DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of graphene oxide/copper ferrite nanoparticles (claim 6); poly-epsilon-lysine (claim 8); Fmoc-diphenylalanine (claim 9); an ophthalmic gel (claim 13); N-vinylpyrrolidone (claim 15); and Staphylococcus (claim 18) in the reply filed on 05/18/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Priority
The instant application filed on 05/02/2024 claims priority to U.S. Provisional Application 63/499,590 filed on 05/02/2023. PRO 63/499,590 finds support for the instantly claimed invention; therefore, the effective filing date of the instant application is 05/02/2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/12/2024 and 07/12/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 1 is objected to because of the following informalities: “ROS” should not be completely spelled out upon first use. Appropriate correction is required. This is an objection, not a rejection, because ROS is abbreviated in the instant specification to be “reactive oxygen species” (see, e.g., instant specification, pg. 1, line 20).
Claims 3-5 are objected to because of the following informalities: Claims 3-5 depend on independent claim 1, which recites that the enzyme capable of generating ROS upon contact with eye tears is optional within the ocular composition. However, claims 3-5 limit the enzyme in the composition despite the enzyme being optional. The Examiner suggests amending independent claim 1 to positively recite that the enzyme capable of generating ROS upon contact with eye tears is required within the composition.
Claim 9 is objected to because of the following informalities: “herein” should be “wherein”. Appropriate correction is required. This is an objection, not a rejection, because this appears to be a typographical error.
Claim 10 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim should refer back to a claim in the alternative only (see, e.g., MPEP 608.01(n)). For claim 10, the claim refers back to claim 8 and claim 9. Accordingly, the claim has not been further treated on the merits.
Claim 15 is objected to because of the following informalities: the “)” after “acrylic acid” should be removed. Appropriate correction is required. This is an objection, not a rejection, because this appears to be a typographical error.
Claim 16 is objected to because of the following informalities: “the subjection” should be “the subject”. Appropriate correction is required. This is an objection, not a rejection, because this appears to be a typographical error.
Claim 19 is objected to because of the following informalities: “resistant” should not be italicized. Appropriate correction is required. This is an objection, not a rejection, because this appears to be a typographical error.
Claim Interpretation
Independent claim 1 recites that the ocular composition comprises one or more photoactive heterojunction materials alone or in combination with an enzyme capable of generating ROS upon contact with eye tears. For the purposes of compact prosecution, since the ocular composition can comprise one or more photoactive heterojunction materials alone, the Examiner has interpreted the enzyme capable of generating ROS upon contact with eye tears to be optional (i.e., not required) within the composition.
Claim Rejections - 35 USC § 112(b), Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 6-9, 12-13, and 17 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 recites “(Urea, Bi-TiO2 group; U, Bi-TiO2)” in parentheses; however, it is unclear if what is recited in parentheses is part of the claimed invention or a preferred embodiment. For the purposes of applying prior art, the Examiner has interpreted “(Urea, Bi-TiO2 group; U, Bi-TiO2)” recited in parentheses to be a preferred embodiment and not part of the claimed invention.
Claim 7 recites “a polysaccharides”; however, it is unclear if one polysaccharide is being claimed in the hydrogel, or if more than one polysaccharide is being claimed in the hydrogel. This is unclear because “a” typically refers to one object; however, “polysaccharides” is recited in the plural; therefore, it is unclear if one or more than one polysaccharide is required. For the purposes of applying prior art, the Examiner has interpreted there to be one polysaccharide in the hydrogel.
Claims 12 and 17 recites “preferably”, however, it is unclear if the limitations recited after “preferably” are preferred embodiments or part of the instantly claimed invention. For the purposes of applying prior art, the Examiner has interpreted the limitations recited after “preferably” to be preferred embodiments and not part of the instantly claimed invention.
Claim 13 recites “(including contact lenses, such as bandage contact lenses (BCL))” in parentheses; however, it is unclear if what is recited in parentheses is part of the claimed invention or a preferred embodiment. For the purposes of applying prior art, the Examiner has interpreted “(including contact lenses, such as bandage contact lenses (BCL))” recited in parentheses to be a preferred embodiment and not part of the claimed invention.
Claims 8-9 are included in this rejection for depending on rejected dependent claim 7 and failing to rectify the noted deficiency.
Claim Rejections - 35 USC § 112(a), Scope of Enablement
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.
Claims 1-20 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for graphene oxide/copper ferrite nanoparticles as the photoactive heterojunction material, and glucose oxidase and lactase oxidase as enzymes capable of generating ROS upon contact with eye tears, does not reasonably provide enablement for all photoactive heterojunction materials and all enzymes capable of generating ROS upon contact with eye tears. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
In re Wands (858 F2d, 721, 727, 8 USPQ 2d 1400, 1404 (Fed Cir. 1988)), the issue of
enablement in molecular biology was considered. It was held that the following factors should be
considered to determine whether the claimed invention would require the skilled artisan undue
experimentation:
1) Amount of experimentation necessary;
2) Amount of direction or guidance presented;
3) Presence or absence of working examples;
4) Nature of the invention;
5) State of the prior art;
6) Relative skill of those in the art;
7) Predictability or unpredictability of the art; and
8) Breadth of the claims.
Nature of the invention: The invention is directed towards a composition comprising an photoactive heterojunction material optionally in combination with an enzyme generating ROS upon contact with eye tears in a pharmaceutically acceptable ocular carrier.
