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 Application
Claims 1-17 are under examination.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Drawings
The drawings are objected to because Figures 3-5 are blurry and difficult to read. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The abstract of the disclosure does not commence on a separate sheet in accordance with 37 CFR 1.52(b)(4) and 1.72(b). A new abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text.
Claim Interpretation
Claim 1 recites a phrase, “plurality of globular nanostructures”. “[P]lurality” and “nanostructures” both mean more than one. Therefore, for the purposes of examination, the examiner interprets this phrase to mean more than one globular nanostructure.
Claim 1 recites that each of R1, R2, R3, R4, R5, R6, R11, R12, R13, R14, R15, R16, R17 R18, R19, R20, R21, and R22 can be independently selected to be a covalent bond. The examiner notes that the claim does not specify what is covalently bound to the respective group. Therefore, for the purposes of examination, the examiner interprets “covalent bond” to mean that these R groups are covalent bonds to any atom or group which can have a covalent bond to it and any prior art containing an atom or group bound to the Si-O through a covalent bond, reads on this limitation.
Claim 1 recites “an anchoring layer surrounding the central part”. The examiner notes that neither the specification nor the claims provide a definition for the “anchoring layer” but the specification does describe it as comprising Formula (II), surrounding the central part, and having the function of strongly binding the coating layer to the nanostructure (specification, page 30, ) and can be made by condensation polymerization of precursors containing -Si(OR)3 groups. However, these descriptions are not limiting. Therefore, for the purposes of examination, the examiner interprets any prior art with a layer surrounding the core layer and can have a coating layer attached reads on “an anchoring layer” regardless of the term used to describe the layer.
Claim 1 recites “lower alkyls”. The examiner notes that the specification defines lower alkyls as C1-C8 (pg 21, lines 26-27). Therefore, for the purposes of examination, the examiner interprets any prior art with an alkyl length in the range of C1-C8 as reading on this limitation.
Claim 1 recites “the coating layer comprises monomer residues according to Formula (III)”. The examiner notes that the monomer residue contains PEG polymers. Therefore, for the purposes of examination, the examiner interprets any prior art with an outer layer of PEG polymer to be equivalent to monomer attached to the anchoring layer as reading on this claim limitation.
Claim 2-4 recite “XCL” as the number of monomer residues of the coating layer. However, the examiner notes that these “monomer” residues contain PEG polymers. The examiner interprets the monomer residue to mean that the portion of the nanostructure containing PEG. Therefore, for the purposes of examination, the examiner interprets XCL to refer to the moiety containing PEG that is attached to the anchoring layer.
Claims 8 and 13 recite “use as a medicament”. This phrase is functional language. For the purposes of examination, the examiner interprets any prior art containing a plurality of globular nanostructures which could be used as a medicament, whether it was used as a medicament or not, as reading on this claim limitation.
Claims 8 and 13 recite “medicament”. Neither the specification nor the claims provide a special definition. Therefore, for the purposes of examination, the examiner interprets any prior art which uses the plurality of globular nanoparticles in any medical treatment, reads on this claim limitation.
Claim 9 recites “use in the treatment of cancer and/or imaging”. This phrase is functional language. For the purposes of examination, the examiner interprets any prior art containing a plurality of globular nanostructures which could be used in the treatment of cancer and/or imaging, whether it was used such or not, as reading on this claim limitation.
Claim Rejections - 35 USC § 112(b)
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 1-2, 4, 9, and 14-15 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 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential structural cooperative relationships of elements, such omission amounting to a gap between the necessary structural connections. See MPEP § 2172.01. The omitted structural cooperative relationships are: it is unclear whether the covalent bond is attached to anything or what the covalent bond is attached to.
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, claim 15 recites the broad recitation “globular nanostructures”, and the claim also recites “preferably wherein the nanostructures are nanostructures according to claim 1” which is the narrower statement of the range/limitation. 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.
Claim 1 recites the limitation "the group" in line 7. There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the group" in line 9. There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the group" in line 18. There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the group" in line 26. There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the group" in line 30. There is insufficient antecedent basis for this limitation in the claim.
Claim 2 recites the limitation "the percentage of the number" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 2 recites the limitation "the percentage of the number" in line 5. There is insufficient antecedent basis for this limitation in the claim.
Claim 2 recites the limitation "the percentage of the number" in line 8. There is insufficient antecedent basis for this limitation in the claim.
Claim 4 recites the limitation "the group consisting of" in line 9. There is insufficient antecedent basis for this limitation in the claim.
Claim 4 recites the limitation "the percentage of the number" in line 11. There is insufficient antecedent basis for this limitation in the claim.
Claim 4 recites the limitation "the percentage of the number" in line 14. There is insufficient antecedent basis for this limitation in the claim.
Claim 4 recites the limitation "the percentage of the number" in line 17. There is insufficient antecedent basis for this limitation in the claim.
Claim 9 recites the limitation "the treatment" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 14 recites the limitation "the treatment" in line 2. There is insufficient antecedent basis for this limitation in the claim.
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.
Claim(s) 1, 3, 5-11, and 13-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Axelsson, O; et al. US 2017/0106105 A1 and Rantala, J. US 7,833,820 B2 and Axelsson, O; et al. US 2019/0352459 A1.
Axelsson, O.; et al. (hereafter referred to as Axelsson-2017) is drawn to globular nanostructures comprising a central and peripheral part where the central part is a crosslinked polymeric framework containing chelating groups, and where the peripheral part comprises a polymer attached to the central part (title; abstract). Axelsson-2017 teaches that systemic radiotherapy offers many solutions to surgical shortcomings and external radiotherapy and that beta emitters and alpha emitters are both used in systemic radiotherapy (pg 1, para [0003]-[0005]) and that advances in nanotechnology have led to development of novel nanocarriers designed for cancer detection and screening, in vivo molecular and cellular imaging, and delivery of therapeutics (pg 1, para [0006], lines 1-6). Axelsson-2017 teaches that globular, bioinert, chelating, polymeric nanostructures may have applications in radiotherapy (pg 1, para [0008], lines 1-3) and that globular nanostructures may have some advantage as a theranostic for diagnosing cancer, delivering tumor-targeted therapy, and monitoring therapy response (pg 2, para [0019], lines 1-15). Axelsson-2017 teaches globular nanostructures with a hydrodynamic diameter of 8-100 nm with a central part of 6-90 nm and a peripheral part of the difference between the total and central diameters (pg 2, para [0020], lines 1-6). Axelsson-2017 teaches the central part is a crosslinked polymeric framework (pg 2, para [0022], lines 1-4) and contains a chelating part which can be an ester, a phosphonate, or a sulfonate (pg 2, para [0024], lines 3-5) and where the peripheral portion comprises a synthetic polymer attached to the central crosslinked polymer (pg 2, para [0025], lines 1-4). Axelsson-2017 teaches the peripheral polymer covers the central part to protect it from interactions with the biological systems (pg 7, par a[0097], lines 1-3) and may be a linear polymer containing PEG (pg 7, para [0098), lines 1-2) and branched polymers (pg 7, para [0100], lines 1-6), and crosslinked polymers (pg 7, para [0101], lines 1-6). Axelsson-2017 teaches polymeric framework with a network structure can be achieved with multifunctional monomers such as bis(trimethoxysilyl)methane or bis(trimethoxysilyl)ethane (pg 7, para [0110], lines 1-8 and 17-18) and that trialkoxyorganosilanes are particularly advantageous (pg 8, para [0118], lines 1-10) and that the choice of alkoxy group can be used to control molecular size during production (pg 8, para [0132], lines 1-9). Axelsson-2017 teaches the peripheral polymers comprise a multitude of PEG residues covalently attached to the outer parts of the central polymer framework (pg 9, para [0145], lines 1-3) and may be selected from polymeric materials that are hydrophilic, bioinert, and electrically neutral or zwitterionic and may be linear, branched, or crosslinked (pg 11, para [0172], lines 1-9) and can have the structure of a copolymer with PEG as the outer block and can be directly linked to the central polymer framework or there can be a linking polymer (pg 11, para [0173], lines 1-6) where the linking polymer can be a carboxysilyl polymers (pg 11, para [0174]). Axelsson-2017 teaches methods of preparing (pg 17, para [0330], lines 1-10), radiolabeling (pg 19, para [0354], lines 1-14), and characterization (pg 21, para [0380], lines 1-12).
As to claim 1, Axelsson-2017 teaches a plurality of globular nanostructures (pg 3, para [0029], lines 1-5; pg 3, para [0033], lines 1-3) having an average hydrodynamic diameter between 8 to 100 nm (pg 2, para [0020], lines 1-3). The claimed range of 20-50 nm lies inside the prior art range of 8-100 nm. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Axelsson-2017 teaches each nanostructure is a polymeric nanostructure (pg 1, para [0001], lines 1-3; pg 1, para [0008], lines 1-3) comprising a central part (pg 2, para [0020], lines 1-5) comprising monomer residues according to Formula (I), reproduced below (pg 8, para [0130], lines 2-4), wherein the instant claimed R1, R2, R3, R4, R5, and R6 are positionally equivalent to the Axelsson-2017 prior art’s R3, R4, R5, R6, R7, and R8 and each are independently selected from a negative charge, H, or bonds (pg 8, para [0130], lines 1-7), and wherein the instant claimed R7, R8, R9, and R10 are positionally equivalent to Axelsson-2017 prior art’s R1 and R2 and R1 and R2 can be independently selected from negative charge or H (pg 8, para [0126], lines 1-3; pg 8, para [0130], lines 2-4). In the case where Axelsson-2017 prior art’s R1 and R2 are either negative charge or H, 100% of R1 and R2 are negative charge or H (pg 8, para [0126], lines 1-2). 100% is within the instant claimed range of at least 95% of all R7, R8, R9, and R10 groups are H or a negative charge. When, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art. See MPEP 2131.03(I). Since the other components of the claim are made obvious, this range is also made obvious. The instant claimed “n” and “m” are positionally equivalent to the prior art Axelsson-2017 “n” (pg 8, para [0130], lines 1-7). Axelsson-2017 teaches n is 1-5 (pg 8, para 0130], line 7). The claimed range for “n” and “m” of 2-5 lie inside the prior art range of 1-5. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
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Axelsson-2017 teaches an anchoring layer surrounding the central part (pg 6, para [0092], lines 1-4) wherein the anchoring layer can be crosslinked (pg 7, par [0101], lines 1-6) and crosslinking may be achieved through a monomer according to the instant claimed Formula (II), bis(trimethoxysilyl)methane and bis(trimethoxysilyl)ethane (pg 7, para [0110], lines 13-18). And Axelsson-2017 teaches that the peripheral layer can be PEG (pg 11, para [0173], lines 1-6) bound to the crosslinked center part through an oragnosilyl group (-OSi(OR11)2(CH2)m- group, where R11 can be bonds to the central part (pg 11, para [0173], lines 1-6).
Axelsson-2017 teaches a coating layer surrounding the inner layer (pg 6, para [0092], lines 1-4), wherein the coating layer comprises polyethylene glycol (pg 11, para [0173], lines 1-4) and trialkoxyorganosilyl groups (pg 11, para [0175], lines 1-4).
Axelsson-2017 does not explicitly teach the monomer according to Formula (II) as fully covering the central part.
Axelsson-2017 does not explicitly teach the monomer according to Formula (III).
