DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendments to the claims and arguments filed on January 12, 2026 have been received and entered. Claims 1-3, 9-10, 14-18 , 28-29, 34 have been amended, while claims 4, 6-8, 11-12, 19-26, 30-33, have been canceled. Claims 35-38 are newly added. Claims 1-3, 5, 9-10, 13-18, 28-29, 34-37 and 38 are pending in the instant application.
Election/Restrictions
Applicant's election with traverse of claims 1-18, 27 and 28 (group I) in the reply filed on June 24, 2025 was acknowledged.
Applicant further elected the species of species (i) a nucleic acid encoding a polypeptide comprising a constitutively active form of transcription factor EB (TFEB) and (ii) wherein the serine at position 467 of SEQ ID NO:1 is substituted with an alanine.
Regarding Applicant’s election of the species for (ii) was acknowledged, however, upon further consideration, election of specie requirement for (ii) generic for claim 1 was withdrawn and elected species directed to serine at position 467 of SEQ ID NO:1 that is substituted with an alanine (h) is rejoined with all the other non-elected species. The requirement is still deemed proper and is therefore made FINAL.
Claims 29, 32 and 34 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention (rAAV or composition comprising AAV), there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on June 24, 2025.
Priority
This application is a 371 of PCT/US20/21540 filed on 03/06/2020 that claims priority from US provisional application no 62/897,800 filed on 09/09/2019.
Claims 1-3, 5, 9-10, 13-18, 28. 35-37 and 38.
Maintained-Claim Rejections - 35 USC § 112-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.
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 1-18, 27 and 28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A method of restoring lysosomal function of retinal pigment epithelial (RPE) cells in a subject in need thereof, said method comprising intraocular or subretinal administration of an effective amount of AAV vector comprising a nucleic acid encoding a polypeptide comprising a constitutively active form of transcription factor EB (TFEB) to a subject in need thereof , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 1, wherein the serine at position 138, 142, 211, 455 or 467 of SEQ ID NO: 1 is substituted with an alanine and wherein subject has age-related dry macular degeneration (AMD), Stargardt's macular retinal degeneration or a neurodegenerative disease, does not reasonably provide enablement for preventing any condition (or is at risk of developing any disease). 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 and use the invention commensurate in scope with these claims.
Applicant disagree with the rejection and argues that claims have been amended to overcome the rejection of record. Applicant argues that claims are fully enabled for using any AAV serotype and promoter. Applicant continue to argue that Applicant has amended the claims herein to remove treatment/prevention of wet age-related macular degeneration, diabetic retinopathy or neurodegenerative disease. Applicants’ arguments have been fully considered, but are not found persuasive.
As an initial matter, applicant’s response to use of different AAV serotype and promoter is enabling for the entire breadth in moot in view of scope indicated in previous non-final office action. It should be noted that previous office action explicitly stated that instant specification does not enable a method of preventing any condition (or is at risk of developing any disease). The specification provides no guidance on restoring lysosomal function of retinal pigment epithelial (RPE) cells for preventing any condition other than treating a subject having dry AMD or Stargardt's macular retinal degeneration. Ghosh teaches that the RPE cells have a major role in the development of dry age-related macular degeneration (AMD) (emphasis added). Ghosh present evidence that βA3/A1-crystallin, encoded by the Cryba1 gene, a protein known to be important for lysosomal clearance in the RPE and also has a role in epithelial-to-mesenchymal transition (EMT) of RPE cells (present in eye) (see Ghosh et al Invest Ophthalmol Vis Sci. 2018; 59(4), 1-13). The guidance provided in the specification is limited to delivering an AAV vectors carrying wild type (WT) and constitutively active TFEB-S210A (FIG. 5) via subretinal injection showing efficient infection of more than 85-90% of RPE cells.
Therefore, the results exemplified in the instant specification is limited to direct intraocular injection or subretinal injection of AAV2-TFEB-GFP showing efficient infection of more than 85-90% of RPE cells of AMD-like phenotype of Cryba1 cKO mice that could not be extrapolated to prophylactic or preventing any disorder as broadly encompassed by the claims.
