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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 3, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1 – 20 are examined here-in.
Claim Objections
Claim 5 is objected to because of the following informalities:
Claim 5 has the abbreviation “CD1” prior to N,N’-carbonyldiimidazole in parentheses. The abbreviation “CD1” or “CDI” is not solely associated with this compound, and therefore it would be more precise to remove the abbreviation and keep the full name of the compound. For example, “The pharmaceutical composition according to Claim 4, wherein the crosslinker is
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.
Claims 1 – 20 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 1, 6, and 8 recite the limitation P7C3, then parenthetically “aminopropyl carbazole” which is a class of compounds and thus a broader recitation than compound PC73. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. A possible amendment to the claim is “ … a nanocomposition including aminopropyl carbazole P7C3…”. Appropriate correction 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 non-obviousness.
Claims 1 – 3, 8 – 11, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Tipparaju (US 2022/0370636 A1) in view of Vujaskovic (US 9,415,065 B2).
Tipparaju teaches nicotinamide adenine dinucleotide (NAD) activator compounds for treating disease (abstract). Tipparaju teaches NAD activators treat inflammatory diseases, changing cellular metabolism by NAD generation leading to increased cellular function and tissue repair, and reducing inflammatory cytokines such as interleukin-6 (paragraphs 0005 – 0009, 0013).
Tipparaju teaches 3,6-dibromo-a-[(phenylamino)methyl]-9H-carbazole-9-ethanol, also known as PC73, is an NAD activator (paragraphs 0010, 0015).
Tipparaju teaches the NAD activator is encapsulated within or associated with a nanoparticle (paragraphs 0011, 0015).
Tipparaju does not teach the nanoparticles are cerium oxide nanoparticles.
Vujaskovic teaches the missing element of Tipparaju.
Vujaskovic teaches cerium oxide nanoparticles (title, abstract). Vujaskovic teaches cerium oxide nanoparticles mitigate the effects of radiation exposure or provide a radioprotective effect (abstract, column 1 lines 26 – 28).
Vujaskovic teaches that radiation injury results in oxidative stress that is amplified through the continuous production of reactive oxygen or reactive nitrogen species (column 2 lines 39 – 41). Vujaskovic teaches that antioxidant therapies may reduce inflammation in some models for radiation injury (column 2 lines 48 – 49) and thus the antioxidant properties of cerium oxide nanoparticles may be instrumental to restoring a suitable balance of reactive oxygen or nitrogen species (column 2 lines 50 – 53).
Vujaskovic teaches that the cerium oxide nanoparticles should be prepared such that more than 50% of the cerium is in the 3+ oxidation state (column 4 lines 4 – 9). Vujaskovic teaches the nanoparticles are prepared in water or a biologically compatible solvent and that they may be complexed or coated with a biologically compatible polymer or polysaccharide (column 4 lines 9 – 13).
The combination of Tipparaju and Vujaskovic’s teachings renders claims 1 – 3, 8 – 11, 19, and 20 prima facie obvious as combining prior art elements according to known methods to yield predictable results (MPEP 2143(i)(a)). A person of ordinary skill in the art would be motivated to deliver P7C3 as taught by Tipparaju with cerium oxide nanoparticles as taught by Vujaskovic because Vujaskovic teaches that the antioxidant properties of cerium oxide nanoparticles reduce inflammation (column 2 lines 48 – 53). Notably Tipparaju’s teachings also emphasize the treatment of inflammatory disease (abstract, paragraphs 0005 – 0009, 0013). Therefore, the combination of Tipparaju and Vujaskovic’s teachings is prima facie obvious according to MPEP 2143(i)(a) because P7C3 and cerium oxide nanoparticles are both known prior art elements combined to yield predictable results (i.e. a nanocomposition with anti-inflammatory effects).
Tipparaju’s teaching for PC73 as an NAD activator associated with a nanoparticle (paragraphs 0010, 0011, 0015) in combination with Vujaskovic’s teachings for cerium oxide nanoparticles in water or a biologically compatible solvent (column 4 lines 9 – 13), reads on instant claim 1. A person of ordinary skill in the art would be motivated to deliver P7C3 as taught by Tipparaju with cerium oxide nanoparticles as taught by Vujaskovic because Vujaskovic teaches that the antioxidant properties of cerium oxide nanoparticles reduce inflammation (column 2 lines 48 – 53) which is consistent with Tipparaju’s emphasis on P7C3 to treat inflammatory diseases (abstract, paragraphs 0005 – 0009, 0013).
