 be amended to “the aqueous solution”, or claim 31 be amended to “a vehicle” to obviate this rejection.
Clarification and/or amendment is required.
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, 8, 11, and 36-38 are rejected under 35 U.S.C. 103 as being unpatentable over Ramdahl (WO 2012 131378; cited on IDS filed May 5, 2024) in view of Arazi et al. (Physics in Medicine & Biology, 2010; cited on PTO-892).
Regarding claim 1, Ramdahl discloses a pharmaceutical preparation (mixture) comprising an alpha-emitting radionuclide and a polysaccharide biopolymer (claim 1). Ramdahl discloses that the therapeutic formulations can be suitable for use in the treatment of cancer diseases (treating a tumor) (page 5, ¶ 2). Regarding claims 6 and 36, Ramdahl discloses that the polysaccharide biopolymer can be alginate (claim 8) and the alginate (agent) can form gel with cations such as calcium ions (page 15, ¶ 2). Ramdahl discloses an injectable solution can comprise pharmaceutically acceptable carriers, excipients, and/or diluents, and that a further component such as a buffer solution (vehicle, aqueous solution) can render the final solution suitable for injection in vivo (page 8, ¶ 5-page 9, ¶ 2). Ramdahl discloses that the polysaccharide biopolymer structures can provide sufficient surface area that they are capable of binding an effective amount of radionuclide (page 13, ¶ 5). Ramdahl discloses the binding of radium-223 (223Ra2+) (radium radionuclide) to alginate gel beads (page 19, ¶ 4).
Ramdahl does not disclose that the mixture does not include targeting elements which make the mixture suitable for targeted therapy (instant claim 1). Ramdahl does not disclose the radium radionuclides are radium-224 radionuclides (instant claims 8 and 37) and that the mixture does not bond to radon and lead (instant claims 11 and 38).
Arazi discloses a diffusing alpha-emitters radiation therapy (DART) as a new form of brachytherapy (abstract). Arazi discloses that incorporated radium-224 from implantable radioactive sources can decay and emit into the tumor its short-lived progeny such as radon-220 and lead-212, which leave the source by virtue of their recoil energy (page 1204; ¶ 3). Arazi discloses that the released radionuclides (radon and lead) spread by diffusive and convective processes in the vicinity of the source, leading to the formation of a continuous region of therapeutic high-linear energy transfer (LET) radiation dose through their alpha decays (page 1204; ¶ 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 mixture of Ramdahl by making the agent bond to a sufficient concentration of radium-224 and release radon-220 and lead-212 for DART, brachytherapy as taught by Arazi. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Ramdahl teaches that a radium radionuclide can bond to the alginate, and Arazi teaches that the diffusion of radioactive daughter atoms such as radon and lead released from incorporated radium-224 can be used for effective cancer treatment. Further, a person of ordinary skill in the art would have been motivated to use the strategy of binding radium-224 to an alginate matrix while leaving radon (Rn-220) and lead (Pb-212) unbound or mobile in order to maximize a localized alpha-emitting radiation effect while reducing systemic toxicity in normal organs by securely holding the parent radium-224 at the target site and allowing daughter radon and lead to diffuse from the matrix to expand the radiation kill zone. It is an inherent physical and chemical phenomenon that radon and lead do not bind to the hydrogel matrix. Radon is a noble gas with a completely filled valence electron shell. It is chemically inert and forms virtually no bonds with organic polymers such as alginate. The recoil energy ejects the lead atom out of the hydrogel structure and lead does not fit optimally into the specific coordination geometry of the guluronate blocks of alginate, leading to rapid leaching/desorption in the interstitial fluid. Utilizing this selective binding of radium-224 and non-binding behaviour of Rn-220 and Pb-212 for therapeutic alpha-radiation therapy would have been obvious to a person of ordinary skill in the art. Additionally, 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 mixture of Ramdahl by not including targeting elements according to the specific requirement of the application as a drug design choice. Further, a person of ordinary skill in the art would have been motivated not to include targeting elements such as large microparticles in order to achieve better tumor coverage by radiation, higher drug stability, and a simpler, more cost-effective clinical workflow. A person of ordinary skill in the art would have been motivated to utilize standard brachytherapy, which relies on physical and anatomical placement rather than a chemical targeting moiety.