Rantala, J. (hereafter referred to as Rantala) is drawn to a method of producing disilane monomer which can be polymerized and combined with nanoparticles to provide polymer compositions (title; abstract). Rantala teaches functionalized disilane precursors are applicable for use as dielectrices (col 1, lines 11-15). Rantala teaches organic polymers can be divided into two different groups with respect to behavior of their dielectric constant, nonpolar and polar polymers (col 1, lines 53-67). Rantala teaches siloxane polymers (col 2, lines 55-59), organo-functionalized molecules (col 2, lines 63-65), poly(organo siloxane)s (col 2, lines 64-67), thin films (col 3, lines 1-4), and dielectric layers (col 3, lines 5-6). Rantala teaches a monomer (R1)xSi-R3-Si(R2)y, where R1 is hydrolyzable, R2 is a functional group, R3 is a bridging hydrocarbyl group, and x and y are 1-3 (col 3, lines 30-37) and that the monomer can be homopolymerized or copolymerized with nanoparticles (col 3, lines 38-41) where the polymer is made by condensation polymerization (col 3, lines 60-65) and can undergo crosslinking (col 4, lines 27-31) which enables high chemical resistance (col 4, lines 32-34). Rantala teaches that the crosslinking group of the monomer (col 5, lines 32-39) can be an organic containing silicon group or a reactive cleaving group, or another group (col 5, lines 42-46) and the group between the Si can be alkyl (col 5, lines 53-57) and the hydrolyzable group can be alkoxy or another group (col 6, lines 55-59). Rantala teaches a method of producing the polymer composition (col 8, lines 37-46). Rantala teaches the polymer can be attached to a nanoparticle (col 9, lines 18-24).
Regarding the monomer according to Formula (II) as fully covering the central part, Rantala also teaches the monomer according to Formula (II) reproduced below (col 3, line 30-41). The instant claimed R11, R12, R13, R14, R15, and R16 are positionally equivalent to the Rantala prior art’s R1 and R2 when “x” and “y” are 3 (col 3, lines 27-41) and the Rantala prior art’s R1 can have covalent bonds to alkoxides (col 3, line 32; col 5, line 25-28) and R2 can have covalent bonds to functional groups (col 3, line 33). And, Rantala teaches “p” is 1-18 (col 5, line 47-48; col 6, lines 6-18) where the claimed range of 1-2 lies inside the prior art range of 1-18. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). Additionally, Rantala teaches this monomer according to the instant claimed Formula (II) as fully covering a nanoparticle (col 9, lines 18-20).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the composition of Axelsson-2017 to include the crosslinked layer fully covering the central part as taught by Rantala because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a crosslinked polymer with the monomer according to Formula (II) covering a nanoparticle.
A person of ordinary skill in the art would have had a reasonable expectation of success in have a layer of crosslinked polymers according to the monomers of Formula (II) because the prior art of Axelsson-2017 disclosed Formula (II) monomers of bis(trimethoxysilyl)methane and bis(trimethoxysilyl)ethane (pg 7, para [0110], lines 13-18) known to serve as crosslinkers attached throughout the bisphosphonate core (pg 7, para [0104], lines 1-10; pg 7, para [0110], lines 13-18). Additional prior art of Rantala suggested a crosslinked homopolymer of monomers according to Formula (II) covering nanoparticles (col 9, lines 18-20) to have similar resistance to degradation (col 4, lines 27-34) because of the overlap of polymer structure.
The skilled artisan would have been motivated to have a layer of the crosslinked polymer with monomers according to Formula (II) fully surround the central part because the additional layer of crosslinked polymer around the core helps prevent any metals on the outer edge of the central part from environmental exposure thus better protecting the central part from degradation.
Regarding the monomer according to Formula (III), the combined teachings of Axelsson-2017 and Rantala do not teach the monomer according to Formula (III).
Axelsson, O; et al. (hereafter referred to as Axelsson-2019) is drawn to chemical compounds containing either aromatic or non-aromatic cores for coating nanostructures using anchoring groups and at least one hydrophilic group extending from the core (title; abstract). Axelsson-2019 teaches polymeric coatings of nanomaterials with especial interest in chelating polymeric nanostructures incorporating paramagnetic manganese (II) (pg 1, para [0001], lines 1-6). Axelsson-2019 teaches that if the coating material has more than one silane anchoring groups, the coating material becomes more stable and that increased stability is a major advantage for commercial value of the product and makes the regulatory approval process easier (pg 1, para [0006], lines 1-10) and that multiple anchors are particularly useful when coating hydroxyl adorned nanomaterials (pg 1, para [0007], lines 1-3). Axelsson-2019 teaches coating around a polymeric framework comprising geminal bisphosphate groups with two organooxysilane groups (pg 3, para [0023], lines 1-9) and that the coating material can be made from polyethylene glycol (pg 6, para [0083], lines 5-9) and that the core can have aromatic rings or can be non-aromatic (pg 6, para [0084], lines 1-17) and that when cyclic groups are used as the core, more than one hydrophilic polymer tends to form gels rather than coat the nanoparticle (pg 6, para [0086], lines 1-6) and that the hydrophilic polymers can be attached to whatever core through common methods known in the art (pg 8, para [0088], lines 1-7) and form bio-inert coatings of nanomaterials (pg 17, para [0108], lines 1-2). Axelsson teaches that a single aromatic core can have two hydrophilic polyethylene glycol polymers and two organosilyl anchoring groups attached to it (pg 24, para [0215], structure 20) and that the core can alternatively be a quaternary carbon with four substituents (pg 28, para [0241], structure 41).
Regarding the monomer according to Formula (III), Axelsson-2019 teaches a monomer comprising two poly(ethylene glycol)s and two organosilyl anchoring groups attached to a core, reproduced below (pg 15, para [0101], structure 14i; pg 24, para [0215], structure 20; pg 28, para [0241], structure 41).
Regarding two organosilyl anchoring moieties, Axelson-2019 teaches a monomer comprising a quaternary carbon with organosilyl anchoring groups and a poly(ethylene glycol) group (pg 28, para [0241], structure 41). The instant claimed “q” and “r” are positionally equivalent to the Axelsson-2019 prior arts alkyl linker between the quaternary carbon and the silyl group where “q” and “r” are each 3. The prior art value of 3 lies within the claimed range of 2-5. When, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art. See MPEP 21231.03(I). In this case, since other features of the claim are rendered obvious, this limitation is also rendered obvious. Axelsson-2019 teaches R17, R18, R19, R20, R21, and R22 are covalent bonds (pg 28, para [0241], structure 41). Axelsson-2019 teaches R23 and R24 are methyl groups which is a C1 alkyl (pg 28, para [0241], structure 41; pg 19, para [0160], lines 1-4). Axelsson-2019 teaches the instant claimed “s” and “t” is 10-500 (pg 19, para [0161], lines 1-3). The claimed range of 30-105 lies inside the prior art range of 10-500. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the PEGylated coating monomer of Axelsson-2017 to include multiple organosilyl anchors as taught by Axelsson-2019 because the prior art contained comparable composition that was improved in the same way as the claimed invention and that a person of ordinary skill in the art could have applied the known “improvement” technique in the same way to the coating monomer and it would have yielded the predictable outcome of a PEGylated coating layer with multiple organosilyl anchors connected through a quaternary carbon.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding additional organosilyl anchors to the PEGylated coating layer because the prior art of Axelsson-2017 disclosed organosilyl anchors known to anchor to a hydroxy coated nanoparticle. Additional prior art of Axelsson-2019 suggested adding organosilyl anchor groups to have similar anchoring behavior due to the overlap of the anchoring chemistry. And, Axelsson-2019 disclosed that when more than one silyl anchor is used, there is a design advantage of improving the stable and that increased stability is a major advantage for commercial value of the product and makes the regulatory approval process easier (pg 1, para [0006], lines 1-10).
The skilled artisan would have been motivated to add an organosilyl anchoring group to the coating layer because of the improved stability of the coated nanoparticles and improved commercial value.
Axelsson-2017 and the above teachings of Axelsson-2019 do not explicitly teach the quaternary carbon with two organosilyl anchoring group substituents with two poly(ethylene glycol) substituents.
Regarding two poly(ethylene glycol) substituents, Axelsson-2019 teaches that hydrophilic polymers such as poly(ethylene glycol) improve solubility (pg 4, para [0040], lines 1-3; pg 4, para [0042], col 1, lines 1-3) and that having more than two organosilyl anchoring groups reduces solubility (pg 6, para [0083], lines 1-11). And, Axelsson teaches that PEG increases solubility of the nanoparticle (pg 4, para [0042], col 1, lines 1-3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the coating polymer from the monomer having two organosilyl anchors and a PEG substituent as taught by the combined teachings of Axelsson-2017 and Axelsson-2019 to include a second PEG substituent as taught by Axelsson-2019 because the prior art contained a comparable coating polymer that has been improved in the same way as the claimed invention and that a person of ordinary skill in the art could have applied the known “improvement” technique in the same way to the “base” composition and it would have yielded the predictable outcome of a coating polymer from a monomer with two organosilyl anchoring substituents and two PEGylated substituents.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding an additional PEG substituent to the core because the prior art of Axelsson-2017 disclosed a PEG moiety attached to a organosilyl anchoring moiety through a carbon (pg 11, para [0175], line 1) Additional prior art of Axelsson-2019 suggested that two PEGylated substituents and two organosilyl substituents coating nanoparticles (pg 23, para [0207], structure 14) known to coat nanoparticles and have solubility and demonstrate resistance to degradation (pg 31, para [0264], Table 1).
The skilled artisan would have been motivated to modify the quaternary carbon from three organosilyl anchors to two organosilyl anchors and two PEGylated solubilizing substituents because three silyl groups had poor solubility and PEGylated substituents improves solubility Therefore, it would have been prima facie obvious to combine the teachings of Axelsson-2017 with Axelsson-2019.
As to claim 3, Axelsson-2017 teaches the monomers according Formula (I) make up 100% when the central part is comprised of a single homopolymer (pg 7, para [0103], lines 1-5). The prior art value of 100% lies inside the claimed range of at least 70% monomer residues. Therefore, the range is rendered obvious.
As to claim 5, Axelsson-2017 teaches globular nanostructures wherein the instant claimed R1, R2, R3, R4, R5, and R6, which are positionally equivalent to the Axelsson-2017 prior art’s R3, R4, R5, R6, R7, and R8, can be 100% bonds (pg 8, para [0130], lines 1-7).
Axelsson-2017 does not teach R11, R12, R13, R14, R15, and R16.
Axelsson-2017 does not teach R17, R18, R19, R20, R21, and R22.
Regarding R11, R12, R13, R14, R15, and R16, Rantala teaches the instant claimed R11, R12, R13, R14, R15, and R16, which are positionally equivalent to the Rantala prior art’s R1 and R2 when “x” and “y” are 3 (col 3, lines 27-41), can be 100% where R1 is covalent bonds to alkoxides (col 3, line 32; col 5, line 25-28) and can be 100% where R2 is covalent bonds to functional groups (col 3, line 33).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the composition of Axelsson-2017 to include the crosslinked layer fully covering the central part as taught by Rantala because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a crosslinked polymer with the monomer according to Formula (II) covering a nanoparticle.
A person of ordinary skill in the art would have had a reasonable expectation of success in having a layer of crosslinked polymers according to the monomers of Formula (II) because the prior art of Axelsson-2017 disclosed Formula (II) monomers of bis(trimethoxysilyl)methane and bis(trimethoxysilyl)ethane (pg 7, para [0110], lines 13-18) known to serve as crosslinkers attached throughout the bisphosphonate core (pg 7, para [0104], lines 1-10; pg 7, para [0110], lines 13-18). Additional prior art of Rantala suggested a crosslinked homopolymer of monomers according to Formula (II) covering nanoparticles (col 9, lines 18-20) to have similar resistance to degradation (col 4, lines 27-34) because of the overlap of polymer structure.
The skilled artisan would have been motivated to have a layer of the crosslinked polymer with monomers according to Formula (II) fully surrounded the central part because the additional layer of crosslinked polymer around the core helps prevent any metals on the outer edge of the central part from environmental exposure thus better protecting the central part from degradation.
Regarding R17, R18, R19, R20, R21, and R22, Axelsson-2019 teaches R17, R18, R19, R20, R21, and R22 can be 100% covalent bonds (pg 28, para [0241], structure 41).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the PEGylated coating monomer of Axelsson-2017 to include multiple organosilyl anchors as taught by Axelsson-2019 because the prior art contained comparable composition that was improved in the same way as the claimed invention and that a person of ordinary skill in the art could have applied the known “improvement” technique in the same way to the coating monomer and it would have yielded the predictable outcome of a PEGylated coating layer with multiple organosilyl anchors connected through a quaternary carbon.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding additional organosilyl anchors to the PEGylated coating layer because the prior art of Axelsson-2017 disclosed organosilyl anchors known to anchor to a hydroxy coated nanoparticle. Additional prior art of Axelsson-2019 suggested adding organosilyl anchor groups to have similar anchoring behavior due to the overlap of the anchoring chemistry. And, Axelsson-2019 disclosed that when more than one silyl anchor is used, there is a design advantage of improving the stable and that increased stability is a major advantage for commercial value of the product and makes the regulatory approval process easier (pg 1, para [0006], lines 1-10).