Vujaskovic’s teaching that the cerium oxide nanoparticles should have more than 50% of the cerium is in the 3+ oxidation state (column 4 lines 4 – 9) reads on instant claims 2 and 3. Vujaskovic’s teaching for more than 50% of cerium in the 3+ oxidation state overlaps on the instantly claimed amounts of increased Ce3+ than Ce4+ and a Ce3+/4+ ratio of 60/40 as recited in claims 2 and 3, respectively. Claimed ranges that overlap teachings of the prior art are prima facie obvious according to MPEP 2144.05(i).
The combination of Tipparaju’s teaching for PC73 as an NAD activator associated with nanoparticles (paragraphs 0010, 0011, 0015) with Vujaskovic’s teaching that the administration of cerium oxide nanoparticles protects against radiation exposure (column 6 lines 36 – 41, claim 20), reads on instant claims 8 – 10. Although Vujaskovic does not specify the protection of bone tissue specifically, Vujaskovic does teach cerium oxide nanoparticles protect a subject against radiation exposure as a whole (column 6 lines 36 – 41, claim 20). A person of ordinary skill in the art would expect general protection against radiation exposure to apply to a subject’s bones because the skeletal system is fundamental for a subject’s form and function.
Vujaskovic’s teaching that the cerium oxide nanoparticles should have more than 50% of the cerium is in the 3+ oxidation state (column 4 lines 4 – 9, claim 1) reads on instant claims 9 and 10. Vujaskovic’s teaching for more than 50% of cerium in the 3+ oxidation state overlaps on the instantly claimed amounts of increased Ce3+ than Ce4+ and a Ce3+/4+ ratio of 60/40 as recited in claims 9 and 10, respectively.
Vujaskovic teaches administration of cerium oxide nanoparticles may occur at some time between 1 hour and 2 weeks following exposure to radiation (column 3 lines 29 – 32), reading on instant claim 11 which recites the composition is administered after 24 or 48 hours.
Tipparaju’s teaching that NAD activators such as P7C3 treat inflammatory diseases and reduce inflammatory cytokines such as interleukin-6 (paragraphs 0005 – 0009, 0013) reads on instant claims 19 and 20 which recite reducing gene expression of pro-inflammatory markers such as IL-6.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Tipparaju (as cited above) and Vujaskovic (as cited above) and further in view of Lee (US 2022/0248990 A1).
The combination of Tipparaju and Vujaskovic’s teachings is discussed above.
The combination of Tipparaju and Vujaskovic does not teach N,N’-carbonyldiimidazole or polyethyleneimine as a crosslinker attaching PC73 to cerium oxide nanoparticle.
Lee teaches the missing element of the combination of Tipparaju and Vujaskovic.
Lee teaches a composition with glucose oxidase coupled to cerium oxide nanoparticles (abstract, paragraph 0009). Lee teaches that cerium oxide nanoparticles and glucose oxidase are conjugated via a biocompatible polymer, which may be poly(ethyleneimine) (paragraphs 0013, 0079, claim 3).
The combination of Tipparaju and Vujaskovic’s teachings is prima facie obvious as combining prior art elements according to known methods to yield predictable results (MPEP 2143(i)(a)). Tipparaju and Vujaskovic, further combined with Lee’s teachings, renders claims 4 and 5 prima facie obvious as simple substitution of one known element (in this case glucose oxidase) for another (P7C3) to yield predictable results (i.e. a cerium oxide nanoparticle conjugated with polyethyleneimine and P7C3). A person of ordinary skill in the art would be motivated to substitute P7C3 for glucose oxidase in Lee because Tipparaju teaches P7C3 is an NAD activator that treats inflammatory diseases by changing cellular metabolism by NAD generation leading to increased cellular function and tissue repair and reducing inflammatory cytokines such as interleukin-6 (paragraphs 0005 – 0010, 0013, 0015). Therefore, Tipparaju’s teaching for P7C3 would be smoothly integrated with a cerium oxide nanoparticle system taught by Vujaskovic with the biocompatible polymer linker as taught by Lee. As such, the combination of Tipparaju, Vujaskovic, and Wei’s teachings is prima facie obvious according to MPEP 2143(i)(a) and MPEP 2143(i)(b) because P7C3, cerium oxide nanoparticles, and biocompatible polymer linkers are all known prior art elements that are combined to yield predictable results, following the teachings of Lee with the simple substitution of glucose oxidase for PC73.
