DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement filed September 5, 2024 is acknowledged and has been considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claims 20, 21, and 31 are objected to because of the following informalities: these claims do not end with periods. Per MPEP § 608.01(m), each claim must end with a period. Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 29 and 30 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claims do not fall within at least one of the four categories of patent eligible subject matter because these claims are “use” claims that do not purport to claim a process, machine, manufacture, or composition of matter. See MPEP 2173.05(q).
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 16-19 and 22-33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 16, 22, 23, 29, 31, and 33 are drawn to compounds of Formula I, a method of making compounds of Formula I, nanoparticles comprising compounds of Formula I, the use of compounds of Formula I, and a kit comprising compounds of Formula I. Formula I, as defined in each of these claims, has a wide scope in terms of the number of possible molecules described by the formula and all the combinations of options for the R groups. However, it is not clear that all potential structures within the scope of this claim would possess similar properties contemplated within the instant application.
The structure of the conjugated system of the C^N ligand containing the required isoquinoline core (the top organic portion of the complex of Formula I) determines the luminescence properties of such a complex. The functional groups permitted at R4, R5, R6, R7, and R8 include various electron withdrawing groups and electron donating groups, and include aromatic and alkenyl and alkynyl groups that could alter the pi conjugation system of such a molecule. Wu (Wu, W.; et al., J. Mater. Chem., 2010) teaches that varying the C^N ligand of cyclometalated platinum complexes through altering the pi conjugation system or the addition of electron withdrawing groups alter the photophysical properties of such complexes, including shifting the emission wavelengths, and luminescent oxygen sensing functions (pg. 9782-9783, Conclusions). Furthermore, Wu describes that skilled artisans are aware that extension of the pi conjugation of the C^N ligand is not always compatible with luminescence (pg. 9776, right column, last paragraph). Furthermore, Zhang (Zhang, M. Y.; et al., J. Phys. Chem. A, 2013) also demonstrates that modification of the pi system in the conjugated C^N ligand containing a thiophene in a platinum complex with a diketone alters the photophysical properties of such molecules (pg. 4, Tables 2 and 3). In view of these references, it is understood that the attachment of groups other than hydrogen to the ring system in this part of cyclometalated platinum complexes can have a profound impact on the properties and function.
Furthermore, per MPEP § 2163, an inventor can show possession by describing the claimed invention using words, structures, figures, diagrams, and formulas. The examiner notes that Applicant provides specific structures of Formula Ia and Ib on pages 7 and 8 of the instant specification and a specific example of making ttiq-Pt-acac on page 22. However, these disclosed species are not representative of the entire genus of molecules being claimed in each of the above referenced independent claims. For example, in every disclosed species, the C^N ligand containing the required isoquinoline core is ttiq. In no example is R4, R5, R6, R7, or R8 any group other than hydrogen. Given this fact, the examiner notes that no disclosed species are within the scope of claims 17 and 19, which do not permit R4 to be hydrogen. Additionally, in no example is X = N or Z = Se or Te. In no disclosed embodiment is the metal anything other than platinum. Furthermore, all figures and detailed examples in the specification only describe the structure and property of ttiq-Pt-acac and no other compound. It is not apparent that the properties of the non-depicted structures are contemplated.
As many claimed structure options are missing from the disclosed embodiments, the examiner considers the disclosure to lack a representative number of species for the broad genus claim in the above independent claims. Therefore, it is understood that the specification does not provide sufficient written support to describe all embodiments of the claimed compounds, methods of making, nanoparticles, methods of use, and kit. Additionally, claims 17-19, 24-28, 30, and 32 are also rejected due to their dependency on the full scope of Formula I, or in the case of claims 17-19, not sufficiently narrowing the scope of Formula I such that the scope of the claim is commensurate with the written disclosure. Therefore, the disclosure does not provide sufficient written support to describe all embodiments of each of these claims.
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 24-26 and 31-32 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 24, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For the purpose of examination, the examiner will interpret the phrase following “such as” to not limit the scope of the claim.
Claim 25 recites the limitation "the PEG-lipid conjugate" in the second line. There is insufficient antecedent basis for this limitation in the claim. No prior claim requires a PEG-lipid conjugate.
Claim 25 recites a limitation for the molecular weight of PEG in a PEG-lipid conjugate. However, none of the listed values of molecular weight have units associated with them. As there are no units to these values, it is unclear what units are meant to be present in this limitation. As different units would result in different scopes, this claim is therefore indefinite. For the purpose of examination, the examiner will interpret the unit of these values to be g/mol.