The skilled artisan would have been motivated to add an organosilyl anchoring group to the coating layer because of the improved stability of the coated nanoparticles and improved commercial value.
As to claim 6, Axelsson-2017 teaches a plurality of globular nanostructures comprising radionuclides (pg 3, para [0029], lines 1-5).
As to claim 7, Axelsson-2017 teaches 177Lu (pg 4, para [0052], line 4).
As to claim 8, Axelsson-2019 teaches the globular nanostructures can be used as a medicament (pg 3, para [0031], lines 1-4).
As to claim 9, Axelsson-2019 teaches the globular nanostructures can be used for imaging (pg 3, para [0031], lines 1-4).
As to claim 10, Axelsson-2019 teaches using the plurality of globular nanostructures as carriers of radionuclides (pg 3, para [0031], lines 1-4; claim 11).
As to claim 11, Axelsson-2019 teaches a pharmaceutical composition comprising globular nanostructures (pg 17, para [0124], lines 1-4), water (pg 18, para [0130], lines 9-13), and at least one excipient (pg 18, para [0130], lines 16-19).
As to claim 13, Axelsson-2019 teaches a pharmaceutical composition with a use as a medicament (pg 3, para [0031], lines 1-4; pg 17, para [0124], lines 1-6).
As to claim 14, Axelsson-2019 teaches a pharmaceutical composition for use in imaging (pg 17, para [0124], lines 1-6) wherein the globular nanostructures comprise radionuclides (pg 3, para [0031], lines 1-4; pg 17, para [0124], lines 1-6).
As to claim 15, Axelsson-2017 teaches a method for radiolabeling globular nanostructures with a multivalent cationic lutetium (pg 19, para [0366], lines 1-10; pg 22, para [0382], line 30), wherein the method comprises providing a solution at 1.93 of the nanostructures (pg 19, para [0366, lines 1-10) and contacting the solution with lutetium chloride (pg 19, para [0366], lines 1-10), and adjusting the pH of the solution to 7.31 (pg19, para [0366], lines 1-10), where chloride is a pharmaceutically acceptable salt (pg 15, para [0280], line 5).
Axelsson-2017 does not explicitly teach the method uses 177Lu.
Axelsson-2017 teaches 177Lu (pg 22, para [0382], line 30).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the unspecified isotope of lutetium in the method of Axelsson-2017 with the lutetium-177 as taught by Axelsson-2017 because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of radiolabeling globular nanostructures with multivalent cationic unspecified isotope of lutetium .
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the unspecified isotope of lutetium with lutetium-177 because the prior art of Axelsson-2017 disclosed a variety of metals known to be able to chelate to the bisphosphonate (pg 19, para [0366], lines 1-20; pg 22, para [0382]). Additional part of Axelsson-2017 suggested lutetium-177 to be useful (pg 22, para [0382], line 30) and that it would have similar chelating properties because the overlap of atomic element between them involves known chemistry.
The skilled artisan would have been motivated to substitute lutetium with lutetium-177 because radionuclides have broader application for imaging or cancer therapy. Therefore, it would have been prima facie obvious to combine the teachings of the lutetium of Axelsson-2017 with the lutetium-177 of Axelsson-2017.
As to claim 16, Axelsson-2017 teaches providing a solution at a pH below 3 (pg 19, para [0366], lines 1-10).
As to claim 17, Axelsson-2017 teaches a kit (pg 16, para [0307]) comprising an aqueous solution of globular nanostructures (pg 16, para [0308]) and an aqueous solution of a pharamaceutically acceptable buffer (pg 14, para [0279], lines 1-4) with a pH of at least 6 (pg 16, para [0309]).
Axelsson-2017 does not explicitly teach a kit comprising the pH of the aqueous solution of globular nanostructures having a pH below 3.5.
Axelsson-2017 teaches an aqueous solution of globular nanostructures having a pH below 3.5, specifically a pH of 1.93 (pg 19, para [0366, lines 1-10).
Axelsson-2017 does not expressly teach a single embodiment comprising all the features of the claimed product. However, it would be prima facie obvious prior to the effective filing date of the claimed invention to combine the embodiments of a kit with an aqueous solution of globular nanoparticles with a pH below 3.5 as taught by Axelsson-2017 as a skilled artisan recognizes that these claim elements are known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a kit with a specified aqueous solution of the globular nanoparticles with a pH below 3.5.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the aqueous solution of globular nanoparticles to have a pH below 3.5 because the prior art of Axelsson-2017 disclosed a kit known to contain an aqueous solution of globular nanostructures, and aqueous solution having a pH of at least 6. Additional reference within the prior art of Axelsson-2017 suggested globular nanostructures to also have an aqueous solution and that the pH could be less than 3.5.
The skilled artisan would have been motivated to use an aqueous solution of globular nanoparticles at a pH below 3.5 because this could enable faster radiolabeling according to the method of Axelsson-2017 which starts the globular nanoparticles at a pH below 3.5. Therefore, it would have been prima facie obvious to combine the teachings within Axelsson-2017.
Claim(s) 2 and 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Axelsson-2017, Rantala, and Axelsson-2019 as applied to claims 1, 3, 5-11, and 13-17 above, and further in view of Liu, R.; et al., Anti-tumor drug delivery of pH-sensitive poly(ethylene glycol)-poly(L-histidine-)-poly(L-lactide) nanoparticles, J. Controlled Release, 2011, 152, 49-56. The teachings of Axelsson-2017, Rantala, and Axelsson-2019 as applied in the previous rejection are incorporated in this rejection.
As to claim 2, Axelsson-2017 teaches adding crosslinking monomers according to anchoring layer Formula (II) (pg 7, para [0110], lines 17-18) in 30-100% the number of central monomers added. 30-100% is equivalent to crosslinking monomer to phosphonate monomer of 0.3:1 – 1:1 which is equivalent to 23-50% monomer ratio of Formula (II) type monomer to the central part monomer.
Axelsson-2017 does not explicitly teach the ratio of the monomers.
Liu, R.; et al. (hereafter referred to as Liu) is drawn to anti-tumor drug delivery using cross-linked polymer nanoparticles comprising a central part, crosslinked anchoring layer, and a coating layer (title; abstract). Liu teaches stimuli-sensitive drug delivery systems can result in drug release in response to the environment (pg 49, col 1, para 1, lines 1-4). Liu teaches triblock copolymers that are self-assembled and divided into three layers (pg 50, col 1, para 2, lines 5-7). Liu teaches synthesis of the nanoparticles containing a central part, anchoring layer, and coating layer (pg 50, col 2, para 2, lines 1-12) and the monomer ratio of the central part to the anchoring part to the PEG (pg 51, col 2, Table 1).
Regarding the ratio of monomers, Liu teaches a nanoparticles comprising a central part, anchoring layer, and coating layer (pg 50, Scheme 1) and that the ratio of the central part monomer number of 82 to the total monomer number of 128 (XCP) (pg 51, Table 1, entry 3) is equivalent to a monomer percent of the central part monomer to the total monomer number is about 64% due to polymer dispersity. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). Liu teaches the anchoring layer number of monomers is 45 (XAL) (pg 51, Table 1, entry 3) and that corresponds to a monomer number ratio of about 35% due to polymer dispersity. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). And Liu teaches the coating monomer PEG is 1 (XCL) (pg 51, Table 1, entry 3) and that corresponds to a monomer PEG number ratio of about 0.78% due to polymer dispersity. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). And Liu teaches the sum of monomers (XCP + XAL + XCL) of the central part, anchoring layer, and coating layer is 100% since they are the only monomers used (pg 50, col 2, para 2, lines 1-12). Additionally, 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. "Where 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 2144.05(II)(A).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the globular nanoparticles as taught by the combined teachings of Axelsson-2017, Rantala, and Axelsson-2019 with the monomer ratios as taught by Liu because the scope and content of the prior art, whether in the same field of endeavor as that of the applicant’s invention or a different field of endeavor, included a similar or analogous device three-layer globular nanostructures, and there were design incentives of improved drug loading content and efficiency as the anchoring layer at the overall monomer ratios (pg 51, col 2, para 2, lines 9-13) which would have prompted adaptation of the known device globular nanostructures and the differences between the claimed invention and the prior art were encompassed in known variations or in a principle known in the prior art and a person of ordinary skill in the art, in view of the identified improved loading of drug in the central part with increasing anchoring monomer ratio at the overall relative monomer ratios, could have implemented the claimed variation of the prior art, and the claimed variation would have yielded the predictable outcome of globular nanostructures with ratios of central part monomers, anchoring layer monomers, and coating layer monomers with similar ratios.
A person of ordinary skill in the art would have had a reasonable expectation of success in making globular nanostructures with similar monomer ratios in the central part, anchoring layer, and the coating layer because the prior art of Axelsson-2017 disclosed crosslinkers known to have various ratios of crosslinker to the central part monomer. Additional prior art of Liu suggested specific ratios of the central part to anchoring layer to the coating layer to have similar properties of stable nanostructures capable of use in humans.
The skilled artisan would have been motivated to use similar monomer ratios for the central part, anchoring layer, and coating layer because the prior art demonstrated that these ratios enabled loading of anticancer therapeutics (pg 51, col 2, para 2, lines 9-11).
As to claim 4, Axelsson-2017 teaches globular nanostructures with a hydrodynamic diameter of 8-100 nm (pg 2, para [0020], lines 1-6). The claimed range of 22 to 37 nm lies inside the prior art range of 8-100 nm. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). Axelsson-2017 teaches n and m are 1-5 (pg 8, para 0130], line 7). The claimed value of “n” and “m” of 3 lie inside the prior art range of 1-5. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). Axelsson-2017 teaches the relative ratio of a monomer according to Formula (I) is 50-77% (pg 7, para [0110], lines 17-18). The prior art range of 50-77% is close to the claimed ratio of 20-40%. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). Additionally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[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 2144.05(II)(A). Axelsson-2017 teaches the relative ratio of a monomer according to Formula (II) is 23-50% (pg 7, para [0110], lines 17-18). The prior art range of 23-50% is close to the claimed ratio of 60-85%. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). Additionally, differences in will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[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 2144.05(II)(A).
Axelsson-2017 does not teach the relative ratios of XCL is 1.5-4%.
Axelsson-2017 does not teach the sum of the relative ratios of XCP, XAL, and XCL is 81.5-100%.
Regarding the relative ratio of XCL is 1.5-4%, Liu teaches the coating monomer PEG is 1 (XCL) (pg 51, Table 1, entry 3) and that corresponds to a monomer PEG number ratio of about 0.78% due to polymer dispersity. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). Additionally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[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 2144.05(II)(A).
Regarding the sum of the relative ratios of XCP, XAL, and XCL is 81.5-100%, Liu teaches the sum of monomers (XCP + XAL + XCL) of the central part, anchoring layer, and coating layer is 100% since they are the only monomers used (pg 50, col 2, para 2, lines 1-12).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the globular nanoparticles as taught by the combined teachings of Axelsson-2017, Rantala, and Axelsson-2019 with the monomer ratios as taught by Liu because the scope and content of the prior art, whether in the same field of endeavor as that of the applicant’s invention or a different field of endeavor, included a similar or analogous device three-layer globular nanostructures, and there were design incentives of improved drug loading content and efficiency as the anchoring layer at the overall monomer ratios (pg 51, col 2, para 2, lines 9-13) which would have prompted adaptation of the known device globular nanostructures and the differences between the claimed invention and the prior art were encompassed in known variations or in a principle known in the prior art and a person of ordinary skill in the art, in view of the identified improved loading of drug in the central part with increasing anchoring monomer ratio at the overall relative monomer ratios, could have implemented the claimed variation of the prior art, and the claimed variation would have yielded the predictable outcome of globular nanostructures with ratios of central part monomers, anchoring layer monomers, and coating layer monomers with similar ratios.
