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 .
Status of the Claims
Claims 1-5 are pending.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Poland on May 24, 2022. It is noted, however, that applicant has not filed a certified English translation of the foreign application. Thus, the instant application is afforded an effective filing date of May 24, 2023 (based on the filing date of the PCT) until foreign priority is perfected.
Information Disclosure Statement
The IDS dated 7/29/2025 has been considered. A signed copy is enclosed herewith.
Claim Objections
Claim 1 is objected to because of the following informalities:
The claim recites, “Formulation of nanoparticles...” at the 1st line of the claim. For improved readability, it is suggested that “Formulation” is replaced with “A formulation”;
The claim recites, “bisphosphonate” at lines 5 and 7 of the claim”. While it does not rise to the level of indefiniteness, for proper antecedent basis, it is suggested that “the” is inserted prior to said recitations of “bisphosphonate”; and
The claim recites, “calcium phosphate nanoparticles” at line 7 of the claim”. While it does not rise to the level of indefiniteness, for proper antecedent basis, it is suggested that “the” is inserted prior to said recitation of “calcium phosphate nanoparticles”.
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 1-5 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.
Regarding claim 1, the phrase "preferably" in lines 1 and 2 of the claim renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 1, the claim recites the limitation, “bisphosphate is selected from the group of bisphosphate drugs approved for medical use, the group comprising alendronate and zolendronate”. The language, “is selected from the group of” implies a Markush grouping (closed language) and is followed by “comprising” (open-ended language) with two examples of bisphosphate drugs. The claim is indefinite because it is unclear a) which bisphosphate drugs are or are not included within group and b) whether the grouping is open-ended or closed.
Claim 4 includes periods in the middle of the claim (lines 2-11 and 13), and as such the claim is indefinite because it is unclear whether the language following the periods further limit the claimed invention. ”. See MPEP 608.01(m). It is suggested that “a.” is replaced with “a)”, “b.” is replaced with “b)” and so on.
Dependent claims 2, 3 and 5 do not remedy the indefinite issues and as such said dependent claims suffer from the same deficiency.
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, 2, 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Wojasiński et al. (“Increased cellular uptake of hydroxyapatite-lecithin-alendronate nanoparticles”, Poster, Seventh International Conference on Multifunctional, Hybrid and Nanomaterials (HYMA 2022), Oct. 19-22, 2022, Genoa, Włochy; hereafter as “Wojasiński 1”) in view of Wojasiński et al. (“Scaled-Up 3D-Printed Reactor for Precipitation of Lecithin-Modified Hydroxyapatite Nanoparticles”, Ind. Eng. Chem. Res. Aug. 24, 2021, 60, pp. 12944−12955; hereafter as “Wojasiński 2”).
The claimed invention is drawn to a formulation of nanoparticles of calcium phosphate, preferably hydroxyapatite, said nanoparticles being modified with lecithin, preferably phosphatidylcholine, said formulation having an enhanced cellular uptake and being a carrier for bisphosphonate, characterised in that bisphosphonate is selected from the group of bisphosphonate drugs approved for medical use, the group comprising alendronate and zoledronate, bisphosphonate is encapsulated in calcium phosphate nanoparticles in an amount up to 40 % by mass, and the nanoparticles are less than 200 nm in size; and a method of making thereof.
Regarding instant claims 1, 2, 4 and 5, Wojasiński 1 teaches alendronate encapsulated in the hydroxyapatite-lecithin nanoparticles, wherein alendronate is present in an amount of about 30 % by mass. Wojasiński 1 also teaches that the nanoparticles were precipitated in previously reported continuous reactors by mixing aqueous solutions of calcium nitrate with lecithin and di-ammonium hydrogen phosphate with sodium alendronate in three concentrations (5 mM, 10 mM, and 15 mM).
Wojasiński 1 is silent to the nanoparticles being less than 200 nm in size (instant claim 1). Wojasiński 1 is also silent to steps c)-h) (instant claim 4).
Wojasiński 2 teaches continuous precipitation of lecithin-modified hydroxyapatite nanoparticles (title; abstract; Fig. 1). Wojasiński 2 also teaches the that nanoparticles were obtained by mixing calcium nitrate tetrahydrate with the addition of lecithin (98% phosphatidylcholine) and diammonium hydrogen phosphate solution; adjusting the pH of the solutions to 10.0; mixing the solutions in a reactor to form a suspension; centrifuging the suspension to obtain a precipitate; washing the precipitate four times with ultrapure water and centrifuging again; drying in the oven at 50 C for 24 hours and powdered in a ball mill for 5 min at 150 rpm (pages 12946-12947, section 2.3). Wojasiński 2 teaches various mean particle sizes that are under 200 nm depending on the reactor used (Table 3).