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 25 recites the broad recitation "about 1000 to about 10,000", and the claim also recites "about 1000 to about 6000" and "about 2000 to about 5000," which are narrower statements of the range/limitation. The claim is 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. For the purpose of examination, the examiner will interpret the scope of this limitation in claim 25 to be a range from about 1000 to about 10,000.
Claim 26 recites the limitation "the PEG-lipid conjugate" in the second line. There is insufficient antecedent basis for this limitation in the claim. No prior claim requires a PEG-lipid conjugate.
Regarding claim 26, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For the purpose of examination, the examiner will interpret the phrase following “such as” to not limit the scope of the claim.
Claim 31 is drawn to a method of measuring the concentration of oxygen in a medium. However, claim 31 does not set forth any steps involved in the claimed process. The claim merely recites a use without any active, positive steps delimiting how this use is actually practiced. See MPEP § 2173.05(q). As it is unclear what steps are required to perform the claimed method, the claim is rendered indefinite. Furthermore, as claim 32 depends upon claim 31 and only narrows the material used and does not add any limitation regarding actionable steps to be performed, claim 32 is rejected for the same reasons.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 16, 18, and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Tsujimoto (Tsujimoto, H.; et al., J. Lumin., 2010) in view of Park (Park, Y.; et al., Adv. Photonics Res., 2021) and Djurovich (Djurovich, P. I.; et al., Dalton Trans., 2007).
Tsujimoto teaches luminescent cyclometalated platinum complexes (pg. 217, Title and Abstract). Tsujimoto teaches that heteroleptic (C^N)Pt(O^O) cyclometalated platinum complexes are good phosphorescent materials (pg. 217, Introduction, first paragraph, lines 13-15). Tsujimoto teaches that these complexes generally have a fourfold-coordinated square-planar structure with diketones such as acetylacetone (acac) and dipivaloylmethane (dpm) as the ancillary (O^O) ligand (pg. 217, Introduction, second paragraph, lines 1-4). Tsujimoto teaches the synthesis of various (C^N)Pt(O^O) complexes composed of combinations of six different C^N groups and three different O^O groups (pg. 219, Schemes 1 and 2). Tsujimoto teaches that these various complexes possess photoluminescent properties (pg. 220, Figures 2 and 3).
Tsujimoto does not teach cyclometalated complexes wherein the C^N ligand is 1-(thieno[3x2-b]thiophen-2-yl)isoquinoline (ttiq).
Park teaches thienophenyl-isoquinoline containing iridium complexes (pg. 1, Title and Abstract). More specifically, Park teaches a complex of iridium and tetramethyl heptanedione (tmd) and ttiq ligands (pg. 2, Figure 1; Scheme 1; and Section 2.1). This complex contains two of the C^N ttiq ligands and one of the tmd O^O ligands. Park teaches that this complex possesses photoluminescence properties (pg. 3, Figure 2). Park teaches that the ttiq ligand extended the conjugation length and resulted in strong irradiation in OLED applications (pg. 5, Section 3).
Djurovich teaches cyclometalated complexes of platinum and iridium with C^N and O^O ligands (pg. 3763, Title and Abstract). Djurovich teaches that such iridium complexes follow the structure (C^N)2Ir(O^O) whereas the platinum complexes have a (C^N)Pt(O^O) structure (pg. 3764, Figure 1). Djurovich teaches acac and dpm as O^O ligands (Figure 1). Djurovich teaches that both iridium and platinum are compatible with a variety of C^N ligands (Figure 1). Djurovich teaches that such complexes have luminescent properties (pg. 3766, Table 1). Djurovich teaches that emission energy, redox potential, and solubility can be adjusted in such complexes by changing cyclometalated and/or ancillary ligands (pg. 3769, right column, second paragraph, lines 12-18).
A person of ordinary skill in the art would have recognized that each of Tsujimoto, Park, and Djurovich teach cyclometalated complexes of platinum and iridium using various C^N and O^O ligands with various structures (though similar core structures). It would be recognized that each of these references teach that these ligands are highly interchangeable in terms of the process of making such complexes. It would be understood in view of Djurovich that iridium complexes have a (C^N)2Ir(O^O) structure and platinum complexes have a (C^N)Pt(O^O) structure when using the same ligands. It would be recognized that the ttiq ligand of Park is very similar in structure to C^N ligand “f” of Tsujimoto (Scheme 2).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the platinum complex of Tsujimoto by substituting the C^N ligands of Tsujimoto with the ttiq C^N ligand of Park because Tsujimoto and Djurovich teach such C^N ligands as being highly interchangeable and serving the same purpose in the complex structures (MPEP § 2143(I)(B)). This modification would predictably yield a metal complex of ttiq and a diketone tautomer with a ratio of 1 C^N ttiq ligand to 1 metal atom to 1 O^O diketone ligand.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this substitution because each of Tsujimoto and Djurovich teach that such C^N ligands are highly interchangeable for platinum and iridium complexes and Djurovich teaches that C^N ligands that complex iridium can be used in complexes of platinum and that the different metals prefer complexes with different stoichiometries (2 C^N ligands for Ir and 1 C^N ligand for Pt).