A person of ordinary skill in the art would have had a reasonable expectation of success in making globular nanostructures with similar monomer ratios in the central part, anchoring layer, and the coating layer because the prior art of Axelsson-2017 disclosed crosslinkers known to have various ratios of crosslinker to the central part monomer. Additional prior art of Liu suggested specific ratios of the central part to anchoring layer to the coating layer to have similar properties of stable nanostructures capable of use in humans.
The skilled artisan would have been motivated to use similar monomer ratios for the central part, anchoring layer, and coating layer because the prior art demonstrated that these ratios enabled loading of anticancer therapeutics (pg 51, col 2, para 2, lines 9-11).
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Axelsson-2017, Rantala, and Axelsson-2019 as applied to claims 1, 3, 5-11, and 13-17 above, and further in view of Patel, H., US 2025/0114375 A1. The teachings of Axelsson-2017, Rantala, and Axelsson-2019 as applied in the previous rejection are incorporated in this rejection.
As to claim 12, Axelsson-2017 teaches pharmaceutical composition (pg 3, para [0031], lines 1-4; pg 17, para [0124], lines 1-6) and teaches glycerol (pg 15, para [0280], lines 1-8).
Axelsson-2017 does not teach glycerol at 3-300 mg/mL.
Axelsson-2017 does not teach thioglycerol at 0.1-10 mg/mL.
Axelsson-2017 does not teach gentisic acid at 0.03-3 mg/mL.
Patel, H. (hereafter referred to as Patel) is drawn to pharmaceutical compositions comprising a combination treatment for eye disease and the pharmaceutically acceptable excipients. Patel teaches only four drugs are approved for dry eye disease (pg 1, para [0008], lines 1-2). Patel teaches a pharmaceutical composition in the form of a solution, dispersion, nano-formulation (pg 3, para [0027], lines 1-5) and comprising pharmaceutically acceptable excipients such as buffering agents, pH-adjusters, preservatives, osmotic/tonicity adjusting agents, stabilizing agents, etc (pg 3, para [0029], lines 1-8) and suitable osmotic adjusting agents such as glycerol, mannitol, sucrose, sodium chloride, etc (pg 5, para [0066], lines 1-15) at concentrations of 0.05-0.51 %w/v (pg 5, para [0066], lines 19-21) and suitable antioxidants such as gentisic acid and thioglycerol and ethanolamide, and ascorbic acid (pg 6, para [0068], lines 1-12) in concentrations ranging from 0.05%-1% w/v of the composition (pg 6, para [0068], lines 13-15).
Regarding glycerol at 3-300 mg/mL, Patel teaches glycerol in pharmaceutical compositions pg 5, para [0066], lines 1-15) at concentrations of 0.05-0.51 %w/v (pg 5, para [0066], lines 19-21). The prior art range of 0.05-0.51 % w/v is equivalent to 0.05-0.51 g/100mL in aqueous solution which is equivalent to 0.5-5.1 mg/mL. The prior art range of 0.5-5.1 mg/mL overlaps the claimed range of 3-300 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the pharmaceutical composition of Axelsson-2017 with glycerol at concentrations as taught by Patel because the scope and content of the prior art, whether in the same field of endeavor as that of the applicant’s invention or a different field of endeavor, included a similar or analogous device (method, or product) of a pharmaceutical composition with glycerol, and there were design incentive of adjusting the osmolarity/tonicity for optimizing for intravenous use to have a certain osmolarity (Axelsson-2017, pg 15, para [0280], lines 8-14) which would have prompted adaptation of the known device pharmaceutical composition with glycerol and the differences between the claimed invention and the prior art were encompassed in known variations or in a principle known in the prior art and a person of ordinary skill in the art, in view of the identified design incentive of optimizing osmolality for intravenous use, could have implemented the claimed variation of the prior art, and the claimed variation would have yielded the predictable outcome of using glycerol as an osmoregulatory in a pharmaceutical composition at the appropriate concentration.
A person of ordinary skill in the art would have had a reasonable expectation of success in using glycerol as an osmoregulatory at the concentration in a pharmaceutical composition because the prior art of Axelsson-2017 disclosed glycerol in pharmaceutical compositions known to be compatible with the pharmaceutical composition. Additional prior art of Patel suggested glycerol to have similar pharmaceutical composition compatibility and to be able to act as an osmoregulatory. And, the person of ordinary skill in the art would have a reasonable expectation of success because of the overlap of using glycerol in pharmaceutical composition between Axelsson-2017 and Patel involves known chemistry and formulation engineering.
The skilled artisan would have been motivated to use glycerol in the pharmaceutical composition at the concentration because obtaining an appropriate solution properties, osmolarity, solubility, etc, can reduce irritation at the site of injection for intravenous use of the pharmaceutical composition. Therefore, it would have been prima facie obvious to combine the teachings of Axelsson-2017 with Patel.
Regarding thioglycerol at 0.1-10 mg/mL, Patel teaches thioglycerol (pg 6, para [0068], line 10) at a concentration of 0.05-1.0% w/v (pg 6, para [0068], lines 13-15). The prior art range of 0.05-1.0% w/v is equivalent to 0.05-1.0 g/100mL in aqueous solution which is equivalent to 0.5-10 mg/mL. The prior art range 0.5-10 mg/mL lies inside or overlaps the claimed range of 0.1-10 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding gentisic acid at 0.03-3 mg/mL, Patel teaches gentisic acid (pg 6, para [0068], line 5) at a concentration of 0.05-1.0% w/v (pg 6, para [0068], lines 13-15). The prior art range of 0.05-1.0% w/v is equivalent to 0.05-1.0 g/100mL in aqueous solution which is equivalent to 0.5-10 mg/mL. The claimed range 0.03-3 mg/mL lies overlaps the prior art range of 0.5-10 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Nonstatutory 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.
U.S. Patent No. 9,040,637
Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-8, and 11-13 of U.S. Patent No. 9,040,637 in view of Axelsson-2017, Rantala, Axelsson-2019, Liu, and Patel. The teachings of Axelsson-2017, Rantala, Axelsson-2019, Liu, and Patel as applied in the previous rejections are incorporated in this rejection.
U.S. Application No. 18/844,712
Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-12, and 15 of copending Application No. 18/844,712 in view of Axelsson-2017, Rantala, Axelsson-2019, Liu, and Patel. The teachings of Axelsson-2017, Rantala, Axelsson-2019, Liu, and Patel as applied in the previous rejections are incorporated in this rejection.
This is a provisional nonstatutory double patenting rejection.
U.S. Application No. 18/841,621
Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-8, and 17 of copending Application No. 18/841,621 in view of Axelsson-2017, Rantala, Axelsson-2019, Liu, and Patel. The teachings of Axelsson-2017, Rantala, Axelsson-2019, Liu, and Patel as applied in the previous rejections are incorporated in this rejection.
This is a provisional nonstatutory double patenting rejection.
The instant claims are drawn globular nanostructures with a central part according to Formula (I), an anchoring layer according to Formula (II), and a coating layer according to Formula (III) where the average hydrodynamic diameter is between 20-50nm and the percentage of monomers in the central part are 5-58% total monomer, and the anchoring layer is 39-93% of the total monomers, and coating layer is 0.75-4.5%; and the globular nanostructures comprise radionuclides such as 177Lu and used for imaging; and a pharmaceutical composition containing water, thioglycerol, gentisic acid, and glycerol; and a method of radiolabeling the globular nanostructures with a multivalent cationic radionuclide at pH 3.5 adjusted to above 6.
The conflicting claims of U.S. Patent No. 9,040,637 (hereafter referred to as ‘637) and U.S. Application No. 18/844,712 (hereafter referred to as ‘712) and U.S. Application No. 18/841,621 (hereafter referred to as ‘621) are drawn to a polymeric nanostructure comprising a central part according to Formula (I) and a coating layer, and the globular nanostructure has a hydrodynamic size of 10-20 nm or 10-90 nm and can comprise a pharmaceutical composition.
The conflicting claims of ‘637 and ‘712 and ‘621 do not teach an anchoring layer according to Formula (II).
The conflicting claims of ‘637 and ‘712 and ‘621 do not teach the coating layer according to Formula (III).
The conflicting claims of ‘637 and ‘712 and ‘621 do not teach XCP is 5-58% of the total monomer residues.
The conflicting claims of ‘637 and ‘712 and ‘621 do not teach XAL is 39-93% of the total monomer residues.
The conflicting claims of ‘637 and ‘712 and ‘621 do not teach XCL is 0.75-4.5% of the total monomer residues.
The conflicting claims of ‘637 and ‘712 and ‘621 do not teach the globular nanostructures comprise radionuclides.
The conflicting claims of ‘637 and ‘712 and ‘621 do not teach the globular nanostructures comprise 177Lu.
The conflicting claims of ‘637 and ‘712 and ‘621 do not teach imaging.
The conflicting claims of ‘637 and ‘712 and ‘621 do not teach a pharmaceutical composition containing water, thioglycerol, gentisic acid, and glycerol.
The conflicting claims of ‘637 and ‘712 and ‘621 do not teach a method of radiolabeling the globular nanostructures with a multivalent cationic radionuclide at a pH of at most 3.5 and then adjusted to a pH of at least 6.
Regarding an anchoring layer according to Formula (II), Rantala teaches the monomer according to Formula (II) reproduced below (col 3, line 30-41). The instant claimed R11, R12, R13, R14, R15, and R16 are positionally equivalent to the Rantala prior art’s R1 and R2 when “x” and “y” are 3 (col 3, lines 27-41) and the Rantala prior art’s R1 can have covalent bonds to alkoxides (col 3, line 32; col 5, line 25-28) and R2 can have covalent bonds to functional groups (col 3, line 33). And, Rantala teaches “p” is 1-18 (col 5, line 47-48; col 6, lines 6-18) where the claimed range of 1-2 lies inside the prior art range of 1-18. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). Additionally, Rantala teaches this monomer according to the instant claimed Formula (II) as fully covering a nanoparticle (col 9, lines 18-20).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the composition of the conflicting claims of ‘637 and ‘712 and ‘621 to include the crosslinked layer fully covering the central part as taught by Rantala because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a crosslinked polymer with the monomer according to Formula (II) covering a nanoparticle.
A person of ordinary skill in the art would have had a reasonable expectation of success in having a layer of crosslinked polymers according to the monomers of Formula (II) because the prior art of Axelsson-2017 disclosed Formula (II) monomers of bis(trimethoxysilyl)methane and bis(trimethoxysilyl)ethane (Axelsson-2017, pg 7, para [0110], lines 13-18) known to serve as crosslinkers attached throughout the central part (Axelsson-2017, pg 7, para [0104], lines 1-10; pg 7, para [0110], lines 13-18). Additional prior art of Rantala suggested a crosslinked homopolymer of monomers according to Formula (II) covering nanoparticles (Rantala, col 9, lines 18-20) to have similar resistance to degradation (Rantala, col 4, lines 27-34) because of the overlap of polymer structure.
The skilled artisan would have been motivated to have a layer of the crosslinked polymer with monomers according to Formula (II) fully surround the central part because the additional layer of crosslinked polymer around the core helps prevent any metals on the outer edge of the central part from environmental exposure thus better protecting the central part from degradation.
Regarding the coating layer according to Formula (III), Axelsson-2019 teaches a monomer comprising two poly(ethylene glycol)s and two organosilyl anchoring groups attached to a core, reproduced below (pg 15, para [0101], structure 14i; pg 24, para [0215], structure 20; pg 28, para [0241], structure 41).
