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 .
Claims 41-43, 45-47, 49-55 and 61-68 are presented for examination.
The amendments and remarks filed on 06/16/2026 have been received and entered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 41 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 41 is indefinite as to the phrase “expressing a therapeutic protein in anterior and posterior compartments of an eye of a mammalian subject”. Such phrase is not directed to a specific disorder. The method is directed to the expression of a protein in the anterior or posterior part of the eye, without any established correlation between such expression and treatment of ophthalmic disorders in the anterior and posterior part of the art.
Claims dependent on claim 41 are also rejected, since they have all the limitations of the rejected claim.
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.
Claim(s) 41-43, 45-47, 49-55 and 61-68 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chevessier et al. (WO 2018172556) in view of Baumhof (WO 2017212008) and further in view of Campochiaro et al. (US 11,883,541) and further in view of Taraborelli et al. (US 20200316225), Peden et al. (Ab-Externo AAV-Mediated Gene Delivery to the Suprachoroidal Space Using a 250 Micron Flexible Microcatheter) and Calias et al. (WO 2015148247).
Chevessier teaches nucleic acids, in particular RNAs, encoding CRISPR-associated proteins. A pharmaceutical composition and kit-of-parts comprising the same are also taught. The use of the composition in a pharmaceutical composition for the treatment and/or prophylaxis of diseases amenable to treatment with CRISPR-associated proteins. See the abstract. The use of CRISPR/Cas9Q is taught in page 1, lines 12-37. Chevessier teaches that nucleic acid molecule comprising at least one coding region encoding at least one CRISPR -associated protein; b. at least one 5' untranslated region (5' UTR) element derived from a5' UTR of a gene selected from the group consisting of ATP5A1, RPL32, HSD17B4, SLC7A3, NOSIP and NDUFA4; and C. at least one 3' untranslated region (3' UTR) element derived from a 3' UTR of a gene selected from the group consisting of GNAS, CASP1, PSMB3, ALB and RPS9. See page 8 lines 32-37 and claim1. The histone stem loop is taught in claim 20. The 5 cap structure is also taught by Chevessier. See page 11, lines6-20. The pseudouridine is taught to be as one nucleotide analogues. See page 86, lines 5-12. Chevessier teaches that in preferred embodiments, the at least one artificial nucleic acid molecule, preferably RNA, of the invention (or any other nucleic acid as described herein) is provided in a complexed form, i.e. complexed or associated with one or more (poly- )cationic compounds, preferably with (poly-)cationic polymers, (poly-)cationic peptides or proteins, e.g. protamine, (poly-)cationic polysaccharides and/or (poly-)cationic lipids. The nucleic acid molecule, preferably RNA, is complexed with one or more cationic or polycationic compounds, preferably with cationic or polycationic polymers, cationic or polycationic peptides or proteins, e.g. protamine, cationic or polycationic polysaccharides and/or cationic or polycationic lipids. See claim 29. The RNA is complexed with one or more lipids, thereby forming liposomes, lipid nanoparticles and/or lipoplexes. See claim 30. Chevessier teaches that the G/C content of the at least one coding region of the artificial nucleic acid is increased compared to the G/C content of the corresponding coding sequence as claimed in claim 50. See claim 19. Chevessier does not teach the treatment of ophthalmic disorders and the administration of the composition to suprachoroidal space.