The skilled artisan would have been motivated to make this substitution because Park teaches the ttiq ligand resulted in strong light emission properties in the iridium complex.
Regarding claim 16, Tsujimoto teaches several (C^N)Pt(O^O) complexes wherein the O^O ligand reads on the enolate of the diketone in Formula I wherein R3 is hydrogen (pg. 219, Schemes 1 and 2). In HO^O-1, R1 and R2 are substituted C6 aryl groups and in HO^O-2 (dpm), R1 and R2 are substituted C2 alkyl groups (Schemes 1 and 2). Tsujimoto also teaches that acac is a common heteroleptic platinum complex ancillary ligand (pg. 217, right column, second paragraph, first sentence; and pg. 218, Figure 1). In acac, R1 and R2 are C1 alkyl and R3 is hydrogen. Additionally, Djurovich teaches acac and dpm complexes of iridium and platinum (pg. 3764, Figure 1). Furthermore, Park teaches an iridium complex wherein the O^O ligand is labeled as tmd, which the examiner interprets to have the same structure as dpm as taught in Tsujimoto and Djurovich, thus also reading on the O^O ligand of Formula I. Furthermore, Park teaches a ttiq C^N ligand (pg. 2, figure 1) which reads on the claimed analogous C^N ligand in Formula I wherein Z is S; X is C; n is 0; and R4, R5, R6, R7, and R8 are each hydrogen. Furthermore, Tsujimoto teaches such complexes using platinum (Scheme 2), which the examiner interprets to be a transition metal. As evidenced by Djurovich, a C^N ligand present in a stoichiometry of 2 C^N to 1 Ir would complex with Pt at a ratio of 1 C^N ligand to 1 Pt (Figure 1). The combined teachings of Tsujimoto, Park, and Djurovich combined as described above would result in the following three platinum complexes:
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For the reasons described above, each of these structures reads on the structure of Formula I. Therefore, the combined teachings of Tsujimoto, Park, and Djurovich render the compound of claim 16 obvious.
Regarding claim 18, in each of Formulas X, Y, and Z, M is Pt; R3 is H; R5 and R6 are H; R7 and R8 are H; n is 0; X is C; and Z is S. In Formula X, R1 and R2 are C1 alkyl. In formula Y, R1 and R2 are C2 alkyl. In Formula Z, R1 and R2 are C6 aryl. Each of these structures thus reads on claim 18. Therefore, the combined teachings of Tsujimoto, Park, and Djurovich render the compound of claim 18 obvious.
Regarding claim 20, Formula X is identical to that of Formula Ia. Therefore, the combined teachings of Tsujimoto, Park, and Djurovich render claim 20 obvious.
Regarding claim 21, Formula Y is identical to that of Formula Ib. Therefore, the combined teachings of Tsujimoto, Park, and Djurovich render claim 21 obvious.
Regarding claim 22, Park teaches the synthesis of ttiq using a boronic acid derivative of the thienothiophen compound (which reads on Formula (III) wherein Z is S, R7 and R8 are H, and L is -B(OH)2) and reacting it with 1-chloroisoquinoline (which reads on formula (II) wherein R4, R5, and R6 are hydrogen and R9 is chlorine, which is a halogen) to produce a molecule that reads on that of Formula (IV) having R4, R5, R6, R7, and R8 as hydrogen, X as C, and Z as S (pg. 2, Scheme 1). The examiner interprets this synthesis to read on method step (i) of claim 22. Additionally, Tsujimoto teaches forming a complex between a C^N ligand and platinum by the addition of K2PtCl4 (Scheme 2), which reads on the formula of W2M(R10)4 wherein W is potassium (an alkali metal) and R10 is chlorine (a halogen). Park teaches that the addition of a transition metal chloride salt to ttiq results in a complex with two chlorides, two transition metal iridium atoms, and two ttiq groups interacting with each iridium atom (Scheme 1). As evidenced by Djurovich (Figure 1), if using the Pt of Tsujimoto instead of the Ir of Park, it would be expected that there would be just one ttiq per transition metal. Therefore, the examiner considers intermediate 3 of Scheme 1 of Park to indicate that using the platinum salt of Tsujimoto instead would result in a structure that reads on Formula (V). The combined teachings thus read on method step (ii) of claim 22. Furthermore, both Tsujimoto (Scheme 2) and Park (Scheme 1) teach adding diketone O^O ligands that read on Formula (VI) (as described above in the rejection of claim 16) to the metal-C^N complexes, producing (C^N)-metal-(O^O) complexes. This reads on step (iii) of the method of claim 22. As described above, the combined teachings of Tsujimoto, Park, and Djurovich render obvious the structures of Formula I, Formula Ia, and Formula Ib. Therefore, the combined teachings of Tsujimoto, Park, and Djurovich render obvious the method of claim 22.