Breadth of claims: As claimed, the composition comprises all enzymes generating ROS upon contact with eye tears.
Amount of direction or guidance presented: The instant specification states, “Preferably, the oxidoreductive enzyme suspended in the enzyme-modified hydrogel is glucose oxidase (GOx). The microenvironment on infected ocular surface consists of precorneal tear film with a thickness of 3 μm.39 40 Normally, glucose in tear film promotes the growth of pathogenic bacterial, which further aggravates the infection on cornea. The oxidative enzyme of glucose, Glucose oxidase (GOx), can suppress the bacterial growth and produce H2O2 by consuming glucose from around the infectious microenvironment. Meanwhile, H2O2 produced by GOx facilitates the production of highly oxidative ·OH with the presence of GO/CFN through the Fenton(-like) reaction. The ROS generating enzyme can in some forms, be lactic oxidase. Lactate oxidase (LOx) can be used to convert L-lactate and oxygen into pyruvate and hydrogen peroxide. Lactate is a main component in basal tears, and it mainly comes from the corneal epithelium” (see, e.g., instant specification, pg. 14, lines 19-26 & pg. 15, lines 1-3).
Presence or absence of working examples: The instant specification teaches ocular compositions comprising glucose oxidase and graphene oxide/copper ferrite (see, e.g., instant specification, pg. 22, lines 29-31 & pg. 23, lines 1-9 & Fig. 4C). Based on Applicant’s disclosure, the Applicant would not be enabled for all enzymes capable of generating ROS upon contact with eye tears. There is no guidance on preparation of ocular compositions with enzymes besides glucose oxidase and lactate oxidase was described in the specification as an alternative enzyme that can be used in the composition to produce ROS from tears (see, e.g., instant specification, pg. 14, lines 19-26 & pg. 15, lines 1-3).
State of the prior art: The prior art of Deng (Rapid sterilisation and diabetic cutaneous regeneration using cascade bio-heterojunctions through glucose oxidase-primed therapy; 2022 – cited in the IDS filed on 06/12/2024) teaches glucose oxidase in the bio-heterojunction material in order to catalyze glycose into hydrogen peroxide in wounds for starvation therapy (see, e.g., Deng, abstract). Moreover, Deng teaches “when GOx is used in combination with photosensitive materials or Fenton-like reagents, the generated H2O2 could be further catalyzed into highly germicidal ROS, leading to an excellent cascade and synergistic antibacterial effect” (see, e.g., Deng, Introduction, pg. 749). Therefore, Deng teaches glucose oxidase in combination with a photoactive heterojunction material. However, the prior art does not generally teach what enzymes generate ROS production upon contact with tears. Robinson (Enzymes: principles and biotechnological applications; 2015) teaches that there are at least 5000 different enzymes that have been identified (see, e.g., Robinson, “Enzyme names and classification:”, pg. 3). Moreover, there are various methods in the art to determine whether an enzyme generates ROS, such as using small molecule fluorescent probes, spectrometry, luminescence detection, antibodies, etc. (see, e.g., Murphy, Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo; 2022). However, the prior art also teaches that ROS production and accumulation in the eyes can cause various eye diseases, such as glaucoma, diabetic retinopathy, macular degeneration, retinal pigmentosa, etc. (see, e.g., Bissell, The Role of Oxidative Stress in the Pathogenesis of Eye Disease; 2022).
Relative skill of those in the art: Based on the state of the prior art, the relative skill of those in the prior art pertaining to developing a ocular composition comprising photoactive heterojunction materials and an enzyme capable of generating ROS upon contact with eye tears is low due to the fact that there are so many enzymes that exist, and due to the fact that the prior art does not readily teach what enzymes generate ROS upon contact with eye tears.
Predictability or unpredictability of the art: The level of unpredictability within the art is high, as there are many types of enzymes, all with different structures and functions; therefore, it is unpredictable as to whether these enzymes can generate ROS upon contact with eye tears and formulated within an ocular composition with an ocular carrier and photoactive heterojunction material.
Amount of experimentation necessary: Since there are many types of enzymes that exist, one of ordinary skill in the art would have undue experimentation in order to determine if ocular compositions can be produced with other enzymes, besides glucose oxidase and lactate oxidase, in combination with a photoactive heterojunction material. Therefore, the amount of experimentation is high as there is undue experimentation to determine what enzymes produce ROS upon contact with eye tears and if these enzymes can be formulated into an ocular composition with a photoactive heterojunction material.
Claim Rejections - 35 USC § 103, Obviousness
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.
Claims 1-2, 6-8, 12-14, 16-18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Aveyard (Antimicrobial Nitric Oxide Releasing Contact Lens Gels for the Treatment of Microbial Keratitis; 2019 – cited in the IDS filed on 06/12/2024) in view of Zhang (Copper ferrite heterojunction coatings empower polyetheretherketone implant with multi-modal bactericidal functions and boosted osteogenicity through synergistic photo/Fenton-therapy; 2021 – cited in the IDS filed on 06/12/2024).
