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 41-68 are pending in the instant application.
Claims 41, 42, 45-47, 49-55 and 61-68 are presented for examination.
The amendments and remarks filed on 12/03/2025 have been received and entered.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/03/2025 has been 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 “expression of a polypeptide in a mammalian subject”. Such phrase fails to set forth either a composition or method of use intended. There is no specific method of use claimed in the instant application. The phrase “A method for expression of a polypeptide in a mammal” fails to set forth the intended meaning.
The claims depending on claim 41are also rejected since thy have all the limitations of claim 41.
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 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.
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 n 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 (I,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- (I'-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. ln 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]. I t would have been obvious toa person skilled in the art to use the composition of Chevessier 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 toa 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. 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. Calias also teaches that the lipids can be used individually or in combination.
Response to Arguments
Applicant in his response argues that “Campochiaro teaches that their methods of administration to the SCS using PBAE nanoparticles provide the advantage of delivery to the retina while minimizing delivery to anterior structure of the eye. See Campochiaro at col. 6, lines 27-29. In the prosecution history of the application that matured into the Campochiaro patent, the inventors stated that the PBAE used exhibits profound differences in activity for retinal gene delivery. They also demonstrated that naked DNA was unable to be transfected into cells following SCS administration”. The examiner has relied on Taraborelli et al. to show that the administration of RNA by suprachoroidal administration treats corneal ulcer, which is the disease of anterior section of the eye. Although, Campochiaro and Taraborelli teach less amounts of nucleic acid is transported to the anterior part of the eye, the “less amount” reads on the presence of expression of a polypeptide in the anterior section of the eye. Applicant further in his remarks further argues that “Declaration of Dr. Patrick Baumhof submitted herewith. The Declaration states that an experiment has been performed to investigate protein expression in different eye cells after administration of RNA into different compartments of the eye. For this purpose, rabbits were injected with 10 pg. of LNP formulated RNA encoding for luciferase via intravitreal, subretinal, and suprachoroidal administration. Six hours post administration, rabbits were terminated, and the eye compartments dissected. Cell lysates of the different eye compartments were analyzed for luciferase activity on a plate reader, essentially as described in Example 2 of the application as-filed. The results of the experiment are shown in Exhibit B of the Declaration. For each compartment, the left-hand column depicts protein expression (luciferase signal) after intravitreal administration, the middle column after subretinal administration, and the right-hand column belongs to protein expression after suprachoroidal administration (additionally indicated by arrows).
Suprachoroidal administration of LNP formulated mRNA not only proved to be superior for expression in the posterior compartment of the eye, such as retina, RPE/choroid, and sclera, but as well in the anterior compartment, including the cornea, conjunctiva, lens, and iris/ciliary body. Suprachoroidal administration of LNP formulated mRNA leads to unexpectedly high protein expression in anterior as well as posterior compartments of the eye, including expression of large proteins”. The examiner directs applicant’s attention to Para [0051] of Taraborelli, which teaches the intraocular C.sub.max of the nucleic acid, when delivered via the methods described here, is greater than the intraocular C.sub.max of the nucleic acid when the same nucleic acid dose is administered intravitreally, intracamerally, topically, parenterally or orally. In a further embodiment, the intraocular C.sub.max of the nucleic acid when administered via the non-surgical SCS nucleic acid delivery methods provided here, is at least 1.1 times greater, or at least 1.25 times greater, or at least 1.5 times greater, or at least 2 times greater, or at least 5 times greater, than the intraocular C.sub.max of the nucleic acid when the identical dose is administered topically, intracamerally, intravitreally, orally or parenterally. In one embodiment, the intraocular C.sub.max of the nucleic acid when administered via the non-surgical SCS nucleic acid delivery methods provided here, is about 1 to about 2 times greater, or about 1.25 to about 2 times greater, or about 1 to about 5 times greater, or about 1 to about 10 times greater, or about 2 to about 5 times greater, or about 2 to about 10 times greater, than the intraocular C.sub.max of the nucleic acid when the identical dose is administered topically, intracamerally, intravitreally, orally or parenterally. Therefore, the higher amounts of intraocular nucleotide by suprachoroidal administration than any other route of administration is taught by Taraborelli et al. The advantage of suprachoroidal administration as presented in the declaration is taught by Taraborelli et al.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sue Liu can be reached at 571-272-5539. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ZOHREH A FAY/Primary Examiner, Art Unit 1617