Baumhof et al. teach the use of the claimed mRNA in combination with the claimed lipids for the treatment of ophthalmic disorders by intravitreal, intracameral, subconjunctival, subretinal, subtenon, retrobulbar, topical, and/or posterior juxtascleral administration. See Claims. Campochiaro teaches a compositions and methods for administering a nanoparticle or microparticle and a therapeutic agent to the suprachoroidal space in the eye. See the abstract. The therapeutic agent may be a drug, small molecule, nucleic acid sequence, amino acid sequence, gene, transgene, peptide, protein, expression vector, carbohydrate, lipid, sugar, antibody or antibody fragment thereof, hormone, hormone receptor, receptor ligand, or cancer cell specific ligand. See Para (10). The ophthalmic disorders to be treated is taught to be age-related macular degeneration (AMD), neovascular age- related macular degeneration (NVAMD), retinitis pigmentosa (RP), optic neuritis, infection, uveitis, sarcoid, sickle cell disease, retinal detachment, temporal arteritis, retinal ischemia, choroidal ischemia, choroidal ischemia, ischemic optic neuropathy, arteriosclerotic retinopathy, hypertensive retinopathy, retinal artery blockage, retinal vein blockage, glaucoma, hypotension, diabetic retinopathy, diabetic macular edema (DME), macular edema occurring after retinal vein occlusion (RVO), macular edema, and choroidal neovascularization. See Para (13). Campochiaro teaches that wherein the therapeutic agent is selected from the group consisting of DNA, RNA, a peptide, or a protein. See Para (20). Campochiaro further teaches in preferred embodiments, the therapeutic agents may be one or more genes, nucleic acids, expression plasmids, DNA, RNA, siRNA, microRNA, mRNA, cyclic dinucleotides or combinations thereof. See Para (107). The polycationic polymer is taught in para (17). The pharmaceutical acceptable buffers, such as Ringer's solution is taught in Para (122). The use of a needle for injection is taught in para (122). Taraborelli et al. teach a method for administering a nucleic acid to an eye of a mammal. An amount of a formulation is non-surgically administered to the suprachoroidal space (SCS) of an eye of the mammal. See Para [0003]. The treatment of an eye disorder is taught in Para [00017]. Taraborelli et al. teach that an ocular disorder can be treated according to the invention. Such include, without limitation uveitis, glaucoma, macular edema, diabetic macular edema, retinopathy, age-related macular degeneration, scleritis, optic nerve degeneration, geographic atrophy, choroidal disease, ocular sarcoidosis, optic neuritis, choroidal neovascularization, ocular cancer, retinitis pigmentosa, juvenile onset macular degeneration, a genetic disease, autoimmune diseases affecting the posterior segment of the eye, retinitis or corneal ulcers. See Para [0020]. Taraborelli et al. make clear that nucleic acids have been previously used for treating disorders of anterior eye, by suprachoroidal administration. Pedon teaches a method of gene delivery to suprachoroidal space using 250 micron Flexible microcatheter. Pedon teaches the potential use of this technique for the treatment of choroidal angiogenesis. See the entire article.
Calias teaches a method of ocular delivery of messenger RNA (mRNA), comprising administering into an eye of a subject in need of delivery a composition comprising an MRNA encoding a protein, such that the administration of the composition results in expression of the protein encoded by the mRNA in the eye. See the abstract. Calias teaches that the eye disease, disorder or condition is selected from AMD, PU, BRVO, CRVO, DME, CME, UME, CMV retinitis, endophthalmitis, inflammation, glaucoma, macular degeneration, scleritis, chorioretinitis, Dry eye syndrome, Stargardt disease, Norris disease, Coat's disease, persistent hyperplastic primary vitreous, familial exudative vitreoretinopathy, Leber congenital amaurosis, Retinitis Pigmentosa, X-linked retinoschisis, Leber's hereditary optic neuropathy (LHON), and/or uveitis. See Para [0008]. Calias teaches that lipids are selected from DSPC (1,2- distearoyl-sn-glycero-3-phosphocholine), DPPC (1 ,2-dipalmitoyl-sn-glycero-3-phosphocholine), DOPE (I, 2-dioleyl-sn-glycero-3-phosphoethanolamine), DOPC (1,2-dioleyl-sn-glycero-3- phosphatidylcholine) DPPE (|],2-dipalmitoyl-sn-glycero-3-phosphoethanolamine), DMPE (1,2- dimyristoyl-sn-glycero-3-phosphoethanolamine), and DOPG (,2- dioleoyl-s/?-glycero-3-phospho- (l'-rac-glycerol)). See Para [0012]. The use of cationic lipid is taught in Para [0011]. The use of cholesterol based lipid, such as PEGylated cholesterol, is taught in Para [0013]. The use of DSPC of claim 65 is taught in Para [0012]. The use of DMG-PEG and DMA lipid is taught in Para [0010]. Calias teaches that mRNA may be administered naked, or encapsulated within a nanoparticle. Suitable nanoparticle may be lipid or polymer based. In some embodiments, a suitable nanoparticle for mRNA delivery is a liposome. As used herein, the term "liposome" refers to any lamellar, multilamellar, or solid nanoparticle vesicle. Typically, a liposome as used herein can be formed by mixing one or more lipids or by mixing one or more lipids and polymer(s). Thus, the term "liposome" as used herein encompasses both lipid and polymer based nanoparticles. In some embodiments, a liposome suitable for the present invention contains cationic or non-cationic lipid(s), cholesterol-based lipid(s) and PEG-modified lipid(s). See Para [0052]. Calias teaches that as used