A showing that enough of a nucleic acid encoding a polypeptide comprising a constitutively active form of transcription factor EB is expressed in the target cell (cells are affected by the disease), enough nucleic acid is incorporated into the target cells, that such nucleic acid is properly incorporated into such cells as DNA, enough mRNA is produced therefrom, and enough protein is produced and enhanced TFEB gene expression that have an effect on the target cells and such effect is enough of an effect for a long enough period of time to prevent a condition in a subject need thereof in a predictable animal model of preventing a subject at risk of developing atrophic age-related macular degeneration (AMD) or Stargardt's macular retinal degeneration as embraced by the breadth of the claim. An artisan of skill would have to perform undue experimentation to make and use the invention, without reasonable expectation of success. This is because transport barriers for vector selection, sorting targets to maximize efficiency, characterizing the optimum therapeutic window for prevention, and identifying the best route were known to be critical and unpredictable parameter in achieving more favorable AAV gene therapy as supported by the observations in the art record.
Withdrawn-Claim Rejections - 35 USC § 102
Claims 9 and 12 were rejected under 35 U.S.C. 102 (a) (1) as being anticipated by Settembre et al (WO 2012/120044, dated 09/13/2012, IDS). Applicant’s amendments to the claim 9 obviates the basis of the rejection. Therefore, previous rejection of claims is hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn-Claim Rejections - 35 USC § 103
Claims 1-10, 14-18, 27 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Trapani (Molecular. Therapy. 2016, 24, 1 176, S73, 187)/Hose (IVOS ARVO annual meeting Investigative Ophthalmology & Visual Science 2019, V0l.60, 1238, 1-2, IDS) as evidenced by Ballabio et al (US20140038897, dated 2/06/2014) and Groendahl et al (US20230277689, dated 09/7/2023, EFD 10/27/2016). Applicant’s amendments to the claim 1 and 9 obviates the basis of the rejection. Therefore, previous rejection of claim is hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below.
Claims 1, 13 , 35, 36, are rejected under 35 U.S.C. 103 as being unpatentable over Trapani (Molecular. Therapy. 2016, 24, 1 176, S73, 187)/Hose (IVOS ARVO annual meeting 2019, V0l.60, 1238, 1-2, IDS) as evidenced by Ballabio et al (US20140038897, dated 2/06/2014), and Groendahl et al (US20230277689, dated 09/7/2023, EFD 10/27/2016) as applied above and further in view of Choi (US9803217, dated 10/31/2017). The rejection is withdrawn for the reasons discussed above.
Claims 1, 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Trapani (Molecular. Therapy. 2016, 24, 1 176, S73, 187)/Hose (IVOS ARVO annual meeting 2019, V0l.60, 1238, 1-2, IDS) as evidenced by Ballabio et al (US20140038897, dated 2/06/2014) and Groendahl et al (US20230277689, dated 09/7/2023, EFD 10/27/2016) as applied above for claim 1 and further in view of Palmieri et al (Nature Communication, 2017, 1-16). The rejection is withdrawn for the reasons discussed above.
New-Claim Rejections - 35 USC § 103- necessitated by amendments
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.
Claims 1-3, 5, 9-10, 14-18, 27- 28, 37 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Trapani (Molecular. Therapy. 2016, 24, 1 176, S73, 187)/Hose (IVOS Investigative Ophthalmology & Visual Science 2019, V0l.60, 1238, 1-2, IDS) as evidenced by Ballabio et al (US20140038897, dated 2/06/2014), Puertollano et al (The EMBO Journal (2018, 37: e98804 , 1-12) , TFEB (Uniprot TFEB P19484, 1-17), and Groendahl et al (US20230277689, dated 09/7/2023, EFD 10/27/2016).
Claims are directed to a method of restoring lysosomal function of retinal pigment epithelial (RPE) cells comprising administering (i) a nucleic acid encoding a polypeptide comprising a constitutively active form of transcription factor EB (TFEB) to a subject in need thereof. Claim interpretation: Instant rejection of claims 9-10 is applied commensurate with the scope indicated in this office action.