Aveyard’s general disclosure is related to a nitric oxide releasing contact lens gel displaying broad spectrum antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus (see, e.g., Aveyard, abstract). Moreover, Aveyard discloses “The contact lens gel is composed of poly-ε-lysine (pεK) functionalized with nitric oxide (NO) releasing diazeniumdiolate moieties which enables the controlled and sustained release of bactericidal concentrations of NO at physiological pH over a period of 15 h. Diazeniumdiolate functionalization was confirmed by Fourier transform infrared (FTIR), and the concentration of NO released from the gels was determined by chemiluminescence. The bactericidal efficacy of the gels against Pseudomonas aeruginosa and Staphylococcus aureus was ascertained, and between 1 and 4 log reductions in bacterial populations were observed over 24 h. Additional cell cytotoxicity studies with human corneal epithelial cells (hCE-T) also demonstrated that the contact lens gels were not cytotoxic, suggesting that the developed technology could be a viable alternative treatment for microbial keratitis” (see, e.g., Aveyard, abstract).
Regarding claims 1-2, 7-8, 13-14 and 16 pertaining to an ocular composition and a pharmaceutically acceptable ocular carrier, Aveyard teaches synthesis of poly ε lysine contact lens hydrogels (see, e.g., Aveyard, Section 2.1, pg. 37492). Poly ε lysine inherently is a naturally occurring poly(amino acid) that possesses antimicrobial activity (see, e.g., Wang, “Epsilon-poly-L-lysine: Recent Advances in Biomanufacturing and Applications” – Art of Record). One of ordinary skill in the art would readily understand that that poly ε lysine hydrogel contact lens is a soft contact lens.
Regarding claim 18 pertaining to an ocular infection, Aveyard teaches treatment of ocular infections caused by Staphylococcus aureus and Pseudomonas aeruginosa (see, e.g., Aveyard, abstract & Section 2.4, pg. 37493).
However, Aveyard does not teach: one or more photoactive heterojunction materials (claims 1 and 16); or wherein the one or more photoactive heterojunction material is Graphene oxide/copper ferrite nanoparticles (Go/CFN) (claim 6); or wherein the amount of photoactive material incorporated into the hydrogel range from about 50 pg to about 250 pg (claim 12);
Zhang’s general disclosure relates to “a photo-activated copper ferrite (CuFe2O4) heterojunction coating on bioinert polyetheretherketone (PEEK) implant through hydrothermal treatment and π-π-π stacking. The heterojunction coatings not only generate localized hyperthermia and ROS upon 808 nm NIR illumination, but also trigger Fenton(-like) reaction and glutathione (GSH) depletion in bacterial infectious microenvironment (IME), all leading to robust and cyclic antibacterial property through synergistic photothermal/photodynamic/ chemodynamic therapy” (see, e.g., Zhang, abstract).
Regarding claims 1, 6, and 16 pertaining to a photoactive heterojunction material, Zhang teaches synthesis of copper ferrite/graphene oxide heterojunctions (see, e.g., Zhang, Section 2.1, pgs. 2-3).
Regarding claim 12 pertaining to the amount of photoactive material, Zhang teaches “50 μL of 1 g/L CuFe2O4/GO powders suspension was incorporated into the PDA-decorated SP (SP-P) surface” (see, e.g., Zhang, Section 2.2, pg. 3), which one of ordinary skill in the art would know calculates out to 50 μg of CuFe2O4/GO functionalized on the SP-P surface.
Regarding claim 16 pertaining to NIR, Zhang teaches exposure of the SP-P-CFN/GO sample to 808 nm NIR light (see, e.g., Zhang, Section 2.4, pg. 3).
Regarding claim 17 regarding to NIR, Zhang teaches “The release of Cu and Fe ions from SP-P-CFN/GO were detected under different pH value with/without NIR light through the inductive coupled plasma emission spectrometer (ICP-AES, VG PQExCell, TJA, USA). The UV–vis-NIR absorption spectra of samples were measured by a UV–vis-NIR diffuse reflectance spectrometer (UV–vis-NIR, UV-3600, Shimadzu, Japan)” (see, e.g., Zhang, Section 2.3, pg. 3). Moreover, Zhang teaches exposure of the surface at 808 nm NIR light, wherein NIR laser with different powers as used (0.5, 1, 1.5 W/cm2) for 10 min (see, e.g., Zhang, section 2.4, pg. 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Aveyard’s poly ε lysine contact hydrogel composition, wherein the composition comprises copper ferrite/graphene oxide heterojunctions, as taught by Zhang. One would have been motivated to do so because Zhang teaches that for graphene oxide/copper ferrite heterojunctions, “the cycling between the two redox pairs of Fe(III)/Fe(II) and Cu(II)/Cu(I) in CuFe2O4 heterojunctions can continuously catalyze H2O2 to generate germicidal ⋅OH through Fenton(-like) reactions in IME [22,25,42]. NIR illumination not only provide photothermal and photodynamic effect, but also significantly improves the liberation of Cu and Fe ions, which facilitate the tissue regeneration and osteogenesis (Scheme 1). The multiple cooperative antibacterial modalities of PDT/PTT/CDT will lead to greater antibacterial efficacy and cyclic disinfection” (see, e.g., Zhang, Introduction, pg. 2). Moreover, Aveyard teaches that poly ε lysine contact lens gels can be used for the controlled and sustained release of drugs directly to the eye in order to treat microbial keratitis (see, e.g., Aveyard, Introduction, pg. 37492). Additionally, Aveyard teaches that poly ε lysine hydrogels have antimicrobial properties against S. aureus and P. aeruginosa on their own (see, e.g., Aveyard, Figure 5). Therefore, based on the teachings of Aveyard, and Zhang, it would have been obvious to produce a composition comprising a graphene oxide/copper ferrite in an ocular carrier, such as a poly ε lysine hydrogel because each of the individual components exhibit antimicrobial activity against pathogens that cause ocular infections. Additionally, since a graphene oxide/copper ferrite and poly ε lysine hydrogel both exhibit antimicrobial activity against pathogens that cause ocular infections, these two compositions are art recognized equivalents for the same purpose, which are used to produce a third composition to be used for the very same purpose (In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980); therefore, it is obvious to combine the two compositions to make a third composition for treatment of ocular infections. One would have expected success because Aveyard and Zhang all teach the treatment of infections.