Claims 2, 26, and 31-33 are rejected under 35 U.S.C. 103 as being unpatentable over Ramdahl and Arazi as applied to claims 1, 6, 8, 11, and 36-38 above, and further in view of Newey-Keane (Am Pharm Rev, 2016; cited on PTO-892) and Lee et al. (Journal of Biomedical Materials Research Part A, 2009; cited om PTO-892).
In addition to the teachings of Ramdahl discussed above, Ramdahl discloses that alginate gel beads can be added into an aqueous solution (page 23, ¶ 1) and that the radionuclides can be captured on alginate gel beads in phosphated-buffered saline (PBS) (page 19, ¶¶ 1-4).
Arazi is discussed above.
Neither Ramdahl nor Arazi discloses that the agent is dispersed homogenously in the vesicle such as aqueous solution (instant claims 2, 26, and 31). Neither Ramdahl nor Arazi discloses that the vehicle carrying the agent has a viscosity of at least 50 centipoise (cP) or 200 cP (instant claims 32 and 33).
Newey-Keane discloses that homogeneous dispersion of pharmaceutical ingredient is essential for uniform dosing when preparing pharmaceutical suspension in a liquid such as water (vehicle such as aqueous solution) (page 2, ¶ 1; page 2, ¶ 3). Newey-Keane discloses that the parameter such as the viscosity of the continuous phase can be manipulated to achieve acceptable performance, unform dosing (page 2, ¶ 5). Newey-Keane discloses that the sedimentation velocity is inversely proportional to the viscosity of the continuous phase (page 3, ¶ 5).
Lee discloses intradiscal drug delivery system (IDDS) comprising in situ forming hydrogel (abstract). Lee discloses that the viscosity can depend on the temperature and concentration of the hydrogel matrix, and that the viscosity can be about 30 Pa·s (30,000 cP) at room temperature (Figure 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 mixture of Ramdahl and Arazi by configuring the agent to be dispersed homogeneously in aqueous solution and adjusting the viscosity of the vehicle for homogeneous drug distribution during administration. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Newey-Keane teaches that the pharmaceutical ingredient can be homogeneously dispersed in a liquid such as water and parameters such as viscosity can affect the stable, homogeneous drug distribution without settling or sedimentation; and Lee teaches that the viscosity can depend on the temperature and concentration of the hydrogel matrix, and that the viscosity can be about 30 Pa·s (30,000 cP) at room temperature. Further, a person of ordinary skill in the art would have been motivated to optimize the viscosity of the mixture in order to avoid potential gelation before the injection and allow easy injection. The viscosity of the mixture is a 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 viscosity of the mixture by adjusting the temperature and concentration of the gel as taught by Lee in order to best achieve the desired gel formation according to the specific requirements of the applications. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP § 2144.
Claims 3, 10, 12, 27-30, 34, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Ramdahl and Arazi as applied to claims 1, 6, 8, 11, and 36-38 above, and further in view of Chao et al (Nature Biomedical Engineering, 2018; cited on IDS filed May 5, 2024).
Ramdahl and Arazi are discussed above.
Neither Ramdahl nor Arazi discloses that the mixture further comprises a substance which regulates immun-checkpoints dispersed in the mixture (instant claims 3 and 34). Neither Ramdahl nor Arazi discloses that the mixture comprises calcium at a concentration of between 1-10 millimolar, or no more than 10 mM or 3 mM (instant claims 10, 28, and 29); the agent which turns into a hydrogel by addition of calcium ions is between 3.5%-10% of the mixture (instant claims 12 and 39); the mixture does not include calcium or does not include a sufficient amount of calcium for turning the agent into a hydrogel (instant claim 27); and the mixture is such that the agent turns into a gel by collecting endogenous calcium (instant claim 30).