herein, the phrase "non- cationic lipid" refers to any neutral, zwitterionic or anionic lipid. See Para [0104]. Calias teaches that the compositions and methods of the invention comprise mRNA encapsulated in a liposome. In some embodiments, the one or more mRNA species may be encapsulated in the same liposome. In some embodiments, the one or more mRNA species may be encapsulated in different liposomes. In some embodiments, the mRNA is encapsulated in one or more liposomes, which differ in their lipid composition, molar ratio of lipid components, size, charge (Zeta potential), targeting ligands and/or combinations thereof. In some embodiments, the one or more liposome may have a different composition of cationic lipids, neutral lipid, PEG-modified lipid and/or combinations thereof. In some embodiments the one or more liposomes may have a different molar ratio of cationic lipid, neutral lipid, cholesterol and PEG-modified lipid used to create the liposome. See Para [0114]. The intravitreal injection is taught in Paras [0130] and [0131]. It would have been obvious to a person skilled in the art to use the composition of Chevessier and Baumhof for the treatment of ophthalmic disorders by suprachoroidal space, motivated by the teachings of Campochiaro et al., which teach the use of mRNA in combination with a polycationic polymer as a therapeutic agent for the treatment of the claimed ophthalmic disorders by injection to the suprachoroidal space. Taraborelli makes clear that a nucleic acid composition has been used for treating disorders of anterior section of the eye, such as corneal ulcer by suprachoroidal administration. Pedon teaches the delivery of Gene in general to suprachoroidal space by injection using 250 micron flexible microcatheter. The substitution of one MRNA or a gene for another would have been obvious to a person skilled in the art in the absence of evidence to the contrary. The primary reference teaches the use of the claimed RNA having a therapeutic protein for the treatment of different disorders. Baumhof teaches the combination of claimed RNA and with lipid nanoparticles for treating ophthalmic disorders by intravitreal, intracameral, subconjunctival, subretinal, subtenon, retrobulbar, topical, and/or posterior juxtascleral administration. Campochiaro, Taraborelli and Peden teach that mRNA and genes in general have been previously used for the treatment of ophthalmic disorders by suprachoroidal injection. The addition of the claimed lipids to RNA is taught by Calias et al and Baumhof et al. Calias also teaches that the lipids can be used individually or in combination. Calias teaches the mRNA is administered into the eye by intravitreal, intracameral, subconjunctival, subtenon, retrobulbar, topical, and/or posterior juxtascleral administration. Calias teaches wherein the expression and/or activity of the protein is detected in corneal cells, scleral cells, choroid plexus epithelial cells, ciliary body cells, retinal cells, and/or vitreous humor.
Response to Arguments
Applicant’s arguments have been noted. Applicant in his remarks argues that “The Action's response to the Declaration consists solely of pointing to Taraborelli's CTax data as purportedly teaching the same result. The Action concludes that "the higher amounts of intraocular nucleotide by suprachoroidal administration than any other route of administration is taught by Taraborelli et al." and that "[t]he advantage of suprachoroidal administration as presented in the declaration is taught by Taraborelli et al." Office Action at page 10. This response does not constitute a proper weighing of the Declaration evidence.
The Declaration demonstrates protein expression, a functional biological outcome, in both anterior and posterior compartments following suprachoroidal administration of LNP-formulated mRNA. The Action's response addresses only nucleic acid concentration levels (CTax), which, as argued above, is a fundamentally different and legally insufficient metric. The Action has not explained why the Declaration's protein expression data is outweighed by the CTax pharmacokinetic data in Taraborelli, nor has the Action identified any reference that teaches or predicts the specific dual-compartment protein expression demonstrated in the Declaration”. It is the examiner’s position that since the application does not disclose the treatment of any particular ophthalmic disease using CRISPR-associated nuclease through SCS administration, a functional relationship between the expression of a therapeutic protein in the anterior and posteriors has not been established.
The examples of the present application relate to luciferase expression by SCS administration in healthy animals, i.e. it does not have the feature of treating an ophthalmic disorder.
Luciferase was delivered by intravitreal, subretinal or suprachoroidal injection, and tissue distribution was measured in the cornea, conjunctiva, lens, iris / ciliary body, retina, RPE / choroid and sclera.
Suprachoroidal administration was more or less equal to subretinal administration with regard to the cornea, conjunctiva, retina and sclera, and superior to subretinal administration regarding the lens, iris / ciliary body, and RPE / choroid.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZOHREH A FAY whose telephone number is (703)756-1800. The examiner can normally be reached Monday-Friday 9:30AM-6:00.
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/ZOHREH A FAY/Primary Examiner, Art Unit 1617
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