Regarding claim 17’s distance and/or duration limitations, those working in the biological and/or pharmaceutical arts would understand that the adjustments of particular conventional working conditions (e.g., times, distances, amounts, etc.) is deemed a matter of judicious selection and routine optimization, which is within the purview of the skilled artisan (see, e.g., MPEP 2144.05). For example, Zhang teaches exposure of the graphene oxide/copper ferrite heterojunction surface for 10 min (see, e.g., Zhang, section 2.4, pg. 3). Additionally, Zhang teaches “The heterojunction coatings not only generate localized hyperthermia and ROS upon 808 nm NIR illumination, but also trigger Fenton(-like) reaction and glutathione (GSH) depletion in bacterial infectious microenvironment (IME), all leading to robust and cyclic antibacterial property through synergistic photothermal/photodynamic/chemodynamic therapy” (see, e.g., Zhang, abstract). This is motivation for someone of ordinary skill in the art to practice or test the parameter widely to find those that are functional or optimal which then would be inclusive or cover the steps as instantly claimed. Absent any teaching of criticality by the Applicant concerning the distance and/or duration of NIR treatment, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are result effective variables which can be met as a matter of routine optimization.
Regarding claim 20 pertaining to part (b), this is considered an inherent outcome that would result by contacting the eye with the claimed composition and NIR. Moreover, Aveyard and Zhang teach the instantly claimed invention; therefore, contacting an eye with the composition taught by Aveyard and Zhang would inherently lead to a production in reactive oxygen species in an effective amount to inhibit bacterial growth and/or promote bacterial cell death. Therefore, this limitation is rendered obvious by the teachings of Aveyard and Zhang.
Claims 3-4 is rejected under 35 U.S.C. 103 as being unpatentable over Aveyard and Zhang as applied to claims 1-2, 6-8, 12-14, 16-18, and 20 above, and further in view of Deng (Rapid sterilisation and diabetic cutaneous regeneration using cascade bio-heterojunctions through glucose oxidase-primed therapy; 2022 – cited in the IDS filed on 06/12/2024).
The teachings of Aveyard and Zhang, herein referred to as modified-Aveyard-Zhang, are discussed above as it pertains to a composition comprising a photoactive heterojunction material an ocular carrier.
However, modified-Aveyard-Zhang does not teach: wherein the enzyme capable of generating ROS upon contact with eye tears is glucose oxidase and/or lactate oxidase (claim 3); or wherein the enzyme is glucose oxidase (claim 4).
Deng’s general disclosure relates to the development of a “photo-activated cascade bio-heterojunctions (C-bio-HJs) for rapid sterilization and diabetic cutaneous regeneration. In the designed C-bio-HJs, photo-generated electron-hole pairs of graphite-phase carbon nitride (g-C3N4) are effectively separated with the marriage of molybdenum disulfide (MoS2), which achieves the augmented photodynamic antibacterial effect. Moreover, glucose oxidase (GOx) tethered on the bio-HJs catalyzes glucose into hydrogen peroxide (H2O2) in diabetic wounds for starvation therapy. Furthermore, Mo4+ enables the catalysis of H2O2 into a highly effective hydroxyl radical (⋅OH) for chemodynamic-photothermal combined antibacterial therapy. Both in vitro and in vivo results authenticate the cascading antibacterial properties and skin regeneration-promoting effects of the C-bio-HJs, which provide a facile strategy to combat diabetic wound healing through the synergistic GOx-primed dynamic therapies” (see, e.g., Deng, abstract).