Chao discloses a sodium alginate formulation comprising therapeutic 131I radioisotope (abstract). Chao discloses that on intratumoral injection, the soluble polysaccharide rapidly transform into a hydrogel in the presence of endogenous Ca2+, fixing the isotope within the tumors (abstract). Chao discloses alginate concentration-dependent gel formation in the PBS containing Ca2+ at a concentration of 1.8 mM (page 612, column 2, ¶ 2). Cao discloses that 1 mg ml-1 of alginate shows fluid-like behaviour, whereas 5 mg ml-1 or above concentration of alginate rapidly transforms into gels in the presence of Ca2+ (page 612, column 2, ¶ 2). Chao discloses that the mixture without calcium can be injected for in vivo gelation and optimal concentration of alginate can enable homogeneous intratumoral distribution together with effective tumor retention, allowing effective radioisotope therapy treatment of the whole tumor after local administration (page 613, column 1, ¶ 2; page 619, column 2, ¶8). Chao also discloses that the local radiotherapy can be combined with systemic checkpoint blockade therapy using an anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) antibody for the inhibition of tumor metastasis and the prevention of tumor recurrence in patients with advanced-stage cancer (abstract).
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 mixture of Ramdahl and Arazi by adjusting the concentrations of calcium and alginate and including a substance that regulates immun-checkpoints for in vivo gelation-based radioimmunotherapy. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Chao teaches that the mixture comprising alginate can form a hydrogel in the presence of endogenous Ca2+ in vivo, and that checkpoint blockade therapy using an anti-CTLA-4 antibody can be combined with radiotherapy. Further, a person of ordinary skill in the art would have been motivated to utilize in vivo gelation-based radioimmunotherapy by optimizing the concentrations of calcium and alginate of the mixture for in vivo gelation allowing minimal invasion and sustained therapeutic release, and by dispersing immune-checkpoint regulators in the mixture for systemic immune activation allowing more effective treatment. The concentration of calcium is a 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 concentration of calcium in order to best achieve the desired gel formation according to the specific requirements of the applications because the concentration of calcium in the mixture and in vivo critically determines gel formation, which also depends on the concentration of alginate as taught by Chao. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP § 2144.
Claims 4, 13, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Ramdahl and Arazi as applied to claims 1, 6, 8, 11, and 36-38 above, and further in view of Jakhmola et al (Advanced healthcare materials, 2012; cited on PTO-892).
Ramdahl and Arazi are discussed above.
Neither Ramdahl nor Arazi discloses that the mixture comprise a contrast material. Neither Ramdahl nor Arazi discloses that the agent is included in small particles carried by the vehicle, wherein the small particles comprise a metallic core surrounded by the agent.
Jakhmola discloses a inorganic nanoparticle based contrast agents for medical diagnosis and imaging (title; abstract). Jakhmola discloses bismuth-based nanoparticles (small particles, contrast material) for X-ray imaging comprising bismuth core (metallic core) surrounded by a polymer comprising alginate (agent) to avoid toxic effects (page 425, column 2, ¶ 1).
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 mixture of Ramdahl and Arazi by including nanoparticles comprising a metallic core surrounded by the agent comprising alginate for theranostic applications. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Jakhmola teaches that nanoparticles comprising a metallic core such as bismuth and an alginate layer can be used for medical diagnostics and imaging. Further, a person of ordinary skill in the art would have been motivated to utilize a metallic core encapsulated with the agent comprising alginate in order to expand the applications of the mixture of Ramdahl and Arazi as a stable, safe contrast molecule.
Claims 5 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Ramdahl and Arazi as applied to claims 1, 6, 8, 11, and 36-38 above, and further in view of Kim et al. (International Journal of Radiation Oncology Biology Physics, 2014; cited on PTO-892) and Lee et al. (Journal of Biomedical Materials Research Part A, 2009; cited om PTO-892).
Ramdahl and Arazi are discussed above.
Neither Ramdahl nor Arazi discloses that the mixture is thermosensitive such that the viscosity of the mixture increases by at least a factor of two when its temperature increases from room temperature to body temperature.
Kim discloses a temperature-sensitive (thermosensitive) hydrogel for locally targeted delivery of a micron-sized radiation therapy source (title). Kim discloses that the hydrogel can be a water-like liquid at room temperature but gels at body temperature (abstract). Kim discloses that the radiotherapy gel can be successfully injected to a tumor and shows promise as a delivery modality of a radiation source to a local tumor (abstract).