With respect to claims 1-3, 5, 14, 17-18, Hose teaches a method comprising administering 1x109 infective units/mlAAV-2 vector comprising a nucleic acid encoding a constitutively active form of a -serine mutant (S210A) form of TFEB transcription factor EB (TFEB) to a mouse RPE cell derived from Cryba1 KO mice. The results show increased mRNA expression of CLEAR network genes like CTSB (Cathepsin B), LAMP2 and ATP6VOA1 (V-ATPase). Hose states these studies support shows that TFEB can induce lysosomal activity in RPE cells and increase clearance of cellular waste products. Since lysosomal efficiency declines with age and dysfunction in cellular clearance has been implicated in AMD, these findings have potential therapeutic implications, Likewise, Trapani teaches a method comprising administering a plasmid comprising a nucleic acid encoding a constitutively active form of a double-serine mutant (S142A, S211A) form of TFEB transcription factor EB (TFEB) to a human RPE cell to evaluate TFEB activation of its transcriptional targets and ability to clear diretinoid-pyridinium-ethanolamine (A2E) responsible for leading to Stargardt disease (STGD) and age-related macular degeneration (AMD) (see abstract). It is disclosed that TFEB overexpression in ARPE19 cells results in the induction of TFEB transcriptional targets involved in cellular clearance that is associated with reduction of intracellular A2E accumulation (abstract). These results suggests that TFEB overexpression is an effective strategy to promote A2E clearance that have implications for the therapy of both STGD and the more common AMD (see abstract).
Ballabio provide evidence that TFEB variant protein consists of an amino acid sequence comprised in Seq. ID No. 2 and wherein the substitution of a serine residue is at SER 142 and/or at SER 211 of Seq. Id No. 2 with alanine. It is relevant to note that SEQ ID NO: 2 disclosed in Ballabio has 100% sequence identity to recited SEQ ID NO: 1 (see para. 10 and sequence search results). Ballabio teaches a method of treating a disorder that needs of the induction of the cell authophagic/lysosomal system, preferably for use in the treatment of any of the following pathologies: lysosomal storage disorders, neurodegenerative diseases including Alzheimer's disease, Parkinson's disease (see para12, 17). Ballabio teaches a method of administering AAV2 comprising a nucleic acid encoding TFEB (see para. 56, 20-21, 72) (limitation of claims 6-7, 9, 14-16).
Trapani/Hose as evidenced by Ballabio differs from claimed invention by not disclosing (i) delivering the nucleic acid to a subject having dry AMD or in need thereof to restoring lysosomal function and (ii) the nucleic acid encoding the polypeptide comprises the amino acid sequence of SEQ ID NO: 1 except that the serine at 455 of SEQ ID NO: 1 is substituted with alanine.
However, before the effective filing date of instant application, Puertollano teaches MiT-TFE regulation by phosphorylation at multiple key sites and identified TFEB carrying an S467A mutation shows an increased nuclear localization (see page 7, col. 2, last para.). Puertollano teaches multiple sequence alignment and highlights the conservation of critical domains and phosphorylation sites between human TFEB as evident form Uniport PTM data P19484 (see fig. 3). The uniport data clearly shows Serine at 455 of TFEB is a known phosphorylation site (see below), it would have been obvious for one of ordinary skill in the art to try
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serine mutant (S455A) form of TFEB transcription factor EB similar to S467A. The combination of references differs from claimed invention by not disclosing delivering the nucleic acid to a human subject having AMD or in need thereof
Before the effective filing date of instant application, use of AAV2 vector to treat the RPE associated with an eye disorder in human was known in art (see para. 10). For instance, Groendahl teaches a method of treating geographic atrophy, diabetic retinopathy or dry AMD by administering by intraocular injection to an eye of said subject an adeno-associated viral (AAV) vector (see claims 38-40) and wherein the subject is a human (see para. 57, 60, 63, 198, 302). (limitation of claims 2-3, 8, 10, 27). Regarding claim 28, Groendahl teaches that nucleic acid or vector of the invention could be delivered to the individual by subretinal, direct retinal, suprachoroidal or intravitreal injections (see para. 269).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art to combine the teachings of prior art to modify the method of using the AAV vector comprising a nucleic acid encoding a constitutively active form of a -serine mutant form of TFEB as disclosed in Trapani/Hose by substituting one serine mutant form of TFEB with other known serine mutation at phosphorylation site of TFEB including at position S455 and/or S467 as disclosed in Uniport PTM data P19484 in an in vivo method of treating RPE associated with an eye disorder as disclosed in Groendahl, in a method of restoring lysosomal function of retinal pigment epithelial (RPE) cells, as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant application. Said use amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in art would be motivated to deliver a nucleic acid encoding a constitutively active form of TFEB because prior explicitly reported overexpression in RPE cells results in the induction of TFEB transcriptional targets involved in cellular clearance that is associated with reduction of intracellular A2E accumulation that have implications for the therapy of both STGD and the more common AMD (supra). The limitation of claim 18 would be obvious to one of ordinary skill in the art to try because prior art explicitly reported S455 as a phosphorylation site of TFEB that is expected to increase nuclear localization as demonstrated for other serine mutant as in Puertollano. Absent evidence of any unexpected and/or superior result, one of skill in the art would have had a reasonable expectation of success in combining the teachings of Trapani/Hose with those of Uniport PTM data and Groendahl,to try other serine mutant form of TFEB transcription factor EB because prior art successfully reported (i) overexpressing TFEB as an effective strategy to promote A2E clearance suggesting potential treatment of STGD, AMD and neurodegenerative disorder, (ii) multiple serine at position 142, 211, 455 or 467 of TFEN as phosphorylation site and (iii) AAV is capable of transducing RPE cells. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf). Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art at the time of the invention.