Regarding claims 3-4 pertaining to glucose oxidase, Deng teaches glucose oxidase in the bio-heterojunction material in order to catalyze glycose into hydrogen peroxide in wounds for starvation therapy (see, e.g., Deng, abstract). Moreover, Deng teaches “when GOx is used in combination with photosensitive materials or Fenton-like reagents, the generated H2O2 could be further catalyzed into highly germicidal ROS, leading to an excellent cascade and synergistic antibacterial effect” (see, e.g., Deng, Introduction, pg. 749).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Aveyard-Zhang’s poly ε lysine and copper ferrite/graphene oxide heterojunction contact hydrogel composition, wherein the composition comprises glucose oxidase, as taught by Deng. One would have been motivated to do so because Deng teaches “Glucose oxidase (GOx), an endogenous oxidoreductase enzyme in organisms, can catalyze glucose into gluconic acid and H2O2, which enables the rapid glucose consumption at the infection site [45,46]. Moreover, when GOx is used in combination with photosensitive materials or Fenton-like reagents, the generated H2O2 could be further catalyzed into highly germicidal ROS, leading to an excellent cascade and synergistic antibacterial effect [47,48]. Therefore, the combination of GOx with other therapies such as PTT, PDT, or CDT could further elevate the antibacterial effect and enrich the strategy of antibacterial therapy” (see, e.g., Deng, Introduction, pg. 749). Furthermore, modified-Aveyard-Zhang teaches that for graphene oxide/copper ferrite heterojunctions, “the cycling between the two redox pairs of Fe(III)/Fe(II) and Cu(II)/Cu(I) in CuFe2O4 heterojunctions can continuously catalyze H2O2 to generate germicidal ⋅OH through Fenton(-like) reactions in IME [22,25,42]. NIR illumination not only provide photothermal and photodynamic effect, but also significantly improves the liberation of Cu and Fe ions, which facilitate the tissue regeneration and osteogenesis (Scheme 1). The multiple cooperative antibacterial modalities of PDT/PTT/CDT will lead to greater antibacterial efficacy and cyclic disinfection” (see, e.g., Zhang, Introduction, pg. 2). Moreover, modified-Aveyard-Zhang teaches that poly ε lysine contact lens gels can be used for the controlled and sustained release of drugs directly to the eye in order to treat microbial keratitis (see, e.g., Aveyard, Introduction, pg. 37492). Additionally, modified-Aveyard-Zhang teaches that poly ε lysine hydrogels have antimicrobial properties against S. aureus and P. aeruginosa on their own (see, e.g., Aveyard, Figure 5). Therefore, based on the teachings of modified-Aveyard-Zhang and Zhang, it would have been obvious to produce a composition comprising a graphene oxide/copper ferrite and glucose oxidase in an ocular carrier, such as a poly ε lysine hydrogel because each of the individual components exhibit antimicrobial activity against pathogens that cause ocular infections. One would have expected success because modified-Aveyard-Zhang and Deng all teach the treatment of infections.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Aveyard and Zhang as applied to claims 1-2, 6-8, 12-14, 16-18, and 20 above, and further in view of Bari (L-lactate generates hydrogen peroxide in purified rat liver mitochondria due to the putative L-lactate oxidase localized in the intermembrane space; 2010) and Dokwal (Tear Lactate Levels as a Surrogate Marker of Oxidative Stress in Myopia: A Case-control Study; 2022).
The teachings of Aveyard and Zhang, herein referred to as modified-Aveyard-Zhang, are discussed above as it pertains to a composition comprising a photoactive heterojunction material an ocular carrier.
However, modified-Aveyard-Zhang does not teach: wherein the enzyme is lactate oxidase (claim 5).
Bari’s general disclosure relates to “H2O2 generation in rat liver mitochondria and in submitochondrial fractions free of peroxisomal and cytosolic contamination. We found that H2O2 is produced independently on the respiratory chain with 1:1 stoichiometry with pyruvate, due to a putative flavine-dependent L-lactate oxidase restricted to the intermembrane space. The L-lactate oxidase reaction shows a hyperbolic dependence on L-lactate concentration and is inhibited by NAD+ in a competitive manner, being the enzyme different from the L-lactate dehydrogenase isoenzymes as shown by their pH profiles” (see, e.g., Bari, abstract).
Regarding claim 5 pertaining to lactate oxidase, Bari teaches that lactate can generate H2O2 via “a putative flavine-dependent L-lactate oxidase restricted to the intermembrane space” of the mitochondria (see, e.g., Bari, abstract & Introduction, pg. 2285). Furthermore, Bari teaches that H2O2 is a reactive oxygen species that is important in redox signaling (see, e.g., Bari, Introduction, pg. 2285).
Dokwal’s general disclosure relates to studying lactate levels in tears in various degrees of myopia (see, e.g., Dokwal, abstract). Moreover, Dokwal discloses that “Oxygen deficit due to environmental stress leads to increase in anaerobic glycolysis which results in lactate production. Increase in Reactive Oxygen Species (ROS) and inability of defense system to eliminate them is also responsible for alteration of regulatory pathways” (see, e.g., Dokwal, abstract). Furthermore, Dokwal discloses that “Increase in the level of lactate in tear was directly proportional to the degree of myopia. Tear lactate levels can be used as a non invasive method to study oxidative stress in individuals” (see, e.g., Dokwal, abstract).
Regarding claim 5 pertaining to lactate oxidase and enzyme(s) generating ROS in tears, Dokwal teaches that “Elevated levels of lactate and pyruvate along with the decreased activity of the antioxidant system in the tear were found in a study, which concluded that lactate is an important biomarker to monitor due to its reflectiveness of the current status of the underlying oxidative stress [9]” (see, e.g., Dokwal, Introduction, pg. 8). Moreover, Dokwal teaches “Lactate in tears was increased in the various degree of myopia patients as compared to the controls” (see, e.g., Dokwal, Conclusions, pg. 11).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Aveyard-Zhang’s ocular composition comprising a photoactive heterojunction material and an ocular carrier, wherein the composition further comprises lactate oxidase, as taught by Bari and Dokwal. One would have been motivated to do so because Dokwal teaches that tears comprise lactate, and lactate levels can be used as a non-invasive method to study oxidative stress in tears (see, e.g., Dokwal, abstract). Moreover, Bari teaches that lactate can generate hydrogen peroxide, which is a reactive oxygen species, via lactate oxidase (see, e.g., Bari, abstract). Moreover, modified-Aveyard-Zhang teaches that hydrogen peroxide can generate germicidal ROS leading to an antibacterial effect (see, e.g., Deng, Introduction, pg. 749 & Zhang, Introduction, pg. 2). Therefore, based on the teachings of modified-Aveyard-Zhang, Bari, and Dorkal, one would have been motivated to produce comprising a photoactive heterojunction material, lactate oxidase, and an ocular carrier in order to produce hydrogen peroxide for downstream production of germicidal ROS leading to an antibacterial effect. One would have expected success because modified-Aveyard-Zhang, Bari, and Dorkal all teach production of ROS and oxidative stress.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Aveyard and Zhang as applied to claims 1-2, 6-8, 12-14, 16-18, and 20 above, and further in view of McCloskey (Ultrashort self-assembling Fmoc-peptide gelators for anti-infective biomaterial applications; 2017 – cited in the IDS filed on 06/12/2024).