Claims 17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Tsujimoto, Park, and Djurovich, as applied to claims 16, 18, and 20-22 above, and further in view of Yen (US 10,400,002 B2).
As described above, Tsujimoto, Park, and Djurovic teach (C^N)-metal-(O^O) complexes of transition metals. As described above, the combined teachings of Tsujimoto, Park, and Djurovic would result in the structures of Formula X, Formula Y, and Formula Z, which render the structure of claim 16 obvious. Furthermore, both Tsujimoto (Scheme 1) and Park (Scheme 1) teach preparation of the metal-binding C^N ligand by the reaction of a thiophene boronic acid with a chloro-isoquinoline. Tsujimoto teaches that this reaction can work for molecules like isoquinolines, like pyridines (Scheme 1).
The combined teachings of Tsujimoto, Park, and Djurovic do not teach modification of the isoquinoline portion of the C^N ligand of a metal complex.
Yen teaches iridium metal complexes with C^N ligands (Title and Abstract). Yen teaches that these complexes adopt a (C^N)2Ir(O^O) structure and that the O^O ligand is a diketone tautomer (column 3, lines 1-40). Yen teaches multiple embodiments of the O^O ligand (column 5, lines 1-50). Yen also teaches several embodiments with variable C^N ligands (columns 5-53, EX1-EX190). Yen teaches synthesis of C^N ligands by reacting a modified thiophene boronic ester with a chloro-pyridine (column 58) or a chloro-isoquinoline (column 61). Yen teaches examples wherein the isoquinoline group is modified by alkyl groups, such as EX173 (column 48), EX176 (column 49), and EX181 (column 50). In EX173, the isoquinoline is modified by a hexyl (C6 alkyl) group; in EX176, the modification is a methyl (C1 alkyl) group; and in EX181, the modification is a substituted C2 alkyl group.
A person of ordinary skill in the art would recognize that each of Tsujimoto, Park, Djurovich, and Yen teach C^N-metal-O^O complexes. It would also be recognized that Tsujimoto, Park, and Yen each teach synthesis of the C^N ligand by the same Suzuki coupling reaction. It would be recognized that Tsujimoto, Djurovich, and Yen teach that many variations of C^N ligands are suitable for the preparation of metal complexes.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the platinum complexes of Formulas X, Y, and Z taught by the combination of Tsujimoto, Djurovich, and Yen by substituting the unmodified isoquinoline portion of the C^N ligand with the alkyl-modified isoquinolines taught by Yen because these groups can be used to prepare very similar C^N ligands to perform the same function of preparing metal complexes (MPEP § 2143(I)(B)). This modification would predictably result in a platinum metal complex with both a diketone O^O ligand and a C^N ligand containing a modified isoquinoline group.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Tsujimoto and Yen demonstrate that the Suzuki coupling reaction can be used to prepare a wide variety of C^N ligands that are combination of isoquinolines, isoquinoline-like molecules, or modified isoquinolines with modified thiophene groups.
The skilled artisan would have been motivated to make this modification because it enables further tailoring the properties of the metal complex by altering its hydrophobicity and potentially altering luminescence properties, as alkyl groups are electron-donating.
Regarding claim 17, as described above, the combined teachings of Tsujimoto, Park, and Djurovich teach the structures of Formulas X, Y, and Z and render claim 16 obvious. Additionally, Yen teaches C^N ligands with alkyl-modification on the 6-position of isoquinoline groups: EX173 (column 48), EX176 (column 49), and EX181 (column 50). In EX173, the isoquinoline is modified by a hexyl (C6 alkyl) group; in EX176, the modification is a methyl (C1 alkyl) group; and in EX181, the modification is a substituted C2 alkyl group. As described above, it would have been prima facie obvious to use these alkyl-modified isoquinoline groups in the structures of Formulas X, Y, and Z. Making such modifications to the compound of Formula X would result in structures in which Z is S; X is C; n is 0; M is Pt; R1 and R2 are C1 alkyl; R3, R5, R6, R7, and R8 are all hydrogen; and R4 is either C1 alkyl, substituted C2 alkyl, or C6 alkyl. Therefore, the combined teachings of Tsujimoto, Park, Djurovich, and Yen render claim 17 obvious.