Tipparaju’s teaching for PC73 as an NAD activator associated with a nanoparticle (paragraphs 0010, 0011, 0015) with Vujaskovic’s teachings for cerium oxide nanoparticles in water or a biologically compatible solvent (column 4 lines 9 – 13) and further in combination with Lee’s teaching for poly(ethyleneimine) as a biocompatible polymer linker (paragraphs 0013, 0079, claim 3) reads on instant claims 4 and 5. As discussed above, a person of ordinary skill in the art would be motivated to substitute PC73 as taught by Tipparaju for glucose oxidase in the composition of Lee because Lee teaches that poly(ethyleneimine) is a suitable biocompatible linker for use with cerium oxide nanoparticles (paragraphs 0013, 0079, claim 3). The simple substitution of one known element for another to obtain predictable results is prima facie obvious according to MPEP 2143(i)(a).
Claims 6, 7, and 12 – 15 are rejected under 35 U.S.C. 103 as being unpatentable over Tipparaju (as cited above) and Vujaskovic (as cited above) and further in view of Wei (Wei, et al. “A novel multifunctional radioprotective strategy using P7C3 as a countermeasure against ionizing radiation-induced bone loss” Bone Research, 2023, 11:34, p. 1 – 20).
The combination of Tipparaju and Vujaskovic’s teachings is discussed above.
The combination of Tipparaju and Vujaskovic does not teach a method for enhancing bone deposition in a subject in need thereof or a method for protecting bone tissue from radiation damage in a subject undergoing radiation therapy.
Wei teaches the missing element of the combination of Tipparaju and Vujaskovic.
Wei teaches the administration of P7C3 as a radioprotective strategy repressed ionizing radiation-induced osteoclastic activity, inhibited adipogenesis, and promoted osteoblastogenesis and mineral deposition (abstract, Figure 9).
Wei teaches that the administration of P7C3 to hBMSC led to increased cell growth (page 2 column 2, Figure 2). Wei teaches that treatment with P7C3 reduces ionizing radiation-induced bone loss (page 4 column 2, Figure 4).
The combination of Tipparaju, Vujaskovic, and Wei’s teachings renders claims 6, 7, and 12 – 15 prima facie obvious as combining prior art elements according to known methods to yield predictable results (MPEP 2143(i)(a)). A person of ordinary skill in the art would be motivated to deliver P7C3 as taught by Tipparaju with cerium oxide nanoparticles as taught by Vujaskovic because Vujaskovic teaches that the antioxidant properties of cerium oxide nanoparticles reduce inflammation (column 2 lines 48 – 53). Notably Tipparaju’s teachings also emphasize the treatment of inflammatory disease (abstract, paragraphs 0005 – 0009, 0013). A person of ordinary skill in the art would be further motivated to apply the combination of Tipparaju and Vujaskovic’s teachings for methods of enhancing bone deposition in a subject in need thereof or for protecting bone tissue from radiation damage in a subject undergoing radiation therapy because Wei teaches that administration of PC73 repressed ionizing radiation-induced osteoclastic activity, inhibited adipogenesis, and promoted osteoblastogenesis and mineral deposition (abstract). Therefore, the combination of Tipparaju, Vujaskovic, and Wei’s teachings is prima facie obvious according to MPEP 2143(i)(a) because P7C3 and cerium oxide nanoparticles are both known prior art elements combined to yield predictable results (i.e. a nanocomposition with anti-inflammatory effects including repressed ionizing radiation-induced osteoclastic activity, inhibited adipogenesis, and promoted osteoblastogenesis and mineral deposition).
Tipparaju’s teaching for PC73 as an NAD activator associated with a nanoparticle (paragraphs 0010, 0011, 0015) in combination with Vujaskovic’s teachings for cerium oxide nanoparticles in water or a biologically compatible solvent (column 4 lines 9 – 13), and further in combination with Wei’s teachings for PC73 administration to promote osteoblastogenesis and mineral deposition (abstract, page 2 column 2, Figure 2) reads on instant claim 6.
Wei’s teaching that the subject was receiving radiation consistent with radiation therapy (abstract, page 15 column 1) reads on instant claim 7.