The teachings of Aveyard and Zhang, herein referred to as modified-Aveyard-Zhang, are discussed above as it pertains to a composition comprising a photoactive heterojunction material an ocular carrier.
However, modified-Aveyard-Zhang does not teach: wherein the hydrogel is made from an Fmoc-capped peptide, such as Fmoc-diphenylalanine (FmocFF) (claim 9).
McCloskey’s general disclosure relates to studying the effect of “ increasing the cationicity of FmocFF via addition of di-lysine and di-orntithine” with regard to antibacterial activity (see, e.g., McCloskey, abstract). Furthermore, McCloskey discloses “Our studies demonstrated that Fmoc-peptides (FmocFF, FmocFFKK, FmocFFFKK, FmocFFOO) formed surfactant-like soft gels at concentrations of 1% w/v and above using a method of glucono-δ-Lactone pH induction. The majority of Fmoc-peptides (0.5-2% w/v) demonstrated selective action against established (grown for 24 h) biofilms of Gram-positive and Gram-negative pathogens” (see, e.g., McCloskey, abstract).
Regarding claim 9 pertaining to the Fmoc-capped peptide, McCloskey teaches Fmoc-peptide hydrogels produced from FmocFF, FmocFFKK, FmocFFFKK, and FmocFFOO (see, e.g., McCloskey, Materials and Methods & Figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Aveyard-Zhang’s ocular composition comprising a photoactive heterojunction material and an ocular carrier, wherein the ocular carrier is a hydrogel made from an Fmoc-capped peptide, as taught by McCloskey. One would have been motivated to do so because McCloskey teaches “Fmoc conjugated hydrogels demonstrated broad-spectrum antibiofilm activity with FmocFF in particular displaying significant activity against all pathogens at all concentrations tested (0.5–2%w/v) relative to the negative PBS control” (see, e.g., McCloskey, “Biofilm susceptibility”, pg. 135). Additionally, McCloskey teaches “FmocFFOO demonstrated significant reduction against only Gram-positive staphylococcal species at 2% w/v (Figures 5 andS1). Only FmocFF showed significant reduction in biofilm viability for all isolates at 0.5% w/v. Incubation with 2% w/v FmocFF resulted in significant mean viable biofilm reduction values of greater than90% for all pathogens (93% S. aureus [Figure 5], 97% E. coli [Figure 6] and 92% for P. aeruginosa [Figure S2])” (see, e.g., McCloskey, “Biofilm susceptibility”, pg. 137). Moreover, poly ε lysine contact lens gels can be used for the controlled and sustained release of drugs directly to the eye in order to treat microbial keratitis (see, e.g., Aveyard, Introduction, pg. 37492). Additionally, modified-Aveyard-Zhang teaches that poly ε lysine hydrogels have antimicrobial properties against S. aureus and P. aeruginosa on their own (see, e.g., Aveyard, Figure 5). Therefore, based on the teaching of modified-Aveyard-Zhang and McCloskey, it would have been obvious to produce a poly ε lysine hydrogel, wherein the hydrogel is made of Fmoc-capped peptides because both the poly ε lysine hydrogel and Fmoc-capped peptides exhibit antimicrobial properties against various microorganisms. One would have expected success because modified-Aveyard-Zhang and McCloskey both teach hydrogels with antimicrobial properties against microorganisms.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Aveyard and Zhang as applied to claims 1-2, 6-8, 12-14, 16-18, and 20 above, and further in view of Park (WO 2012/060544; Date of Publication: May 10, 2012).
The teachings of Aveyard and Zhang, herein referred to as modified-Aveyard-Zhang, are discussed above as it pertains to a composition comprising a photoactive heterojunction material an ocular carrier.
Regarding claim 11 pertaining to the structure, modified-Aveyard-Zhang teaches the structure for poly ε lysine, which is the top left part of the structure in claim 11 (see, e.g., Aveyard, Figure 1A). Furthermore, modified-Aveyard-Zhang teaches that n is 4 (see, e.g., Aveyard, Figure 1A).
However, modified-Aveyard-Deng-Zhang does not teach: the claimed constitutional unit bound to poly ε lysine (claim 11); or wherein m is any natural number of 50 to 70 (claim 11).
Park’s general disclosure relates to a method “immobilizing a bioactive molecule onto a surface using polyphenol oxidase” (see, e.g., Park, abstract). Moreover, Park discloses “Based on the surface immobilization of bioactive molecules using polyphenol oxidase, various bioactive molecules such as osteogenetic peptides and growth factors can be simply immobilized to medical metal or polymer substrate surfaces such as orthopedic or dental implants which can be then effectively used to induce rapid osteogenesis after being transplanted. Also, antithrombotic agents and/or endothelialization inducing agents may be immobilized to medical substrates for vascular systems, such as stents and artificial blood vessels, thus guaranteeing hemocompatibility to the medical substrates” (see, e.g., Park, abstract).