Both Wojasiński 1 and Wojasiński 2 are drawn to lecithin hydroxyapatite particles produced via continuous reactors, thus, it would have been prima facie obvious before the effective filing date of the claimed invention to include the steps taught in Wojasiński 2 into the invention of Wojasiński 1 with a reasonable expectation of success. A skilled artisan would have been motivated to do so because Wojasiński 1 explains that they had previously reported the method and Wojasiński 2 appears to expound on the same method. Thus, a skilled artisan would have reasonably expected the more detailed method of Wojasiński 2 is the method referred to by Wojasiński 1. Furthermore, Wojasiński 2 teaches that the method is suitable in making lecithin-hydroxyapatite nanoparticles such as those taught in Wojasiński 1 and such a method yields nanoparticles of less than 200 nm.
While Wojasiński 2 teaches milling in a ball mill for 5 min, Wojasiński 2 is silent to a time of 10 min. However, modifying the amount of time the precipitate is in a ball mill directly effects the particle size. Thus, it would have been prima facie obvious before the effective filing date of the claimed invention to optimize the amount of time the precipitate is subjected to a ball mill by way of routine experimentation with a reasonable expectation of success. A skilled artisan would have been motivated to do so because it is understood in the art that modifying the amount of time the precipitate is in a ball mill directly effects the particle size and, as such, the amount of time would be adjusted to yield the desired particle size.
Thus, the combined teachings of Wojasiński 1 and Wojasiński 2 render the instant claims prima facie obvious.
Claims 1 and 2 are rejected under 35 U.S.C. 103 as being unpatentable over Ciach et al. (PL 229015 B1, May 30, 2018, machine translation, hereafter as “Ciach”) in view of Boanini et al. (“Alendronate–hydroxyapatite nanocomposites and their interaction with osteoclasts and osteoblast-like cells”, Biomaterials, Volume 29, Issue 7, March 2008, Pages 790-796; hereafter as “Boanini”).
The claimed invention is described above.
Regarding instant claim 1, Ciach teaches a method of obtaining hydroxyapatite nanoparticles by wet chemical precipitation, in which a water-soluble calcium salt (e.g., Ca(NO3)2 · 4H2O) and a water-soluble phosphate (e.g., (NH4)2HPO4) are reacted in an aqueous solution at a molar ratio of calcium to phosphorus atoms of about Ca / P 1.67 and in the presence of a dispersing agent which is lecithin (e.g., chicken egg lecithin or phoshatidylcholine) in an amount of from 0.05 wt. to 20.00% by weight, the reaction is carried out at a temperature in the range of 20°C to 95°C, at a pH of 7 to 14 (abstract; page 4, paragraphs 5-7). Ciach teaches hydroxyapatite is known for various biomedical applications including as drug carriers and bone repair (page 2, 2nd full paragraph). Ciach teaches that the method of the invention is carried out by adding an aqueous solution of lecithin in demineralized water to the aqueous solution of the calcium ion source compound in demineralized water. The reaction mixture is heated to a temperature in the range from 20°C to 95°C, preferably 60°C, and the pH is adjusted in the range from 6 to 14, preferably about 10; after stable conditions are obtained, an aqueous solution is added to the reaction mixture of phosphate, such that the stoichiometric amount is added over a period of up to 24 hours, preferably 1-2 hours; the solution is then cooled to ambient temperature and centrifuged to isolate the product; after decanting, the obtained product is washed with an organic solvent (hexane, gasoline, ethanol, acetone, isopropanol) or water to remove residual lecithin from the product; and the obtained product is dried at ambient or elevated temperature (paragraph bridging pages 4-5). Ciach teaches that the lecithin is partially bound to the product or it is physically bound in the pores of the particles formed (page 5, 2nd to last paragraph). Ciach also teaches that said lecithin is responsible for influencing the shape of the nanoparticles and improving the biocompatibility of the hydroxyapatite nanoparticles (page 5, last paragraph – page 6, 1st paragraph). Ciach further teaches nanoparticles that are less than 200 nm in size (Examples; Figs. 5 and 6).
Ciach is silent to bisphosphonates such as alendronate in an amount up to 40% by mass.
Boanini teaches alendronate–hydroxyapatite composite nanocrystals with a bisphosphonate content up to about 7 wt% (abstract). Boanini teaches bisphosphonates are a class of compounds widely used for the management of disorders of bone metabolism (page 790, left col.). Boanini teaches that the presence of alendronate in composite nanocrystals inhibits osteoclast proliferation and promotes osteoblast growth and differentiation (page 796, left col.). Boanini teaches that the results of the study demonstrate that alendronate is able to influence bone cells even in composite nanocrystals and such composite nanocrystals could be effective in hard tissue repair applications (page 796, left col.).
Ciach and Boanini are drawn to hydroxyapatite nanoparticles for the purpose of bone repair, thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include a bisphosphonate such as alendronate in an amount of about 7wt% into the invention of Ciach, as suggested by Boanini, with a reasonable expectation of success. A skilled artisan would have been motivated to do so because Boanini teaches that alendronate in an amount of about 7wt% influences bone cells when incorporated into hydroxyapatite nanocrystals and, thereby, further improve the bone repair properties hydroxyapatite-based nanoparticles.