Vujaskovic’s teaching that cerium oxide nanoparticles protect a subject against radiation exposure (column 6 lines 36 – 41, claim 20) in combination with Wei’s teaching that administration of PC73 repressed ionizing radiation-induced osteoclastic activity, inhibited adipogenesis, and promoted osteoblastogenesis and mineral deposition (abstract, page 2 column 2) reads on instant claim 12, which recites protecting bone tissue from radiation damage in a subject undergoing radiation therapy.
Wei teaches that radiotherapy for cancer treatments can result in ionizing radiation damage (page 1 column 1) which can be mitigated by the administration of PC73 (abstract), reading on instant claim 13. Wei teaches PC73 administration as pretreatment or posttreatment for exposure to radiation (page 15 columns 1 and 2) reading on instant claim 14.
Wei teaches that administration of PC73 maintains bone architecture and area in a condition which would otherwise be subject to osteoporosis (Figure 4b), reading on instant claim 15 which recites a method for treating osteoporosis.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Tipparaju (as cited above) and Vujaskovic (as cited above) and further in view of Li (Li et al. “Attenuates of NAD+ impair BMSC osteogenesis and fracture repair through OXPHOS” Stem Cell Research & Therapy 2022, 13:77, pages 1 – 16).
The combination of Tipparaju and Vujaskovic’s teachings is discussed above.
The combination of Tipparaju and Vujaskovic does not teach a method for treating bone trauma/injury in a subject in need thereof.
Li teaches the missing element of the combination of Tipparaju and Vujaskovic.
Li teaches that P7C3 promotes osteogenesis (page 8 column 1, page 13 column 2). Li introduced mid-point femur fractures in mice (page 4 column 2), then observed that attenuates of NAD+ impaired bone fracture repair (page 8 column 1, Figure 3). Li teaches that NAD+ is critical from BMSC osteogenesis (page 8 column 1, Figure 3, page 13 column 2), and that administration of PC73 elevates NAD+ levels and stimulates osteogenesis (page 13 column 2). Taken together, these results suggest that PC73 administration may be an appropriate treatment for bone fracture repair because PC73 stimulates osteogenesis.
The combination of Tipparaju, Vujaskovic, and Li’s teachings renders claim 16 prima facie obvious as combining prior art elements according to known methods to yield predictable results (MPEP 2143(i)(a)). As discussed above, a person of ordinary skill in the art would be motivated to deliver P7C3 as taught by Tipparaju with cerium oxide nanoparticles as taught by Vujaskovic because Vujaskovic teaches that the antioxidant properties of cerium oxide nanoparticles reduce inflammation (column 2 lines 48 – 53). Notably Tipparaju’s teachings also emphasize the treatment of inflammatory disease (abstract, paragraphs 0005 – 0009, 0013). Li’s teachings that administration of PC73 leads to increased NAD+, which leads to increased osteogenesis (page 13 column 2), would motivate a person of ordinary skill in the art to administer PC73 to treat bone injury or trauma, because increased osteogenesis would be expected to help with injury and trauma repair. Therefore, the combination of Tipparaju, Vujaskovic, and Li’s teachings is prima facie obvious according to MPEP 2143(i)(a) because P7C3 and cerium oxide nanoparticles are both known prior art elements combined to yield predictable results (i.e. a nanocomposition with anti-inflammatory effects and increased NAD+ generation, leading to increased osteogenesis).
Tipparaju’s teaching for PC73 as an NAD activator associated with a nanoparticle (paragraphs 0010, 0011, 0015) in combination with Vujaskovic’s teachings for cerium oxide nanoparticles in water or a biologically compatible solvent (column 4 lines 9 – 13), and further in combination with Li’s teaching that administration of PC73 elevates NAD+ levels and stimulates osteogenesis (page 13 column 2), thereby suggesting that PC73 administration promotes bone fracture repair because PC73 stimulates osteogenesis reads on instant claim 16.
Potentially Allowable Subject Matter
Claims 17 and 18 appear to be free of prior art as Tipparaju, Vujaskovic, Lee, Wei, and Li alone or in combination do not teach administration of PC73-conjugated cerium oxide nanoparticles protects DNA of bone cells exposed to radiation. In fact, Wei’s teachings indicate that PC73 does not confer radioprotection to ionizing radiation induced DNA damage (page 3 column 1, page 9 columns 1 and 2). Therefore, claims 17 and 18 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
All claims are rejected. No claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Toriana N. Vigil whose telephone number is (571)270-7549. The examiner can normally be reached Monday - Friday 9:00 a.m. - 5:00 p.m. EST.
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/TORIANA N. VIGIL/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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