Regarding claim 11 pertaining to the constitutional unit, Park teaches in Figure 4 two tyramine (TA) molecules bound to polyethylene glycol (PEG) (see, e.g., Park, Figure 4). Furthermore, Park teaches m is 112-113 (see, e.g., Park, Figure 5).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Aveyard-Zhang’s ocular composition comprising a photoactive heterojunction material and an ocular carrier which is a hydrogel, wherein the hydrogel is a poly ε lysine based hydrogel with polyethylene glycol (PEG) and tyramine (TA), as taught by Park. One would have been motivated to do so because Park teaches that PEG is a hydrophilic polymer linker and TA is a phenol derivative (see, e.g., Park, [52], [55]). Moreover, PEG-TA can be used to immobilize a bioactive molecule onto a metal or polymer surface (see, e.g., Park, [66]). Moreover, modified-Aveyard-Zhang teaches a poly ε lysine hydrogel with a photoactive heterojunction material and ROS generating enzyme (see, e.g., Aveyard, Deng, Zhang – abstracts). Therefore, based on the teachings of modified-Aveyard-Zhang and Park it would have been obvious to produce a poly ε lysine based hydrogel with polyethylene glycol (PEG) and tyramine (TA) in order to immobilize bioactive onto the surface of the hydrogel. One would have expected success because modified-Aveyard-Zhang and Park all teach production of bioactive compositions for medical therapies and uses.
Regarding claim 11’s “n” and “m” values, those working in the biological and/or pharmaceutical arts would understand that the adjustments of particular conventional working conditions (e.g., times, distances, amounts, etc.) is deemed a matter of judicious selection and routine optimization, which is within the purview of the skilled artisan (see, e.g., MPEP 2144.05). For example, modified-Aveyard-Zhang teaches that n is 4 (see, e.g., Aveyard, Figure 1A) and Park teaches m is 112-113 (see, e.g., Park, Figure 5). Moreover, one of ordinary skill in the art would readily understand that increasing the m and v values would increase the size of the molecule. This is motivation for someone of ordinary skill in the art to practice or test the parameter widely to find those that are functional or optimal which then would be inclusive or cover the steps as instantly claimed. Absent any teaching of criticality by the Applicant concerning the m and n values, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are result effective variables which can be met as a matter of routine optimization.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Aveyard and Zhang as applied to claims 1-2, 6-8, 12-14, 16-18, and 20 above, and further in view of Zidan (Medicated ocular bandages and corneal health: potential excipients and active pharmaceutical ingredients; 2017 – cited in the IDS filed on 06/12/2024).
The teachings of Aveyard and Zhang, herein referred to as modified-Aveyard-Zhang, are discussed above as it pertains to a composition comprising a photoactive heterojunction material an ocular carrier.
However, modified-Aveyard-Zhang does not teach: a soft contact lens comprising crosslinked hydrogels including N-Vinylpyrrolidone (claim 15).
Zidan’s general disclosure relates to a review highlighting “materials and therapeutics that can be used in medicated ocular bandages and various ways of incorporating drugs, while discussing the limitations and challenges associated with bringing medicated ocular bandages in the market” (see, e.g., Zidan, abstract).
Regarding claim 15 pertaining to hydrophilic monomers, Zidan teaches that the hydrogel is copolymerized with a hydrophobic monomer such as N-Vinylpyrrolidone (see, e.g., Zidan, Section 2.2.3, pg. 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Aveyard-Zhang’s ocular composition comprising a photoactive heterojunction material, an enzyme capable of generating ROS upon contact with tears, and an ocular carrier which is a hydrogel, wherein the hydrogel is crosslinked with N-Vinylpyrrolidone, as taught by Zidan. One would have been motivated to do so because Zidan teaches hydrogel lenses are composed of a hydrogel phase that consists of a hydrophobic monomer, such as N-Vinylpyrrolidone, wherein the hydrogel phase “increases the lens wettability which is essential for comfort, adequate lens movement, and sufficient ion transfer. Silicone hydrogel contact lenses can be used to deliver ophthalmic drugs to the eye with controlled release of medication from 20 days up to more than 3 months depending on the ratio between the hydrophobic and hydrophilic components” (see, e.g., Zidan, Section 2.2.3, pg. 2). Moreover, modified-Aveyard-Zhang teaches a poly ε lysine hydrogel comprising a photoactive heterojunction material and an ROS-producing enzyme (see, e.g., Aveyard, Section 2.1, pg. 37492 & Deng, abstract & Zhang, abstract). Therefore, based on the teachings of modified-Aveyard-Zhang and Zidan, it would have been obvious to produce a ocular hydrogel contact lens composition comprising N-Vinylpyrrolidone because this would increase lens wettability which is essential for comfort, adequate lens movement, and sufficient ion transfer. Moreover, one would have expected success because modified-Aveyard-Zhang and Zidan both teach production of hydrogels and contact lens hydrogels.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Aveyard and Zhang as applied to claims 1-2, 6-8, 12-14, 16-18, and 20 above, and further in view of Breidenstein (Pseudomonas aeruginosa: all roads lead to resistance; 2011 – cited in the IDS filed on 06/12/2024) and Weiner (MRSA Ophthalmic Infection, Part 1: Current Realities; 2013).
The teachings of Aveyard and Zhang, herein referred to as modified-Aveyard-Zhang, are discussed above as it pertains to a composition comprising a photoactive heterojunction material an ocular carrier.