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Regarding two organosilyl anchoring moieties, Axelson-2019 teaches a monomer comprising a quaternary carbon with organosilyl anchoring groups and a poly(ethylene glycol) group (pg 28, para [0241], structure 41). The instant claimed “q” and “r” are positionally equivalent to the Axelsson-2019 prior arts alkyl linker between the quaternary carbon and the silyl group where “q” and “r” are each 3. The prior art value of 3 lies within the claimed range of 2-5. When, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art. See MPEP 21231.03(I). In this case, since other features of the claim are rendered obvious, this limitation is also rendered obvious. Axelsson-2019 teaches R17, R18, R19, R20, R21, and R22 are covalent bonds (pg 28, para [0241], structure 41). Axelsson-2019 teaches R23 and R24 are methyl groups which is a C1 alkyl (pg 28, para [0241], structure 41; pg 19, para [0160], lines 1-4). Axelsson-2019 teaches the instant claimed “s” and “t” is 10-500 (pg 19, para [0161], lines 1-3). The claimed range of 30-105 lies inside the prior art range of 10-500. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the PEGylated coating monomer of conflicting claims ‘637 and ‘712 and ‘621 to include multiple organosilyl anchors as taught by Axelsson-2019 because the prior art contained comparable composition that was improved in the same way as the claimed invention and that a person of ordinary skill in the art could have applied the known “improvement” technique in the same way to the coating monomer and it would have yielded the predictable outcome of a PEGylated coating layer with multiple organosilyl anchors connected through a quaternary carbon.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding additional organosilyl anchors to the PEGylated coating layer because the prior art of Axelsson-2017 disclosed organosilyl anchors known to anchor to a hydroxy coated nanoparticle. Additional prior art of Axelsson-2019 suggested adding organosilyl anchor groups to have similar anchoring behavior due to the overlap of the anchoring chemistry. And, Axelsson-2019 disclosed that when more than one silyl anchor is used, there is a design advantage of improving the stable and that increased stability is a major advantage for commercial value of the product and makes the regulatory approval process easier (pg 1, para [0006], lines 1-10).
The skilled artisan would have been motivated to add an organosilyl anchoring group to the coating layer because of the improved stability of the coated nanoparticles and improved commercial value.
The conflicting claims of ‘637 and ‘712 and ‘621 and the above teachings of Axelsson-2019 do not explicitly teach the quaternary carbon with two organosilyl anchoring group substituents with two poly(ethylene glycol) substituents.
Regarding two poly(ethylene glycol) substituents, Axelsson-2019 teaches that hydrophilic polymers such as poly(ethylene glycol) improve solubility (pg 4, para [0040], lines 1-3; pg 4, para [0042], col 1, lines 1-3) and that having more than two organosilyl anchoring groups reduces solubility (pg 6, para [0083], lines 1-11). And, Axelsson teaches that PEG increases solubility of the nanoparticle (pg 4, para [0042], col 1, lines 1-3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the coating polymer from the monomer having two organosilyl anchors and a PEG substituent as taught by the combined teachings of the conflicting claims of ‘637 and ‘712 and ‘621 and Axelsson-2019 to include a second PEG substituent as taught by Axelsson-2019 because the prior art contained a comparable coating polymer that has been improved in the same way as the claimed invention and that a person of ordinary skill in the art could have applied the known “improvement” technique in the same way to the “base” composition and it would have yielded the predictable outcome of a coating polymer from a monomer with two organosilyl anchoring substituents and two PEGylated substituents.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding an additional PEG substituent to the core because the conflicting claims of ‘637 and ‘712 and ‘621 disclosed a PEG moiety attached to an organosilyl anchoring moiety through a carbon. Additional prior art of Axelsson-2019 suggested that two PEGylated substituents and two organosilyl substituents coating nanoparticles (pg 23, para [0207], structure 14) known to coat nanoparticles and have solubility and demonstrate resistance to degradation (pg 31, para [0264], Table 1).
The skilled artisan would have been motivated to modify the quaternary carbon from three organosilyl anchors to two organosilyl anchors and two PEGylated solubilizing substituents because three silyl groups had poor solubility and PEGylated substituents improves solubility Therefore, it would have been prima facie obvious to combine the teachings of conflicting claims ‘637 and ‘712 and ‘621 with Axelsson-2019.
Regarding XCP is 5-58% of the total monomer residues, XAL is 39-93% of the total monomer residues, and XCL is 0.75-4.5% of the total monomer residues, Axelsson-2017 teaches adding crosslinking monomers according to anchoring layer Formula (II) (pg 7, para [0110], lines 17-18) in 30-100% the number of central monomers added. 30-100% is equivalent to crosslinking monomer to phosphonate monomer of 0.3:1 – 1:1 which is equivalent to 23-50% monomer ratio of Formula (II) type monomer to the central part monomer.
Axelsson-2017 does not explicitly teach the ratio of the monomers.
Liu teaches a nanoparticles comprising a central part, anchoring layer, and coating layer (pg 50, Scheme 1) and that the ratio of the central part monomer number of 82 to the total monomer number of 128 (XCP) (pg 51, Table 1, entry 3) is equivalent to a monomer percent of the central part monomer to the total monomer number is about 64% due to polymer dispersity. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). Liu teaches the anchoring layer number of monomers is 45 (XAL) (pg 51, Table 1, entry 3) and that corresponds to a monomer number ratio of about 35% due to polymer dispersity. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). And Liu teaches the coating monomer PEG is 1 (XCL) (pg 51, Table 1, entry 3) and that corresponds to a monomer PEG number ratio of about 0.78% due to polymer dispersity. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). And Liu teaches the sum of monomers (XCP + XAL + XCL) of the central part, anchoring layer, and coating layer is 100% since they are the only monomers used (pg 50, col 2, para 2, lines 1-12). Additionally, 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. "Where 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 2144.05(II)(A).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the globular nanoparticles as taught by the combined teachings of the conflicting claims of ‘637 and ‘712 and ‘621, Axelsson-2017, Rantala, and Axelsson-2019 with the monomer ratios as taught by Liu because the scope and content of the prior art, whether in the same field of endeavor as that of the applicant’s invention or a different field of endeavor, included a similar or analogous device three-layer globular nanostructures, and there were design incentives of improved drug loading content and efficiency as the anchoring layer at the overall monomer ratios (pg 51, col 2, para 2, lines 9-13) which would have prompted adaptation of the known device globular nanostructures and the differences between the claimed invention and the prior art were encompassed in known variations or in a principle known in the prior art and a person of ordinary skill in the art, in view of the identified improved loading of drug in the central part with increasing anchoring monomer ratio at the overall relative monomer ratios, could have implemented the claimed variation of the prior art, and the claimed variation would have yielded the predictable outcome of globular nanostructures with ratios of central part monomers, anchoring layer monomers, and coating layer monomers with similar ratios.
A person of ordinary skill in the art would have had a reasonable expectation of success in making globular nanostructures with similar monomer ratios in the central part, anchoring layer, and the coating layer because the prior art of Axelsson-2017 disclosed crosslinkers known to have various ratios of crosslinker to the central part monomer. Additional prior art of Liu suggested specific ratios of the central part to anchoring layer to the coating layer to have similar properties of stable nanostructures capable of use in humans.
The skilled artisan would have been motivated to use similar monomer ratios for the central part, anchoring layer, and coating layer because the prior art demonstrated that these ratios enabled loading of anticancer therapeutics (pg 51, col 2, para 2, lines 9-11).
Regarding the globular nanostructures comprise radionuclides, Axelsson-2019 teaches a globular nanostructures comprising radionuclides (pg 3, para [0031], lines 1-4; pg 17, para [0124], lines 1-6).
Regarding the globular nanostructures comprise 177Lu, Axelsson-2017 teaches globular nanostructures comprising 177Lu (pg 19, para [0366], lines 1-10; pg 22, para [0382], line 30; pg 22, para [0382], line 30).
Regarding imaging, Axelsson-2019 teaches a pharmaceutical composition for use in imaging (pg 17, para [0124], lines 1-6)
Regarding a pharmaceutical composition containing water, thioglycerol, gentisic acid, and glycerol, Axelsson-2017 teaches pharmaceutical composition (pg 3, para [0031], lines 1-4; pg 17, para [0124], lines 1-6) and teaches glycerol (pg 15, para [0280], lines 1-8).
Axelsson-2017 does not teach glycerol at 3-300 mg/mL.
Axelsson-2017 does not teach thioglycerol at 0.1-10 mg/mL.
Axelsson-2017 does not teach gentisic acid at 0.03-3 mg/mL.
Regarding glycerol at 3-300 mg/mL, Patel teaches glycerol in pharmaceutical compositions pg 5, para [0066], lines 1-15) at concentrations of 0.05-0.51 %w/v (pg 5, para [0066], lines 19-21). The prior art range of 0.05-0.51 % w/v is equivalent to 0.05-0.51 g/100mL in aqueous solution which is equivalent to 0.5-5.1 mg/mL. The prior art range of 0.5-5.1 mg/mL overlaps the claimed range of 3-300 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the pharmaceutical composition of the conflicting claims of ‘637 and ‘712 and ‘621 with Axelsson-2017 and with glycerol at concentrations as taught by Patel because the scope and content of the prior art, whether in the same field of endeavor as that of the applicant’s invention or a different field of endeavor, included a similar or analogous device (method, or product) of a pharmaceutical composition with glycerol, and there were design incentive of adjusting the osmolarity/tonicity for optimizing for intravenous use to have a certain osmolarity (Axelsson-2017, pg 15, para [0280], lines 8-14) which would have prompted adaptation of the known device pharmaceutical composition with glycerol and the differences between the claimed invention and the prior art were encompassed in known variations or in a principle known in the prior art and a person of ordinary skill in the art, in view of the identified design incentive of optimizing osmolality for intravenous use, could have implemented the claimed variation of the prior art, and the claimed variation would have yielded the predictable outcome of using glycerol as an osmoregulatory in a pharmaceutical composition at the appropriate concentration.
A person of ordinary skill in the art would have had a reasonable expectation of success in using glycerol as an osmoregulatory at the concentration in a pharmaceutical composition because the prior art of Axelsson-2017 disclosed glycerol in pharmaceutical compositions known to be compatible with the pharmaceutical composition. Additional prior art of Patel suggested glycerol to have similar pharmaceutical composition compatibility and to be able to act as an osmoregulatory. And, the person of ordinary skill in the art would have a reasonable expectation of success because of the overlap of using glycerol in pharmaceutical composition between Axelsson-2017 and Patel involves known chemistry and formulation engineering.
The skilled artisan would have been motivated to use glycerol in the pharmaceutical composition at the concentration because obtaining an appropriate solution properties, osmolarity, solubility, etc, can reduce irritation at the site of injection for intravenous use of the pharmaceutical composition. Therefore, it would have been prima facie obvious to combine the teachings of conflicting claims of ‘637 and ‘712 and ‘621 with Axelsson-2017 and with Patel.
Regarding thioglycerol at 0.1-10 mg/mL, Patel teaches thioglycerol (pg 6, para [0068], line 10) at a concentration of 0.05-1.0% w/v (pg 6, para [0068], lines 13-15). The prior art range of 0.05-1.0% w/v is equivalent to 0.05-1.0 g/100mL in aqueous solution which is equivalent to 0.5-10 mg/mL. The prior art range 0.5-10 mg/mL lies inside or overlaps the claimed range of 0.1-10 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding gentisic acid at 0.03-3 mg/mL, Patel teaches gentisic acid (pg 6, para [0068], line 5) at a concentration of 0.05-1.0% w/v (pg 6, para [0068], lines 13-15). The prior art range of 0.05-1.0% w/v is equivalent to 0.05-1.0 g/100mL in aqueous solution which is equivalent to 0.5-10 mg/mL. The claimed range 0.03-3 mg/mL lies overlaps the prior art range of 0.5-10 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding a method of radiolabeling the globular nanostructures with a multivalent cationic radionuclide at a pH of at most 3.5 and then adjusted to a pH of at least 6, Axelsson-2017 teaches a method for radiolabeling globular nanostructures with a multivalent cationic lutetium (pg 19, para [0366], lines 1-10; pg 22, para [0382], line 30), wherein the method comprises providing a solution at 1.93 of the nanostructures (pg 19, para [0366, lines 1-10) and contacting the solution with lutetium chloride (pg 19, para [0366], lines 1-10), and adjusting the pH of the solution to 7.31 (pg19, para [0366], lines 1-10), where chloride is a pharmaceutically acceptable salt (pg 15, para [0280], line 5).