Regarding instant claim 2, said claim is considered a product-by-process claim due to the limitation, “is introduced to the formulation as sodium alendronate at a concentration in the range 5 mM – 15 mM based on the volume of the reaction mixture” and as such, determination of patentability is based on the product itself, not by the method in which it is made. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process (MPEP 2113). The cited art teaches alendronate in amounts of less than 40% by mass, as discussed above. Therefore, the cited art meets the limitations of the instant claim.
Thus, the combined teachings of Ciach and Boanini render the instant claims prima facie obvious.
Claims 1 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Ciach et al. (PL 229015 B1, May 30, 2018, machine translation, hereafter as “Ciach”) in view of Kettenberger et al. (“In vitro and in vivo investigation of bisphosphonate loaded hydroxyapatite particles for peri-implant bone augmentation”, J Tissue Eng Regen Med 2015; 11: 1974–1985; hereafter as “Kettenberger”).
The claimed invention is described above.
Regarding instant claim 1, Ciach teaches a method of obtaining hydroxyapatite nanoparticles by wet chemical precipitation, in which a water-soluble calcium salt (e.g., Ca(NO3)2 · 4H2O) and a water-soluble phosphate (e.g., (NH4)2HPO4) are reacted in an aqueous solution at a molar ratio of calcium to phosphorus atoms of about Ca / P 1.67 and in the presence of a dispersing agent which is lecithin (e.g., chicken egg lecithin or phosphatidylcholine) in an amount of from 0.05 wt. to 20.00% by weight, the reaction is carried out at a temperature in the range of 20°C to 95°C, at a pH of 7 to 14 (abstract; page 4, paragraphs 5-7). Ciach teaches hydroxyapatite is known for various biomedical applications including as drug carriers and bone repair (page 2, 2nd full paragraph). Ciach teaches that the method of the invention is carried out by adding an aqueous solution of lecithin in demineralized water to the aqueous solution of the calcium ion source compound in demineralized water. The reaction mixture is heated to a temperature in the range from 20°C to 95°C, preferably 60°C, and the pH is adjusted in the range from 6 to 14, preferably about 10; after stable conditions are obtained, an aqueous solution is added to the reaction mixture of phosphate, such that the stoichiometric amount is added over a period of up to 24 hours, preferably 1-2 hours; the solution is then cooled to ambient temperature and centrifuged to isolate the product; after decanting, the obtained product is washed with an organic solvent (hexane, gasoline, ethanol, acetone, isopropanol) or water to remove residual lecithin from the product; and the obtained product is dried at ambient or elevated temperature (paragraph bridging pages 4-5). Ciach teaches that the lecithin is partially bound to the product or it is physically bound in the pores of the particles formed (page 5, 2nd to last paragraph). Ciach also teaches that said lecithin is responsible for influencing the shape of the nanoparticles and improving the biocompatibility of the hydroxyapatite nanoparticles (page 5, last paragraph – page 6, 1st paragraph). Ciach further teaches nanoparticles that are less than 200 nm in size (Examples; Figs. 5 and 6).
Ciach is silent to bisphosphonates such as zoledronate in an amount up to 40% by mass.
Kettenberger teaches that locally applied bisphosphonates, such as zoledronate, have been shown in several studies to inhibit peri-implant bone resorption and recently to enhance peri-implant bone formation (abstract). Kettenberger also teaches that studies have demonstrated positive effects of hydroxyapatite (HA) particles on peri-implant bone regeneration and an enhancement of the anti-resorptive effect of bisphosphonates in the presence of calcium (abstract). Kettenberger showed a synergistic effect between zoledronate and hydroxyapatite nanoparticles (nHA) in vitro, as the inhibitory effect of the drug on osteoclast precursors was enhanced when administering zoledronate absorbed on hydroxyapatite nanoparticles (page 1984, paragraph bridging left and right columns). Kettenberger teaches a formulation comprising 2 mg/ml zolendronate (approximately 9%) and 20 mg/ml nHA (page 1975, right column, 3rd paragraph).
Ciach and Kettenberger are drawn to hydroxyapatite nanoparticles for the purpose of bone repair, thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include a bisphosphonate such as zolendronate in an amount of about 9wt% into the invention of Ciach, as suggested by Kettenberger, with a reasonable expectation of success. A skilled artisan would have been motivated to do so because Kettenberger teaches that zoledronate in an amount of about 9wt% inhibit peri-implant bone resorption and enhance peri-implant bone formation and the combination of nHA and zolendronate provides an enhanced inhibitory effect on osteoclast precursors.
Regarding instant claim 3, said claim is considered a product-by-process claim due to the limitation, “is introduced to the formulation as zoledronic acid at a concentration of 5 mM based on the volume of the reaction mixture” and as such, determination of patentability is based on the product itself, not by the method in which it is made. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process (MPEP 2113). The cited art teaches zoledronate in amounts of less than 40% by mass, as discussed above. Therefore, the cited art meets the limitations of the instant claim.
Thus, the combined teachings of Ciach and Kettenberger render the instant claims prima facie obvious.
Conclusion
All claims have been rejected; no claims are allowed.
Correspondence
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/CASEY S HAGOPIAN/Examiner, Art Unit 1617
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