Regarding claim 19, in the above described example of the alkyl-isoquinoline-modified version of Formula X, M is Pt; R1 and R2 are C1 alkyl; R3 is H; R5 and R6 are H; R7 and R8 are H; n is 0; X is C; and Z is S. Therefore, the combined teachings of Tsujimoto, Park, Djurovich, and Yen render claim 19 obvious.
Claims 23-28 are rejected under 35 U.S.C. 103 as being unpatentable over Tsujimoto, Park, and Djurovich, as applied to claims 16, 18, and 20-22 above, and further in view of Meng (Meng, X.; et al., ACS Appl. Mater. Interfaces, 2018).
As described above, Tsujimoto, Park, and Djurovic teach (C^N)-metal-(O^O) complexes of transition metals. As described above, the combined teachings of Tsujimoto, Park, and Djurovic would result in the structures of Formula X, Formula Y, and Formula Z, which render the structure of claim 16 obvious. Furthermore, Tsujimoto teaches that various (C^N)Pt(O^O) complexes possess photoluminescent properties (pg. 220, Figures 2 and 3). Additionally, Park teaches that the ttiq ligand metal complex produces strong light emission properties (pg. 5, Section 3).
The combined teachings of Tsujimoto, Park, and Djurovich do not teach loading a metal complex according to Formula I, Formula Ia, or Formula Ib in a polymeric nanoparticle.
Meng teaches a phosphorescent nanoprobe comprising iridium complexes in a DSPE-mPEG5000 nanoparticle (pg. 1, Title and Abstract). More specifically, Meng teaches the complexes of Ir1 and Ir2 (pg. 2, Scheme 1), which are complexes of (C^N)2Ir(N^N) structure wherein the C^N ligand of Ir2 is an isoquinoline connected to a modified thiophene. Meng teaches the nanoprecipitation of the metal complexes with DSPE-mPEG5000 to prepare the nanoparticles (Scheme 2 and Section 2.2, lines 1-9). Meng teaches using the metal complex loaded polymeric nanoparticles to measure the amount of hypochlorite in cells (pg. 4, Section 2.3; and pg. 5, Figures 4 and 5).
A person of ordinary skill in the art would recognize that the (C^N)2Ir(N^N) complexes of Meng are similar to that of the (C^N)2Ir(O^O) complexes of Park and Djurovich and analogous to the (C^N)Pt(N^N) complexes of Tsujimoto and Djurovich. It would also be recognized that Meng, Park, and Tsujimoto teach such complexes as having luminescence properties. Additionally, it would be recognized that the DSPE-mPEG5000 nanoparticle of Meng enables the use of such complexes in cellular and organismal systems.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the platinum complex taught by the combination of Tsujimoto, Park, and Djurovich by incorporating it into a DSPE-mPEG5000 polymeric nanoparticle as taught by Meng because this modification would improve a similar complex (the iridium complex of Meng is structurally similar to that of the combination of Tsujimoto, Park, and Djurovich of similarly possesses luminescent properties) in the same way, allowing the platinum complex to be used in cellular and living systems (MPEP § 2143(I)(C)). This would predictably result in a polymeric nanoparticle loaded with a complex that reads on Formula I.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because the iridium complex of Meng is very similar in structure to the platinum complex taught by the combination of Tsujimoto, Park, and Djurovic. Additionally, Meng demonstrates that luminescent complexes incorporated in such nanoparticles produce luminescent nanoparticles.
The skilled artisan would have been motivated to incorporate the platinum complexes of Formulas X, Y, and Z in polymeric nanoparticles because it would enable the use of such luminescent complexes in cellular and living systems.
Regarding claim 23, as described above, the combined teachings of Tsujimoto, Park, and Djurovich teach the structures of Formulas X, Y, and Z and render obvious the structures of Formula I, Ia, and Ib. Additionally, Meng teaches the incorporation of luminescent metal complexes in polymeric nanoparticles (Scheme 1 and pg. 3, Section 2.2). As described above, it would have been prima facie obvious to incorporate the structures of Formulas X, Y, and Z into such polymeric nanoparticles. Therefore, the combined teachings of Tsujimoto, Park, Djurovich, and Meng render claim 23 obvious.