Axelsson-2017 does not explicitly teach the method uses 177Lu.
Axelsson-2017 teaches 177Lu (pg 22, para [0382], line 30).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the unspecified isotope of lutetium in the method of Axelsson-2017 with the lutetium-177 as taught by Axelsson-2017 with the conflicting claims of ‘637 and ‘712 and ‘621 because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of radiolabeling globular nanostructures with multivalent cationic unspecified isotope of lutetium .
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the unspecified isotope of lutetium with lutetium-177 because the prior art of Axelsson-2017 disclosed a variety of metals known to be able to chelate to the bisphosphonate (pg 19, para [0366], lines 1-20; pg 22, para [0382]). Additional part of Axelsson-2017 suggested lutetium-177 to be useful (pg 22, para [0382], line 30) and that it would have similar chelating properties because the overlap of atomic element between them involves known chemistry.
The skilled artisan would have been motivated to substitute lutetium with lutetium-177 because radionuclides have broader application for imaging or cancer therapy. Therefore, it would have been prima facie obvious to combine the teachings of the lutetium of Axelsson-2017 with the lutetium-177 of Axelsson-2017 with the conflicting claims of ‘637 and ‘712 and ‘621.
U.S. Patent No. 9,999,693
Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-13 of U.S. Patent No. 9,999,693 in view of Axelsson-2017, Rantala, Axelsson-2019, Liu, and Patel. The teachings of Axelsson-2017, Rantala, Axelsson-2019, Liu, and Patel as applied in the previous rejections are incorporated in this rejection.
The instant claims are drawn globular nanostructures with a central part according to Formula (I), an anchoring layer according to Formula (II), and a coating layer according to Formula (III) where the average hydrodynamic diameter is between 20-50nm and the percentage of monomers in the central part are 5-58% total monomer, and the anchoring layer is 39-93% of the total monomers, and coating layer is 0.75-4.5%; and the globular nanostructures comprise radionuclides such as 177Lu and used for imaging; and a pharmaceutical composition containing water, thioglycerol, gentisic acid, and glycerol; and a method of radiolabeling the globular nanostructures with a multivalent cationic radionuclide at pH 3.5 adjusted to above 6.
The conflicting claims of U.S. Patent No. 9,999,693 (hereafter referred to as ‘693) are drawn to globular nanostructure comprising monomers according to Formula and an outer layer, and the globular nanostructures have a hydrodynamic diameter of 8-100 nm; and wherein the nanostructure comprises radionuclides which are 177Lu.
The conflicting claims of ‘693 do not teach an anchoring layer according to Formula (II).
The conflicting claims of ‘693 do not teach the coating layer according to Formula (III).
The conflicting claims of ‘693 do not teach XCP is 5-58% of the total monomer residues.
The conflicting claims of ‘693 do not teach XAL is 39-93% of the total monomer residues.
The conflicting claims of ‘693 do not teach XCL is 0.75-4.5% of the total monomer residues.
The conflicting claims of ‘693 do not teach the globular nanostructures comprise 177Lu.
The conflicting claims of ‘693 do not teach a pharmaceutical composition containing water, thioglycerol, gentisic acid, and glycerol.
The conflicting claims of ‘693 do not teach a method of radiolabeling the globular nanostructures with a multivalent cationic radionuclide at a pH of at most 3.5 and then adjusted to a pH of at least 6.
Regarding an anchoring layer according to Formula (II), Rantala teaches the monomer according to Formula (II) reproduced below (col 3, line 30-41). The instant claimed R11, R12, R13, R14, R15, and R16 are positionally equivalent to the Rantala prior art’s R1 and R2 when “x” and “y” are 3 (col 3, lines 27-41) and the Rantala prior art’s R1 can have covalent bonds to alkoxides (col 3, line 32; col 5, line 25-28) and R2 can have covalent bonds to functional groups (col 3, line 33). And, Rantala teaches “p” is 1-18 (col 5, line 47-48; col 6, lines 6-18) where the claimed range of 1-2 lies inside the prior art range of 1-18. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). Additionally, Rantala teaches this monomer according to the instant claimed Formula (II) as fully covering a nanoparticle (col 9, lines 18-20).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the composition of the conflicting claims of ‘693 to include the crosslinked layer fully covering the central part as taught by Rantala because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a crosslinked polymer with the monomer according to Formula (II) covering a nanoparticle.
A person of ordinary skill in the art would have had a reasonable expectation of success in having a layer of crosslinked polymers according to the monomers of Formula (II) because the prior art of Axelsson-2017 disclosed Formula (II) monomers of bis(trimethoxysilyl)methane and bis(trimethoxysilyl)ethane (Axelsson-2017, pg 7, para [0110], lines 13-18) known to serve as crosslinkers attached throughout the central part (Axelsson-2017, pg 7, para [0104], lines 1-10; pg 7, para [0110], lines 13-18). Additional prior art of Rantala suggested a crosslinked homopolymer of monomers according to Formula (II) covering nanoparticles (Rantala, col 9, lines 18-20) to have similar resistance to degradation (Rantala, col 4, lines 27-34) because of the overlap of polymer structure.
The skilled artisan would have been motivated to have a layer of the crosslinked polymer with monomers according to Formula (II) fully surround the central part because the additional layer of crosslinked polymer around the core helps prevent any metals on the outer edge of the central part from environmental exposure thus better protecting the central part from degradation.
Regarding the coating layer according to Formula (III), Axelsson-2019 teaches a monomer comprising two poly(ethylene glycol)s and two organosilyl anchoring groups attached to a core, reproduced below (pg 15, para [0101], structure 14i; pg 24, para [0215], structure 20; pg 28, para [0241], structure 41).
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Regarding two organosilyl anchoring moieties, Axelson-2019 teaches a monomer comprising a quaternary carbon with organosilyl anchoring groups and a poly(ethylene glycol) group (pg 28, para [0241], structure 41). The instant claimed “q” and “r” are positionally equivalent to the Axelsson-2019 prior arts alkyl linker between the quaternary carbon and the silyl group where “q” and “r” are each 3. The prior art value of 3 lies within the claimed range of 2-5. When, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art. See MPEP 21231.03(I). In this case, since other features of the claim are rendered obvious, this limitation is also rendered obvious. Axelsson-2019 teaches R17, R18, R19, R20, R21, and R22 are covalent bonds (pg 28, para [0241], structure 41). Axelsson-2019 teaches R23 and R24 are methyl groups which is a C1 alkyl (pg 28, para [0241], structure 41; pg 19, para [0160], lines 1-4). Axelsson-2019 teaches the instant claimed “s” and “t” is 10-500 (pg 19, para [0161], lines 1-3). The claimed range of 30-105 lies inside the prior art range of 10-500. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the PEGylated coating monomer of conflicting claims ‘693 to include multiple organosilyl anchors as taught by Axelsson-2019 because the prior art contained comparable composition that was improved in the same way as the claimed invention and that a person of ordinary skill in the art could have applied the known “improvement” technique in the same way to the coating monomer and it would have yielded the predictable outcome of a PEGylated coating layer with multiple organosilyl anchors connected through a quaternary carbon.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding additional organosilyl anchors to the PEGylated coating layer because the prior art of Axelsson-2017 disclosed organosilyl anchors known to anchor to a hydroxy coated nanoparticle. Additional prior art of Axelsson-2019 suggested adding organosilyl anchor groups to have similar anchoring behavior due to the overlap of the anchoring chemistry. And, Axelsson-2019 disclosed that when more than one silyl anchor is used, there is a design advantage of improving the stable and that increased stability is a major advantage for commercial value of the product and makes the regulatory approval process easier (pg 1, para [0006], lines 1-10).
The skilled artisan would have been motivated to add an organosilyl anchoring group to the coating layer because of the improved stability of the coated nanoparticles and improved commercial value.
The conflicting claims of ‘693 and the above teachings of Axelsson-2019 do not explicitly teach the quaternary carbon with two organosilyl anchoring group substituents with two poly(ethylene glycol) substituents.
Regarding two poly(ethylene glycol) substituents, Axelsson-2019 teaches that hydrophilic polymers such as poly(ethylene glycol) improve solubility (pg 4, para [0040], lines 1-3; pg 4, para [0042], col 1, lines 1-3) and that having more than two organosilyl anchoring groups reduces solubility (pg 6, para [0083], lines 1-11). And, Axelsson teaches that PEG increases solubility of the nanoparticle (pg 4, para [0042], col 1, lines 1-3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the coating polymer from the monomer having two organosilyl anchors and a PEG substituent as taught by the combined teachings of the conflicting claims of ‘693 and Axelsson-2019 to include a second PEG substituent as taught by Axelsson-2019 because the prior art contained a comparable coating polymer that has been improved in the same way as the claimed invention and that a person of ordinary skill in the art could have applied the known “improvement” technique in the same way to the “base” composition and it would have yielded the predictable outcome of a coating polymer from a monomer with two organosilyl anchoring substituents and two PEGylated substituents.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding an additional PEG substituent to the core because the conflicting claims of ‘693 disclosed a PEG moiety attached to an organosilyl anchoring moiety through a carbon. Additional prior art of Axelsson-2019 suggested that two PEGylated substituents and two organosilyl substituents coating nanoparticles (pg 23, para [0207], structure 14) known to coat nanoparticles and have solubility and demonstrate resistance to degradation (pg 31, para [0264], Table 1).
The skilled artisan would have been motivated to modify the quaternary carbon from three organosilyl anchors to two organosilyl anchors and two PEGylated solubilizing substituents because three silyl groups had poor solubility and PEGylated substituents improves solubility Therefore, it would have been prima facie obvious to combine the teachings of conflicting claims of ‘693 with Axelsson-2019.
Regarding XCP is 5-58% of the total monomer residues, XAL is 39-93% of the total monomer residues, and XCL is 0.75-4.5% of the total monomer residues, Axelsson-2017 teaches adding crosslinking monomers according to anchoring layer Formula (II) (pg 7, para [0110], lines 17-18) in 30-100% the number of central monomers added. 30-100% is equivalent to crosslinking monomer to phosphonate monomer of 0.3:1 – 1:1 which is equivalent to 23-50% monomer ratio of Formula (II) type monomer to the central part monomer.
Axelsson-2017 does not explicitly teach the ratio of the monomers.
Liu teaches a nanoparticles comprising a central part, anchoring layer, and coating layer (pg 50, Scheme 1) and that the ratio of the central part monomer number of 82 to the total monomer number of 128 (XCP) (pg 51, Table 1, entry 3) is equivalent to a monomer percent of the central part monomer to the total monomer number is about 64% due to polymer dispersity. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). Liu teaches the anchoring layer number of monomers is 45 (XAL) (pg 51, Table 1, entry 3) and that corresponds to a monomer number ratio of about 35% due to polymer dispersity. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). And Liu teaches the coating monomer PEG is 1 (XCL) (pg 51, Table 1, entry 3) and that corresponds to a monomer PEG number ratio of about 0.78% due to polymer dispersity. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). And Liu teaches the sum of monomers (XCP + XAL + XCL) of the central part, anchoring layer, and coating layer is 100% since they are the only monomers used (pg 50, col 2, para 2, lines 1-12). Additionally, 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. "Where 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 2144.05(II)(A).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the globular nanoparticles as taught by the combined teachings of the conflicting claims of ‘693, Axelsson-2017, Rantala, and Axelsson-2019 with the monomer ratios as taught by Liu because the scope and content of the prior art, whether in the same field of endeavor as that of the applicant’s invention or a different field of endeavor, included a similar or analogous device three-layer globular nanostructures, and there were design incentives of improved drug loading content and efficiency as the anchoring layer at the overall monomer ratios (pg 51, col 2, para 2, lines 9-13) which would have prompted adaptation of the known device globular nanostructures and the differences between the claimed invention and the prior art were encompassed in known variations or in a principle known in the prior art and a person of ordinary skill in the art, in view of the identified improved loading of drug in the central part with increasing anchoring monomer ratio at the overall relative monomer ratios, could have implemented the claimed variation of the prior art, and the claimed variation would have yielded the predictable outcome of globular nanostructures with ratios of central part monomers, anchoring layer monomers, and coating layer monomers with similar ratios.