In addition to the teachings of Lee discussed above, Lee discloses that the phase transition (liquid at room temperature, gel at around body temperature) can be manipulated by changing the composition of the hydrogel (abstract). Lee discloses the relationship between viscosity and temperature depending on the hydrogel (Figures 2 and 3). Lee discloses that the viscosity of IDDS can be at most ∼50 Pa·s at 20°C but it can raise to above 300 Pa·s at 37°C (page 382, column 1, ¶ 1). It would be expected that the viscosity of the mixture can increase by at least a factor of two when its temperature increases from room temperature to body temperature.
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 mixture of Ramdahl and Arazi by further including a thermosensitive gel material for preparing an in situ-forming hydrogel mixture. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Kim teaches that a temperature-sensitive hydrogel which is a water-like liquid at room temperature but gels at body temperature can be used for radiation therapy; and Lee teaches that the viscosity of the mixture can be increased by at least a factor of two when its temperature increases from room temperature to body temperature. Further, a person of ordinary skill in the art would have been motivated to utilize a thermosensitive mixture in order to enable minimally invasive injection and precise local retention of therapeutic agents. A person of ordinary skill in the art would have been motivated to optimize the composition of the thermosensitive gel in order to prepare a mixture with a specific viscosity and increase the viscosity by at least a factor of two when its temperature increases from room temperature to body temperature according to the specific requirements of the applications as taught by Lee.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6, 8, 10-14, and 26-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 19/269,157 (US 2025 0339572; cited on PTO-892) in view of Jakhmola et al (Advanced healthcare materials, 2012; cited on PTO-892), Kim et al. (International Journal of Radiation Oncology Biology Physics, 2014; cited on PTO-892), and Lee et al. (Journal of Biomedical Materials Research Part A, 2009; cited om PTO-892), Chao et al (Nature Biomedical Engineering, 2018; cited on IDS filed May 5, 2024), Arazi et al. (Physics in Medicine & Biology, 2010; cited on PTO-892), and Newey-Keane (Am Pharm Rev, 2016; cited on PTO-892).
Regarding claims 1 and 31, claim 21 of the ‘157 recites a medicament (mixture) for treating a tumor, comprising an agent which turns into a hydrogel by addition of calcium ions; a water-based solution (vehicle) carrying the agent in a manner allowing injection of the medicament into a patient; and radium radionuclides bounded to the agent in a concentration sufficient to treat the tumor by radiotherapy. Claim 23 of the ‘157 recites that the medicament does not include targeting elements sufficient for targeted therapy of the medicament.
Regarding claims 2, 26, and 31, claim 22 of the ‘157 recites that the agent is dispersed homogenously in the water-based solution (aqueous solution).
Regarding claims 3 and 34, claim 24 of the ‘157 recites that the medicament can further comprise further a substance which regulates immune-checkpoints dispersed in the medicament.
Regarding claims 4, 13, 14, claims of the ‘157 do not disclose that the mixture comprise a contrast material. Claims of the ‘157 do not disclose that that the agent is included in small particles carried by the vehicle, wherein the small particles comprise a metallic core surrounded by the agent. As discussed above, Jakhmola discloses a inorganic nanoparticle based contrast agents for medical diagnosis and imaging (title; abstract). Jakhmola discloses bismuth-based nanoparticles (small particles, contrast material) for X-ray imaging comprising bismuth core (metallic core) surrounded by a polymer comprising alginate (agent) to avoid toxic effects (page 425, column 2, ¶ 1). 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 mixture of the ‘157 by including nanoparticles comprising a metallic core surrounded by the agent comprising alginate for theranostic applications. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Jakhmola teaches that nanoparticles comprising a metallic core such as bismuth and an alginate layer can be used for medical diagnostics and imaging. Further, a person of ordinary skill in the art would have been motivated to utilize a metallic core encapsulated with the agent comprising alginate in order to expand the applications of the mixture of the ‘157 as a stable, safe contrast molecule.