Regarding claim 24, Meng teaches a polymeric nanoparticle formed with DSPE-mPEG5000 (Scheme 1). On pg. 15 of the instant specification, Applicant defines a nanolipid carrier as “a nanoparticle formed from a polymer comprising a lipid.” The examiner interprets DSPE-mPEG5000 to be the polymer PEG conjugated to the lipid DSPE. This structure thus reads on “nanolipid carrier.” Therefore, the combined teachings of Tsujimoto, Park, Djurovich, and Meng render claim 24 obvious.
Regarding claim 25, Meng teaches a polymeric nanoparticle formed with DSPE-mPEG5000 (Scheme 1). The examiner interprets this notation to mean that the molecular weight of the PEG in the PEG-lipid conjugate is about 5000 g/mol. Therefore, the combined teachings of Tsujimoto, Park, Djurovich, and Meng render claim 25 obvious.
Regarding claim 26, Meng teaches a polymeric nanoparticle formed with DSPE-mPEG5000 (Scheme 1). The examiner interprets this to be a polymer-lipid conjugate wherein the lipid is DSPE, which is a phospholipid. Therefore, the combined teachings of Tsujimoto, Park, Djurovich, and Meng render claim 26 obvious.
Regarding claim 27, Meng teaches loading the Ir1 and Ir2 complexes in the polymeric nanoparticles in amounts of 8.7 µg and 64 µg, respectively, per 1 mg of nanoparticle (pg. 3, left column, last 3 lines, through right column, first two lines). The examiner notes that this means the loading percentage of the complexes was 0.87% w/w for Ir1 and 6.4% w/w for Ir2. As 6.4% is within the claimed range of 0.1-1.0% w/w, it renders the claimed range obvious (MPEP § 2144.05(I)). Therefore, the combined teachings of Tsujimoto, Park, Djurovich, and Meng render claim 27 obvious.
Regarding claim 28, Meng teaches acquiring luminescence emission data of the metal complex loaded nanoparticles in phosphate buffered saline. The examiner interprets this to be an aqueous solution. Thus, the examiner interprets the preparation used in the experiment to be an aqueous composition comprising a plurality of polymeric nanoparticles according to claim 23. Therefore, the combined teachings of Tsujimoto, Park, Djurovich, and Meng render claim 28 obvious.
Claims 29-32 are rejected under 35 U.S.C. 103 as being unpatentable over Tsujimoto, Park, Djurovich, and Meng, as applied to claims 23-28 above, and further in view of Zheng (Zheng, X.; et al., Nat. Commun., 2015) and Wu (Wu, W.; at al., J. Mater. Chem., 2010).
As described above, Tsujimoto, Park, and Djurovic teach (C^N)-metal-(O^O) complexes of transition metals. As described above, the combined teachings of Tsujimoto, Park, and Djurovic would result in the structures of Formula X, Formula Y, and Formula Z, which render obvious the structures of Formulas I, Ia, and Ib. Additionally, Meng teaches loading cyclometalated complexes in polymeric nanoparticles (Scheme 1). As described above, the combined teachings of Tsujimoto, Park, Djurovic, and Meng render the complex-loaded polymeric nanoparticle of claim 23 and the aqueous composition of said nanoparticles of claim 28 obvious. Furthermore, Tsujimoto teaches that organometallic complexes with heavy metal centers have been applied to oxygen sensors (pg. 217, Introduction, first sentence).
The combined teachings of Tsujimoto, Park, Djurovich, and Meng do not teach using the metal complex loaded polymeric nanoparticle to measure the concentration of oxygen in a medium.
Zheng teaches the use of a phosphorescent probe for imaging hypoxia in vivo (Abstract). More specifically, Zheng teaches a conjugate of a (C^N)2Ir(O^O) complex with a polymer (polyvinylpyrrolidone) as the probe, which may be further conjugated (pg. 3, Figure 1a). Zheng teaches that this probe produces different emission intensity at different oxygen levels (Figure 1). Zheng teaches the use of the probe to measure hypoxia in vitro in cultured cells (Figure 2). In this method, the metal complex probe is added to the cells incubated at different oxygen levels and emission spectra are obtained. The probe is conjugated to rhodamine B, providing constant emission around 590 nm, while the oxygen-sensing iridium complex varies intensity around 700 nm in response to the oxygen concentration (Figure 2). Zheng further teaches that this probe can be used in vivo (Figure 3). Zheng teaches that this probe also works with substituting rhodamine B for N797 as the constant emission component (Figure 4). Zheng also teaches that the Ir-PVP probe can be used in the absence of conjugated dyes to detect hypoxia in vivo (Figure 6).