A person of ordinary skill in the art would have had a reasonable expectation of success in making globular nanostructures with similar monomer ratios in the central part, anchoring layer, and the coating layer because the prior art of Axelsson-2017 disclosed crosslinkers known to have various ratios of crosslinker to the central part monomer. Additional prior art of Liu suggested specific ratios of the central part to anchoring layer to the coating layer to have similar properties of stable nanostructures capable of use in humans.
The skilled artisan would have been motivated to use similar monomer ratios for the central part, anchoring layer, and coating layer because the prior art demonstrated that these ratios enabled loading of anticancer therapeutics (pg 51, col 2, para 2, lines 9-11).
Regarding imaging, Axelsson-2019 teaches a pharmaceutical composition for use in imaging (pg 17, para [0124], lines 1-6)
Regarding a pharmaceutical composition containing water, thioglycerol, gentisic acid, and glycerol, Axelsson-2017 teaches pharmaceutical composition (pg 3, para [0031], lines 1-4; pg 17, para [0124], lines 1-6) and teaches glycerol (pg 15, para [0280], lines 1-8).
Axelsson-2017 does not teach glycerol at 3-300 mg/mL.
Axelsson-2017 does not teach thioglycerol at 0.1-10 mg/mL.
Axelsson-2017 does not teach gentisic acid at 0.03-3 mg/mL.
Regarding glycerol at 3-300 mg/mL, Patel teaches glycerol in pharmaceutical compositions pg 5, para [0066], lines 1-15) at concentrations of 0.05-0.51 %w/v (pg 5, para [0066], lines 19-21). The prior art range of 0.05-0.51 % w/v is equivalent to 0.05-0.51 g/100mL in aqueous solution which is equivalent to 0.5-5.1 mg/mL. The prior art range of 0.5-5.1 mg/mL overlaps the claimed range of 3-300 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the pharmaceutical composition of the conflicting claims of ‘693 with Axelsson-2017 and with glycerol at concentrations as taught by Patel because the scope and content of the prior art, whether in the same field of endeavor as that of the applicant’s invention or a different field of endeavor, included a similar or analogous device (method, or product) of a pharmaceutical composition with glycerol, and there were design incentive of adjusting the osmolarity/tonicity for optimizing for intravenous use to have a certain osmolarity (Axelsson-2017, pg 15, para [0280], lines 8-14) which would have prompted adaptation of the known device pharmaceutical composition with glycerol and the differences between the claimed invention and the prior art were encompassed in known variations or in a principle known in the prior art and a person of ordinary skill in the art, in view of the identified design incentive of optimizing osmolality for intravenous use, could have implemented the claimed variation of the prior art, and the claimed variation would have yielded the predictable outcome of using glycerol as an osmoregulatory in a pharmaceutical composition at the appropriate concentration.
A person of ordinary skill in the art would have had a reasonable expectation of success in using glycerol as an osmoregulatory at the concentration in a pharmaceutical composition because the prior art of Axelsson-2017 disclosed glycerol in pharmaceutical compositions known to be compatible with the pharmaceutical composition. Additional prior art of Patel suggested glycerol to have similar pharmaceutical composition compatibility and to be able to act as an osmoregulatory. And, the person of ordinary skill in the art would have a reasonable expectation of success because of the overlap of using glycerol in pharmaceutical composition between Axelsson-2017 and Patel involves known chemistry and formulation engineering.
The skilled artisan would have been motivated to use glycerol in the pharmaceutical composition at the concentration because obtaining an appropriate solution properties, osmolarity, solubility, etc, can reduce irritation at the site of injection for intravenous use of the pharmaceutical composition. Therefore, it would have been prima facie obvious to combine the teachings of conflicting claims of ‘693 with Axelsson-2017 and with Patel.
Regarding thioglycerol at 0.1-10 mg/mL, Patel teaches thioglycerol (pg 6, para [0068], line 10) at a concentration of 0.05-1.0% w/v (pg 6, para [0068], lines 13-15). The prior art range of 0.05-1.0% w/v is equivalent to 0.05-1.0 g/100mL in aqueous solution which is equivalent to 0.5-10 mg/mL. The prior art range 0.5-10 mg/mL lies inside or overlaps the claimed range of 0.1-10 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding gentisic acid at 0.03-3 mg/mL, Patel teaches gentisic acid (pg 6, para [0068], line 5) at a concentration of 0.05-1.0% w/v (pg 6, para [0068], lines 13-15). The prior art range of 0.05-1.0% w/v is equivalent to 0.05-1.0 g/100mL in aqueous solution which is equivalent to 0.5-10 mg/mL. The claimed range 0.03-3 mg/mL lies overlaps the prior art range of 0.5-10 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding a method of radiolabeling the globular nanostructures with a multivalent cationic radionuclide at a pH of at most 3.5 and then adjusted to a pH of at least 6, Axelsson-2017 teaches a method for radiolabeling globular nanostructures with a multivalent cationic lutetium (pg 19, para [0366], lines 1-10; pg 22, para [0382], line 30), wherein the method comprises providing a solution at 1.93 of the nanostructures (pg 19, para [0366, lines 1-10) and contacting the solution with lutetium chloride (pg 19, para [0366], lines 1-10), and adjusting the pH of the solution to 7.31 (pg19, para [0366], lines 1-10), where chloride is a pharmaceutically acceptable salt (pg 15, para [0280], line 5).
Axelsson-2017 does not explicitly teach the method uses 177Lu.
Axelsson-2017 teaches 177Lu (pg 22, para [0382], line 30).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the unspecified isotope of lutetium in the method of Axelsson-2017 with the lutetium-177 as taught by Axelsson-2017 with the conflicting claims of ‘637 because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of radiolabeling globular nanostructures with multivalent cationic unspecified isotope of lutetium .
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the unspecified isotope of lutetium with lutetium-177 because the prior art of Axelsson-2017 disclosed a variety of metals known to be able to chelate to the bisphosphonate (pg 19, para [0366], lines 1-20; pg 22, para [0382]). Additional part of Axelsson-2017 suggested lutetium-177 to be useful (pg 22, para [0382], line 30) and that it would have similar chelating properties because the overlap of atomic element between them involves known chemistry.
The skilled artisan would have been motivated to substitute lutetium with lutetium-177 because radionuclides have broader application for imaging or cancer therapy. Therefore, it would have been prima facie obvious to combine the teachings of the lutetium of Axelsson-2017 with the lutetium-177 of Axelsson-2017 with the conflicting claims of ‘693.
U.S. Application No. 18/841,583
Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 14, and 16-20 of copending Application No. 18/841,583 in view of Axelsson-2017, Rantala, Axelsson-2019, Liu, and Patel. The teachings of Axelsson-2017, Rantala, Axelsson-2019, Liu, and Patel as applied in the previous rejections are incorporated in this rejection.
This is a provisional nonstatutory double patenting rejection.
The instant claims are drawn globular nanostructures with a central part according to Formula (I), an anchoring layer according to Formula (II), and a coating layer according to Formula (III) where the average hydrodynamic diameter is between 20-50nm and the percentage of monomers in the central part are 5-58% total monomer, and the anchoring layer is 39-93% of the total monomers, and coating layer is 0.75-4.5%; and the globular nanostructures comprise radionuclides such as 177Lu and used for imaging; and a pharmaceutical composition containing water, thioglycerol, gentisic acid, and glycerol; and a method of radiolabeling the globular nanostructures with a multivalent cationic radionuclide at pH 3.5 adjusted to above 6.
The conflicting claims of U.S. Application No. 18/841,583 (hereafter referred to as '583) is drawn to globular nanostructures comprising a coating layer according to Formula (III) and globular nanostructures and a hydrodynamic size of 10-100 nm and a pharmaceutical composition comprising a radionuclide.
The conflicting claims of ‘583 do not teach a central part according to Formula (I).
The conflicting claims of ‘583 do not teach the anchoring layer according to Formula (II).
The conflicting claims of ‘583 do not teach XCP is 5-58% of the total monomer residues.
The conflicting claims of ‘583 do not teach XAL is 39-93% of the total monomer residues.
The conflicting claims of ‘583 do not teach 0.75-4.5% of the total monomer residues.
The conflicting claims of ‘583 do not teach the globular nanostructures comprising 177Lu.
The conflicting claims of ‘583 do not teach imaging.
The conflicting claims of ‘583 do not teach a pharmaceutical composition containing water, thioglycerol, gentisic acid, and glycerol.
The conflicting claims of ‘583 do not teach a method of radiolabeling the globular nanostructures with a multivalent cationic radionuclide at a pH of at most 3.5 and then adjusted to a pH of at least 6.
Regarding an central part according to Formula (I), Axelsson-2017 teaches a central part (pg 2, para [0020], lines 1-5) comprising monomer residues according to Formula (I), reproduced below (pg 8, para [0130], lines 2-4), wherein the instant claimed R1, R2, R3, R4, R5, and R6 are positionally equivalent to the Axelsson-2017 prior art’s R3, R4, R5, R6, R7, and R8 and each are independently selected from a negative charge, H, or bonds (pg 8, para [0130], lines 1-7), and wherein the instant claimed R7, R8, R9, and R10 are positionally equivalent to Axelsson-2017 prior art’s R1 and R2 and R1 and R2 can be independently selected from negative charge or H (pg 8, para [0126], lines 1-3; pg 8, para [0130], lines 2-4). In the case where Axelsson-2017 prior art’s R1 and R2 are either negative charge or H, 100% of R1 and R2 are negative charge or H (pg 8, para [0126], lines 1-2). 100% is within the instant claimed range of at least 95% of all R7, R8, R9, and R10 groups are H or a negative charge. When, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art. See MPEP 2131.03(I). Since the other components of the claim are made obvious, this range is also made obvious. The instant claimed “n” and “m” are positionally equivalent to the prior art Axelsson-2017 “n” (pg 8, para [0130], lines 1-7). Axelsson-2017 teaches n is 1-5 (pg 8, para 0130], line 7). The claimed range for “n” and “m” of 2-5 lie inside the prior art range of 1-5. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the globular nanostructures of the conflicting claims of ‘583 to include the central part according to Formula (I) as taught by Axelsson-2017 because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of globular nanostructures with a central part according to Formula (I).
A person of ordinary skill in the art would have had a reasonable expectation of success in using a central part according to Formula (I) because the conflicting claims of ‘583 disclosed globular nanostructures known to have a central part. Additional prior art of Axelsson-2017 suggested globular nanostructures to have similar central part and specified it was according to Formula (I).
The skilled artisan would have been motivated to modify the globular nanostructures of conflicting claims of ‘583 with the central part according to Formula (I) because the central part according to Formula (I) enables loading with metals for PET, SPECT, or MRI type applications. Therefore, it would have been prima facie obvious to combine the teachings of the conflicting claims of ‘583 with Axelsson-2017.
Regarding the coating layer according to Formula (III), Axelsson-2019 teaches a monomer comprising two poly(ethylene glycol)s and two organosilyl anchoring groups attached to a core, reproduced below (pg 15, para [0101], structure 14i; pg 24, para [0215], structure 20; pg 28, para [0241], structure 41).