Regarding claims 5 and 35, claims of the ‘157 does not disclose that the mixture is thermosensitive such that the viscosity of the mixture increases by at least a factor of two when its temperature increases from room temperature to body temperature. As discussed above, Kim discloses a temperature-sensitive (thermosensitive) hydrogel for locally targeted delivery of a micron-sized radiation therapy source (title). Kim discloses that the hydrogel can be a water-like liquid at room temperature but gels at body temperature (abstract). Kim discloses that the radiotherapy gel can be successfully injected to a tumor and shows promise as a delivery modality of a radiation source to a local tumor (abstract). AS discussed above, Lee discloses that the phase transition (liquid at room temperature, gel at around body temperature) can be manipulated by changing the composition of the hydrogel (abstract). Lee discloses the relationship between viscosity and temperature depending on the hydrogel (Figures 2 and 3). Lee discloses that the viscosity of IDDS can be at most ∼50 Pa·s at 20°C but it can raise to above 300 Pa·s at 37°C (page 382, column 1, ¶ 1). It would be expected that the viscosity of the mixture can increase by at least a factor of two when its temperature increases from room temperature to body temperature. 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 mixture of the ‘157 by further including a thermosensitive gel material for preparing an in situ-forming hydrogel mixture. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Kim teaches that a temperature-sensitive hydrogel which is a water-like liquid at room temperature but gels at body temperature can be used for radiation therapy; and Lee teaches that the viscosity of the mixture can be increased by at least a factor of two when its temperature increases from room temperature to body temperature. Further, a person of ordinary skill in the art would have been motivated to utilize a thermosensitive mixture in order to enable minimally invasive injection and precise local retention of therapeutic agents. A person of ordinary skill in the art would have been motivated to optimize the composition of the thermosensitive gel in order to prepare a mixture with a specific viscosity and increase the viscosity by at least a factor of two when its temperature increases from room temperature to body temperature according to the specific requirements of the applications as taught by Lee.
Regarding claims 6 and 36, claim 16 of the ‘157 recites that the agent comprises alginate.
Regarding claims 8 and 37, claim 17 of the ‘157 recites that the radium radionuclides are radium-224 radionuclides.
Regarding claims 10, 27-30, claims of the ‘157 does not disclose that the mixture comprises calcium at a concentration of between 1-10 millimolar, or no more than 10 mM or 3 mM (instant claims 10, 28, and 29); the mixture does not include calcium or does not include a sufficient amount of calcium for turning the agent into a hydrogel (instant claim 27); and the mixture is such that the agent turns into a gel by collecting endogenous calcium (instant claim 30). As discussed above, Chao discloses a sodium alginate formulation comprising therapeutic 131I radioisotope (abstract). Chao discloses that on intratumoral injection, the soluble polysaccharide rapidly transform into a hydrogel in the presence of endogenous Ca2+, fixing the isotope within the tumors (abstract). Chao discloses alginate concentration-dependent gel formation in the PBS containing Ca2+ at a concentration of 1.8 mM (page 612, column 2, ¶ 2). Cao discloses that 1 mg ml-1 of alginate shows fluid-like behaviour, whereas 5 mg ml-1 or above concentration of alginate rapidly transforms into gels in the presence of Ca2+ (page 612, column 2, ¶ 2). Chao discloses that the mixture without calcium can be injected for in vivo gelation and optimal concentration of alginate can enable homogeneous intratumoral distribution together with effective tumor retention, allowing effective radioisotope therapy treatment of the whole tumor after local administration (page 613, column 1, ¶ 2; page 619, column 2, ¶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 mixture of the ‘157 by adjusting concentrations of calcium and alginate for in vivo gelation-based radiotherapy. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Chao teaches that the mixture comprising alginate can form hydrogel in the presence of endogenous Ca2+ in vivo. Further, a person of ordinary skill in the art would have been motivated to utilize in vivo gelation-based radiotherapy by optimizing the concentrations of calcium and alginate of the mixture for in vivo gelation allowing minimal invasion and sustained therapeutic release allowing more effective treatment. The concentration of calcium is a 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 concentration of calcium in order to best achieve the desired gel formation according to the specific requirements of the applications because the concentration of calcium in the mixture and in vivo critically determines gel formation, which also depends on the concentration of alginate as taught by Chao. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP § 2144.