Regarding claim 19 pertaining to S. aureus and P. aeruginosa, modified-Aveyard-Zhang teaches a contact lens gel composed of poly-ε-lysine functionalized with nitric oxide that exhibits bactericidal efficacy against Pseudomonas aeruginosa and Staphylococcus aureus (see, e.g., Aveyard, abstract).
However, modified-Aveyard-Zhang does not teach: methicillin-resistant Staphylococcus aureus and multi-drug resistant Pseudomonas aeruginosa (claim 19).
Breidenstein’s general disclosure relates to a review of P. aeruginosa, which is an opportunistic pathogen, becoming a superbug due to resistance to practically all antimicrobial drugs on the market (see, e.g., Breidenstein, “Pseudomonas aeruginosa as a superbug”, pg. 419).
Regarding claim 19 pertaining to multi-drug resistant Pseudomonas aeruginosa, Breidenstein teaches infection caused by multi-drug resistant P. aeruginosa, wherein “Compared with other pathogens, P. aeruginosa is very difficult to eradicate as it displays high intrinsic resistance to a wide variety of antibiotics, including aminoglycosides, fluoroquinolones and β-lactams. This is largely because of the low permeability of its outer membrane [4], which limits the rate of penetration of antibiotic molecules into the cells due to the inefficient porins in this bacterium. This then enables secondary adaptive resistance mechanisms to work more efficiently, including increased efflux and enzymatic antibiotic modifications (e.g. β-lactamase)” (see, e.g., Breidenstein, “Pseudomonas aeruginosa as a superbug”, pg. 419).
Weiner’s general disclosure relates to ophthalmic infections caused by methicillin-resistant S. aureus (MRSA), wherein “MRSA now accounts for more than 30 percent of all serious S. aureus ocular infections, and the incidence is rising annually” (see, e.g., Weiner, pg. 33). Furthermore, Weiner discloses “Furthermore, over 80 percent of MRSA strains are resistant to all fluoroquinolones, a class of antibiotics that has been a mainstay in ophthalmology for the past two decades” (see, e.g., Weiner, pg. 33).
Regarding claim 19 pertaining to MRSA infections, Weiner teaches MRSA infections cause ophthalmic infections and are increasing in prevalence (see, e.g., Weiner, pg. 33). Furthermore, Weiner teaches that “Although earlier studies reported conjunctivitis as the most common ophthalmic manifestation of MRSA, the Dallas study found that preseptal cellulitis was the most common presentation from 2000 to 2009,4,5 followed by conjunctivitis, corneal ulcer, endophthalmitis, and orbital cellulitis” (see, e.g., Weiner, “Possible different manifestations”, pg. 34).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Aveyard-Zhang’s ocular composition comprising a photoactive heterojunction material, an enzyme capable of generating ROS upon contact with tears, and an ocular carrier which is a hydrogel, wherein the composition is used to treat ocular infections caused by MRSA and multi-drug resistant P. aeruginosa, as taught by Breidenstein and Weiner. One would have been motivated to do so because Breidenstein teaches of P. aeruginosa is becoming a superbug due to resistance to practically all antimicrobial drugs on the market (see, e.g., Breidenstein, “Pseudomonas aeruginosa as a superbug”, pg. 419). Additionally, Weiner teaches MRSA infections cause ophthalmic infections and are increasing in prevalence (see, e.g., Weiner, pg. 33). Moreover, modified-Aveyard-Zhang teach that Poly ε lysine inherently is a naturally occurring poly(amino acid) that possesses antimicrobial activity (see, e.g., Wang, “Epsilon-poly-L-lysine: Recent Advances in Biomanufacturing and Applications” – Art of Record). Furthermore, modified-Aveyard-Zhang teach that for graphene oxide/copper ferrite heterojunctions, “the cycling between the two redox pairs of Fe(III)/Fe(II) and Cu(II)/Cu(I) in CuFe2O4 heterojunctions can continuously catalyze H2O2 to generate germicidal ⋅OH through Fenton(-like) reactions in IME [22,25,42]. NIR illumination not only provide photothermal and photodynamic effect, but also significantly improves the liberation of Cu and Fe ions, which facilitate the tissue regeneration and osteogenesis (Scheme 1). The multiple cooperative antibacterial modalities of PDT/PTT/CDT will lead to greater antibacterial efficacy and cyclic disinfection” (see, e.g., Zhang, Introduction, pg. 2). Therefore, based on the teachings of modified-Aveyard-Zhang, Breidenstein, and Weiner, it would have been obvious to treat MRSA and multi-drug resistant P. aeruginosa infections with the composition taught by modified-Aveyard-Zhang because each individual component of the composition exhibits antimicrobial properties against microorganisms, and MRSA and multi-drug resistant P. aeruginosa are prevalent antibiotic resistant microorganisms; therefore, alternative treatments are needed. One would have expected success because modified-Aveyard-Zhang, Breidenstein, and Weiner all teach treatment of infections.
Art of Record
Wang L, Zhang C, Zhang J, Rao Z, Xu X, Mao Z, Chen X. Epsilon-poly-L-lysine: Recent Advances in Biomanufacturing and Applications. Front Bioeng Biotechnol. 2021 Sep 28;9:748976. doi: 10.3389/fbioe.2021.748976. PMID: 34650962; PMCID: PMC8506220.
Conclusion
Claims 1-20 are rejected.
No claims are allowed.
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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