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Regarding two organosilyl anchoring moieties, Axelson-2019 teaches a monomer comprising a quaternary carbon with organosilyl anchoring groups and a poly(ethylene glycol) group (pg 28, para [0241], structure 41). The instant claimed “q” and “r” are positionally equivalent to the Axelsson-2019 prior arts alkyl linker between the quaternary carbon and the silyl group where “q” and “r” are each 3. The prior art value of 3 lies within the claimed range of 2-5. When, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art. See MPEP 21231.03(I). In this case, since other features of the claim are rendered obvious, this limitation is also rendered obvious. Axelsson-2019 teaches R17, R18, R19, R20, R21, and R22 are covalent bonds (pg 28, para [0241], structure 41). Axelsson-2019 teaches R23 and R24 are methyl groups which is a C1 alkyl (pg 28, para [0241], structure 41; pg 19, para [0160], lines 1-4). Axelsson-2019 teaches the instant claimed “s” and “t” is 10-500 (pg 19, para [0161], lines 1-3). The claimed range of 30-105 lies inside the prior art range of 10-500. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the PEGylated coating monomer of conflicting claims of ‘583 to include multiple organosilyl anchors as taught by Axelsson-2019 because the prior art contained comparable composition that was improved in the same way as the claimed invention and that a person of ordinary skill in the art could have applied the known “improvement” technique in the same way to the coating monomer and it would have yielded the predictable outcome of a PEGylated coating layer with multiple organosilyl anchors connected through a quaternary carbon.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding additional organosilyl anchors to the PEGylated coating layer because the prior art of Axelsson-2017 disclosed organosilyl anchors known to anchor to a hydroxy coated nanoparticle. Additional prior art of Axelsson-2019 suggested adding organosilyl anchor groups to have similar anchoring behavior due to the overlap of the anchoring chemistry. And, Axelsson-2019 disclosed that when more than one silyl anchor is used, there is a design advantage of improving the stable and that increased stability is a major advantage for commercial value of the product and makes the regulatory approval process easier (pg 1, para [0006], lines 1-10).
The skilled artisan would have been motivated to add an organosilyl anchoring group to the coating layer because of the improved stability of the coated nanoparticles and improved commercial value.
The conflicting claims of ‘583 and the above teachings of Axelsson-2019 do not explicitly teach the quaternary carbon with two organosilyl anchoring group substituents with two poly(ethylene glycol) substituents.
Regarding two poly(ethylene glycol) substituents, Axelsson-2019 teaches that hydrophilic polymers such as poly(ethylene glycol) improve solubility (pg 4, para [0040], lines 1-3; pg 4, para [0042], col 1, lines 1-3) and that having more than two organosilyl anchoring groups reduces solubility (pg 6, para [0083], lines 1-11). And, Axelsson teaches that PEG increases solubility of the nanoparticle (pg 4, para [0042], col 1, lines 1-3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the coating polymer from the monomer having two organosilyl anchors and a PEG substituent as taught by the combined teachings of the conflicting claims of ‘583 and Axelsson-2019 to include a second PEG substituent as taught by Axelsson-2019 because the prior art contained a comparable coating polymer that has been improved in the same way as the claimed invention and that a person of ordinary skill in the art could have applied the known “improvement” technique in the same way to the “base” composition and it would have yielded the predictable outcome of a coating polymer from a monomer with two organosilyl anchoring substituents and two PEGylated substituents.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding an additional PEG substituent to the core because the conflicting claims of ‘583 disclosed a PEG moiety attached to an organosilyl anchoring moiety through a carbon. Additional prior art of Axelsson-2019 suggested that two PEGylated substituents and two organosilyl substituents coating nanoparticles (pg 23, para [0207], structure 14) known to coat nanoparticles and have solubility and demonstrate resistance to degradation (pg 31, para [0264], Table 1).
The skilled artisan would have been motivated to modify the quaternary carbon from three organosilyl anchors to two organosilyl anchors and two PEGylated solubilizing substituents because three silyl groups had poor solubility and PEGylated substituents improves solubility Therefore, it would have been prima facie obvious to combine the teachings of conflicting claims of ‘583 with Axelsson-2019.
Regarding XCP is 5-58% of the total monomer residues, XAL is 39-93% of the total monomer residues, and XCL is 0.75-4.5% of the total monomer residues, Axelsson-2017 teaches adding crosslinking monomers according to anchoring layer Formula (II) (pg 7, para [0110], lines 17-18) in 30-100% the number of central monomers added. 30-100% is equivalent to crosslinking monomer to phosphonate monomer of 0.3:1 – 1:1 which is equivalent to 23-50% monomer ratio of Formula (II) type monomer to the central part monomer.
Axelsson-2017 does not explicitly teach the ratio of the monomers.
Liu teaches a nanoparticles comprising a central part, anchoring layer, and coating layer (pg 50, Scheme 1) and that the ratio of the central part monomer number of 82 to the total monomer number of 128 (XCP) (pg 51, Table 1, entry 3) is equivalent to a monomer percent of the central part monomer to the total monomer number is about 64% due to polymer dispersity. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). Liu teaches the anchoring layer number of monomers is 45 (XAL) (pg 51, Table 1, entry 3) and that corresponds to a monomer number ratio of about 35% due to polymer dispersity. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). And Liu teaches the coating monomer PEG is 1 (XCL) (pg 51, Table 1, entry 3) and that corresponds to a monomer PEG number ratio of about 0.78% due to polymer dispersity. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). And Liu teaches the sum of monomers (XCP + XAL + XCL) of the central part, anchoring layer, and coating layer is 100% since they are the only monomers used (pg 50, col 2, para 2, lines 1-12). Additionally, 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. "Where 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 2144.05(II)(A).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the globular nanoparticles as taught by the combined teachings of the conflicting claims of ‘583, Axelsson-2017, Rantala, and Axelsson-2019 with the monomer ratios as taught by Liu because the scope and content of the prior art, whether in the same field of endeavor as that of the applicant’s invention or a different field of endeavor, included a similar or analogous device three-layer globular nanostructures, and there were design incentives of improved drug loading content and efficiency as the anchoring layer at the overall monomer ratios (pg 51, col 2, para 2, lines 9-13) which would have prompted adaptation of the known device globular nanostructures and the differences between the claimed invention and the prior art were encompassed in known variations or in a principle known in the prior art and a person of ordinary skill in the art, in view of the identified improved loading of drug in the central part with increasing anchoring monomer ratio at the overall relative monomer ratios, could have implemented the claimed variation of the prior art, and the claimed variation would have yielded the predictable outcome of globular nanostructures with ratios of central part monomers, anchoring layer monomers, and coating layer monomers with similar ratios.
A person of ordinary skill in the art would have had a reasonable expectation of success in making globular nanostructures with similar monomer ratios in the central part, anchoring layer, and the coating layer because the prior art of Axelsson-2017 disclosed crosslinkers known to have various ratios of crosslinker to the central part monomer. Additional prior art of Liu suggested specific ratios of the central part to anchoring layer to the coating layer to have similar properties of stable nanostructures capable of use in humans.
The skilled artisan would have been motivated to use similar monomer ratios for the central part, anchoring layer, and coating layer because the prior art demonstrated that these ratios enabled loading of anticancer therapeutics (pg 51, col 2, para 2, lines 9-11).
Regarding imaging, Axelsson-2019 teaches a pharmaceutical composition for use in imaging (pg 17, para [0124], lines 1-6)
Regarding a pharmaceutical composition containing water, thioglycerol, gentisic acid, and glycerol, Axelsson-2017 teaches pharmaceutical composition (pg 3, para [0031], lines 1-4; pg 17, para [0124], lines 1-6) and teaches glycerol (pg 15, para [0280], lines 1-8).
Axelsson-2017 does not teach glycerol at 3-300 mg/mL.
Axelsson-2017 does not teach thioglycerol at 0.1-10 mg/mL.
Axelsson-2017 does not teach gentisic acid at 0.03-3 mg/mL.
Regarding glycerol at 3-300 mg/mL, Patel teaches glycerol in pharmaceutical compositions pg 5, para [0066], lines 1-15) at concentrations of 0.05-0.51 %w/v (pg 5, para [0066], lines 19-21). The prior art range of 0.05-0.51 % w/v is equivalent to 0.05-0.51 g/100mL in aqueous solution which is equivalent to 0.5-5.1 mg/mL. The prior art range of 0.5-5.1 mg/mL overlaps the claimed range of 3-300 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the pharmaceutical composition of the conflicting claims of ‘583 with Axelsson-2017 and with glycerol at concentrations as taught by Patel because the scope and content of the prior art, whether in the same field of endeavor as that of the applicant’s invention or a different field of endeavor, included a similar or analogous device (method, or product) of a pharmaceutical composition with glycerol, and there were design incentive of adjusting the osmolarity/tonicity for optimizing for intravenous use to have a certain osmolarity (Axelsson-2017, pg 15, para [0280], lines 8-14) which would have prompted adaptation of the known device pharmaceutical composition with glycerol and the differences between the claimed invention and the prior art were encompassed in known variations or in a principle known in the prior art and a person of ordinary skill in the art, in view of the identified design incentive of optimizing osmolality for intravenous use, could have implemented the claimed variation of the prior art, and the claimed variation would have yielded the predictable outcome of using glycerol as an osmoregulatory in a pharmaceutical composition at the appropriate concentration.
A person of ordinary skill in the art would have had a reasonable expectation of success in using glycerol as an osmoregulatory at the concentration in a pharmaceutical composition because the prior art of Axelsson-2017 disclosed glycerol in pharmaceutical compositions known to be compatible with the pharmaceutical composition. Additional prior art of Patel suggested glycerol to have similar pharmaceutical composition compatibility and to be able to act as an osmoregulatory. And, the person of ordinary skill in the art would have a reasonable expectation of success because of the overlap of using glycerol in pharmaceutical composition between Axelsson-2017 and Patel involves known chemistry and formulation engineering.
The skilled artisan would have been motivated to use glycerol in the pharmaceutical composition at the concentration because obtaining an appropriate solution properties, osmolarity, solubility, etc, can reduce irritation at the site of injection for intravenous use of the pharmaceutical composition. Therefore, it would have been prima facie obvious to combine the teachings of conflicting claims of ‘583 with Axelsson-2017 and with Patel.
Regarding thioglycerol at 0.1-10 mg/mL, Patel teaches thioglycerol (pg 6, para [0068], line 10) at a concentration of 0.05-1.0% w/v (pg 6, para [0068], lines 13-15). The prior art range of 0.05-1.0% w/v is equivalent to 0.05-1.0 g/100mL in aqueous solution which is equivalent to 0.5-10 mg/mL. The prior art range 0.5-10 mg/mL lies inside or overlaps the claimed range of 0.1-10 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding gentisic acid at 0.03-3 mg/mL, Patel teaches gentisic acid (pg 6, para [0068], line 5) at a concentration of 0.05-1.0% w/v (pg 6, para [0068], lines 13-15). The prior art range of 0.05-1.0% w/v is equivalent to 0.05-1.0 g/100mL in aqueous solution which is equivalent to 0.5-10 mg/mL. The claimed range 0.03-3 mg/mL lies overlaps the prior art range of 0.5-10 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding a method of radiolabeling the globular nanostructures with a multivalent cationic radionuclide at a pH of at most 3.5 and then adjusted to a pH of at least 6, Axelsson-2017 teaches a method for radiolabeling globular nanostructures with a multivalent cationic lutetium (pg 19, para [0366], lines 1-10; pg 22, para [0382], line 30), wherein the method comprises providing a solution at 1.93 of the nanostructures (pg 19, para [0366, lines 1-10) and contacting the solution with lutetium chloride (pg 19, para [0366], lines 1-10), and adjusting the pH of the solution to 7.31 (pg19, para [0366], lines 1-10), where chloride is a pharmaceutically acceptable salt (pg 15, para [0280], line 5).
Axelsson-2017 does not explicitly teach the method uses 177Lu.
Axelsson-2017 teaches 177Lu (pg 22, para [0382], line 30).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the unspecified isotope of lutetium in the method of Axelsson-2017 with the lutetium-177 as taught by Axelsson-2017 with the conflicting claims of ‘583 because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of radiolabeling globular nanostructures with multivalent cationic unspecified isotope of lutetium .
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the unspecified isotope of lutetium with lutetium-177 because the prior art of Axelsson-2017 disclosed a variety of metals known to be able to chelate to the bisphosphonate (pg 19, para [0366], lines 1-20; pg 22, para [0382]). Additional part of Axelsson-2017 suggested lutetium-177 to be useful (pg 22, para [0382], line 30) and that it would have similar chelating properties because the overlap of atomic element between them involves known chemistry.
The skilled artisan would have been motivated to substitute lutetium with lutetium-177 because radionuclides have broader application for imaging or cancer therapy. Therefore, it would have been prima facie obvious to combine the teachings of the lutetium of Axelsson-2017 with the lutetium-177 of Axelsson-2017 with the conflicting claims of ‘583.
Conclusion
No claims allowed.
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/EVAN M LEWOCZKO/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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