Wu teaches luminescent cyclometalated complexes of platinum for oxygen sensing (pg. 1, Title and Abstract). More specifically, Wu teaches five (C^N)Pt(O^O) complexes (pg. 3, Scheme 1). In each of these, the O^O ligand is acac. The modification to the phenyl group attached to the pyridine varies, resulting in differences in conjugation and electron withdrawing effects (pg. 2, right column, 7th paragraph; and pg. 4, right column, first paragraph). Wu teaches that increasing oxygen concentration decreases luminescence of the probe (Figure 3). Wu teaches that complex Pt-2 possesses a dual-emission property wherein in different amounts of oxygen, the emission at 386 nm is constant while the emission at 538 nm is oxygen-dependent (Figure 3b; and pg. 4, right column fourth paragraph). Wu teaches using Pt-2 as an oxygen sensor (Figure 6).
A person of ordinary skill in the art would recognize that Zheng teaches using a (C^N)2Ir(N^N) complex conjugated to a polymer for biocompatibility for oxygen sensing in vitro and in vivo. It would also be recognized that Wu teaches (C^N)Pt(N^N) complexes can be used for oxygen sensing. The skilled artisan would recognize that the structures of the complexes of Zheng and Wu are similar to that of Formulas X, Y, and Z taught by the combination of Tsujimoto, Park, and Djurovich.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the platinum complex loaded polymeric nanoparticle invention taught by the combination of Tsujimoto, Park, Djurovich, and Meng by using it for oxygen sensing, as taught by Zheng because each of 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 (as evidenced by Wu demonstrating the utility of Pt complexes for oxygen sensing) 9MPEP 7 2143(I)(A)). The combination would have predictably yielded a method of using DSPE-mPEG5000 nanoparticles loaded with complexes of Formulas X, Y, or Z being used for luminescence-based oxygen sensing.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because the iridium complex of Zheng is analogous in structure to those of Formulas X, Y, and Z in terms of the presence of similar core components in the C^N and O^O ligands. Additionally, Wu demonstrates that luminescent (C^N)Pt(O^O) complexes can also be used for oxygen sensing. Furthermore, Meng demonstrates biosafety and biocompatibility with the DSPE-mPEG5000 nanoparticle system.
The skilled artisan would have been motivated to make this modification because it would enable the use of the platinum complex for detection of hypoxia, which could provide a diagnostic use of the complex.
Regarding claims 29-32, as described above, the combined teachings of Tsujimoto, Park, Djurovich, and Meng render obvious a polymeric nanoparticle loaded with a compound of Formula I, Ia, or Ib. Additionally, Zheng teaches the use of cyclometalated complexes to measure oxygen concentration in cell culture and living systems (Figures 2, 3, 4, and 6). The examiner interprets the cell culture system of Zheng to involve the measurement of oxygen in the culture media or cytoplasm of cells, both of which read on the limitation of “in a medium” in claim 29; and in the in vivo experiments, the oxygen level is being measured in cells (cytoplasm) or blood, which the examiner also interprets as media. Furthermore, Wu demonstrates that similar platinum complexes can also be used as oxygen sensors (Figure 6). Additionally, Meng teaches providing such metal complex loaded nanoparticles in PBS aqueous medium (Figure 2) or in DMEM cell culture medium (pg. 4, left column, last paragraph), which is also aqueous. As Meng teaches providing the nanoparticles in cell culture media when administering the compound to cells, the skilled artisan would be able to translate this to the in vitro cell culture oxygen sensing of Zheng. Therefore, the combined teachings of Tsujimoto, Park, Djurovich, Meng, Zheng, and Wu render claims 29-32 obvious.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Tsujimoto, Park, and Djurovich, as applied to claims 16, 18, and 20-22 above, and further in view of Pigge (US 2020/0308208 A1).
As described above, Tsujimoto, Park, and Djurovic teach (C^N)-metal-(O^O) complexes of transition metals. As described above, the combined teachings of Tsujimoto, Park, and Djurovic would result in the structures of Formula X, Formula Y, and Formula Z, which render the structure of claim 16 obvious. Furthermore, Tsujimoto teaches that various (C^N)Pt(O^O) complexes possess photoluminescent properties (pg. 220, Figures 2 and 3). Additionally, Park teaches that the ttiq ligand metal complex produces strong light emission properties (pg. 5, Section 3).