Regarding claims 11 and 38, claims of the ‘157 do not recite that the mixture does not bond to radon and lead. As discussed above, Arazi discloses a diffusing alpha-emitters radiation therapy (DART) as a new form of brachytherapy (abstract). Arazi discloses that incorporated radium-224 from implantable radioactive sources can decay and emit into the tumor its short-lived progeny such as radon-220 and lead-212, which leave the source by virtue of their recoil energy (page 1204; ¶ 3). Arazi discloses that the released radionuclides (radon and lead) spread by diffusive and convective processes in the vicinity of the source, leading to the formation of a continuous region of therapeutic high-LET radiation dose through their alpha decays (page 1204; ¶ 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 mixture of the ‘157 by making the agent bond to a sufficient concentration of radium-224 and release radon-220 and lead-212 for DART, brachytherapy as taught by Arazi. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Ramdahl teaches that a radium radionuclide can bond to the alginate, and Arazi teaches that the diffusion of radioactive daughter atoms such as radon and lead released from incorporated radium-224 can be used for effective cancer treatment. Further, a person of ordinary skill in the art would have been motivated to use the strategy of binding radium-224 to an alginate matrix while leaving radon (Rn-220) and lead (Pb-212) unbound or mobile in order to maximize a localized alpha-emitting radiation effect while reducing systemic toxicity in normal organs by securely holding the parent radium-224 at the target site and allowing daughter radon and lead to diffuse from the matrix to expand the radiation kill zone. It is an inherent physical and chemical phenomenon that radon and lead do not bind to the hydrogel matrix. Radon is a noble gas with a completely filled valence electron shell. It is chemically inert and forms virtually no bonds with organic polymers such as alginate. The recoil energy ejects the lead atom out of the hydrogel structure and lead does not fit optimally into the specific coordination geometry of the guluronate blocks of alginate, leading to rapid leaching/desorption in the interstitial fluid. Utilizing this selective binding of radium-224 and non-binding behaviour of Rn-220 and Pb-212 for therapeutic alpha-radiation therapy would have been obvious to a person of ordinary skill in the art.
Regarding claims 12 and 39, claim 3 of the ‘157 recites that the agent which turns into a hydrogel by addition of calcium ions is between 0.5-4% of the water-based solution (mixture). The amount of added calcium ions of the prior art overlap with that instantly claimed. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. Further, the concentration of calcium is a 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 concentration of calcium in order to best achieve the desired gel formation according to the specific requirements of the application as the concentration of calcium in the mixture and in vivo critically determine gel formation also depending on the concentration of alginate as taught by Chao. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP § 2144.
Regarding claims 32 and 33, claims of the ‘157 do not disclose that the vehicle carrying the agent has a viscosity of at least 50 centipoise (cP) or 200 cP. As discussed above, Newey-Keane discloses that homogeneous dispersion of pharmaceutical ingredient is essential for uniform dosing when preparing pharmaceutical suspension in a liquid such as water (vehicle such as aqueous solution) (page 2, ¶ 1; page 2, ¶ 3). Newey-Keane discloses that the parameter such as the viscosity of the continuous phase can be manipulated to achieve acceptable performance, unform dosing (page 2, ¶ 5). Newey-Keane discloses that the sedimentation velocity is inversely proportional to the viscosity of the continuous phase (page 3, ¶ 5). As discussed above, Lee discloses intradiscal drug delivery system (IDDS) comprising in situ forming hydrogel (abstract). Lee discloses that the viscosity can depend on the temperature and concentration of the hydrogel matrix, and that the viscosity can be about 30 Pa·s (30,000 cP) at room temperature (Figure 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 mixture of the ‘157 by adjusting the viscosity of the vehicle for homogeneous drug distribution during administration. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Newey-Keane teaches that parameters such as viscosity can affect the stable, homogeneous drug distribution without settling or sedimentation; and Lee teaches that the viscosity can depend on the temperature and concentration of the hydrogel matrix, and that the viscosity can be about 30 Pa·s (30,000 cP) at room temperature. Further, a person of ordinary skill in the art would have been motivated to optimize the viscosity of the mixture in order to avoid potential gelation before the injection and allow easy injection. The viscosity of the mixture is a 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 viscosity of the mixture by adjusting the temperature and concentration of the gel as taught by Lee in order to best achieve the desired gel formation according to the specific requirements of the applications. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP § 2144.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/JONG HWAN BAEK/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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