The combined teachings of Tsujimoto, Park, and Djurovich do not teach providing the metal complex according to Formula I, Formula Ia, or Formula Ib in a kit further comprising instructions.
Pigge teaches organic platinum complexes (Abstract). More specifically, Pigge teaches (C^N)2Pt organic complexes (Figure 1). Pigge teaches that these complexes are luminescent (Figure 2C). Pigge describes the complexes as luminescent platinum probes (pg. 3, [0062]). Pigge teaches that the platinum complexes may be provided as a kit containing both the compound and instructions for its use (pg. 11, [0137]-[0140]).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the platinum complex taught by the combination of Tsujimoto, Park, and Djurovich by incorporating it into a kit further containing instructions for use as taught by Pigge 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 (MPEP § 2143(I)(A)). This would predictably result in a kit comprising compounds of Formulas X, Y, or Z and instructions for use.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because it would be recognized that both Pigge and the combination of Tsujimoto, Park, and Djurovich teach luminescent organic platinum complex probes.
The skilled artisan would have been motivated to incorporate the platinum complexes of Formulas X, Y, and Z in kits further comprising instructions because it produce a product that could be sold to users and enable the users to utilize the compounds.
Regarding claim 33, as described above, the combined teachings of Tsujimoto, Park, and Djurovich teach the structures of Formulas X, Y, and Z and render obvious the structures of Formula I, Ia, and Ib. Additionally, Tsujimoto teaches providing such complexes in chloroform solutions (Figures 2 and 3); Park teaches providing ttiq containing complexes in tetrahydrofuran (pg. 3, Section 2.2); and Djurovich teaches providing similar metal complexes in toluene (pg. 3765, left column, second paragraph), benzene or methanol (pg. 3765, left column, third paragraph), and DMF (pg. 3765, left column, fourth paragraph). Thus, it would be obvious to provide such metal complexes in the form of a solution comprising them. Furthermore, Pigge teaches including instructions for the use of a platinum organic complex in a kit with such a platinum complex (pg. 11, [0137]-[0140]).
Furthermore, the examiner interprets the phrase “for use of the kit via the method according to claim 31” to describe the written contents of the instructions provided in the kit, therefore amounting to printed matter. Per MPEP § 2112.01(III), where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. Per MPEP § 2111.05(I)(B), in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals, which indicates there is not a functional relationship in the instant scenario.
Therefore, the combined teachings of Tsujimoto, Park, Djurovich, and Pigge render claim 33 obvious.
Pertinent Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
As pertinent art, the examiner cites Dmitriev (Dmitriev, R. I.; et al, Bioconjug. Chem., 2015). Dmitriev teaches porphyrin-platinum complexes and their use as oxygen sensing probes (pg. 439, Title and Abstract). More specifically, complexes of platinum bound to a porphyrin conjugated to a peptide (Figures 1 and 2), a protein (Figure 3), and in nanoparticles (Figure 4). Dmitriev teaches that the platinum organic complex enables the use of these compounds as luminescent oxygen sensors (Figures 1B, 3C, 3E, 4E, and 4F). The examiner notes that this demonstrates that it is taught in the prior art that organic platinum complexes can serve as luminescent oxygen sensors and that such probes can be provided as nanoparticles.
As pertinent art, the examiner cites Roussakis (Roussakis, E.; et al, Angew. Chem. Int. Ed., 2015). Roussakis provides a review of what was known to skilled artisans in the field of oxygen sensing in biomedicine as of 2015. Roussakis summarizes that ruthenium and iridium organic complexes are known to be useful for oxygen sensing (pg. 11, Section 6.1.1). Roussakis discloses an example of such a (C^N)2Ir(O^O) probe (Figure 5). Roussakis also reproduces of an example of an organic platinum complex used as an oxygen sensor (Figure 6). Roussakis teaches that platinum and palladium are known to impart superior photophysical properties for oxygen sensing compared to ruthenium and iridium sensors (pg. 12, Section 6.1.2, first paragraph). Roussakis teaches that the solubility of organic complexes of platinum can be poor in aqueous media, leading to efforts to improve biodistribution through incorporation of such complexes in carriers such as dendrimers (pg. 13, left column, third paragraph). The examiner notes that Roussakis describes that it is known that platinum organic complexes are useful for oxygen sensing (even preferable over analogous iridium sensors) and that providing polymeric carriers for such complexes is desirable.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric P Mosher whose telephone number is (571)272-3258. The examiner can normally be reached Monday-Friday 9am-5pm.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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