Claims 1, 13 , 35, 36, are rejected under 35 U.S.C. 103 as being unpatentable over Trapani (Molecular. Therapy. 2016, 24, 1 176, S73, 187)/Hose (IVOS ARVO annual meeting 2019, V0l.60, 1238, 1-2, IDS), Ballabio et al (US20140038897, dated 2/06/2014), Puertollano et al (The EMBO Journal (2018, 37: e98804 , 1- 12), TFEB Uniport( TFEB PTM data P19484, 1-17) and Groendahl et al (US20230277689, dated 09/7/2023, EFD 10/27/2016) as applied above and further in view of Choi (US9803217, dated 10/31/2017).
The teaching of Trapani/Hose, Ballabio, Groendahl and Uniport PTM have been discussed above and relied in same manner here. The combination of reference differs from claimed invention by not disclosing that the nucleic acid further comprises a hVMD2 promoter.
Choi teaches a method of administering AAV vectors for delivering heterologous genes to the retina (Abstract) and teaches a nucleic acid further comprises a hVMD2 promoter (promoters derived from ... tissue specific genes ... VM02, Col. 5, line 41-43; human VMD2 promoter, Col. 25, middle of page). It is further disclosed that hVMD2 promoter functions well in inducing gene expression in RPE cells (col.143, lines 50-52).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art to combine the teachings of prior art to modify the method of administering the vector comprising a nucleic acid encoding a constitutively active form of a serine mutant form of TFEB as disclosed in Trapani/Hose, Uniport Groendahl by further in including a tissue specific hVMD2 promoter as disclosed in Choi, in a method of restoring lysosomal function of retinal pigment epithelial (RPE) cells, as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant application. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in art would be motivated to include hVMD2 promoter because prior art recognized that higher expression of TFEB in RPE cells can induce lysosomal activity in said cells and increase clearance of cellular waste products. One of skill in the art would have had a reasonable expectation of success in combining the teachings of Trapani/Hose, Groendahl with those of Choi because prior art successfully reported (i) use of VMD2 promoter to express heterologous gene in RPE cells. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf). Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art at the time of the invention.
Claims 1, 17 are rejected under 35 U.S.C. 103 as being unpatentable over Trapani (Molecular. Therapy. 2016, 24, 1 176, S73, 187)/Hose (IVOS ARVO annual meeting 2019, V0l.60, 1238, 1-2, IDS) , Ballabio et al (US20140038897, dated 2/06/2014), Puertollano et al (The EMBO Journal (2018, 37: e98804 , 1- 12) as evidenced by TFEB Uniport PTM data (P19484, 1-17) and Groendahl et al (US20230277689, dated 09/7/2023, EFD 10/27/2016) as applied above, and further in view of Palmieri et al (Nature Communication, 2017, 1-16).
The teaching of Trapani/Hose as evidenced by Ballabio, Uniport PTM data and Groendahl have been discussed above and relied in same manner here. The combination of reference differs from claimed invention by not disclosing the nucleic acid encoding the polypeptide comprises the amino acid sequence of SEQ ID NO: 1 except that the serine at one or more of positions 467, and 469 of SEQ ID NO: 1.
Palmieri cure the deficiency by disclosing TFEB activity is modulated by Akt phosphorylation at Ser467, and that Akt pharmacological inhibition promotes cellular clearance in a variety of models of genetic diseases presenting with impairment of lysosomal pathways (see page 2, col. 1, last para.). It is disclosed that 467 refers to the human protein sequence (see fig. 7f). Palmieri teaches transfection of bicistronic TFEB-Flag–internal ribosomal entry site (IRES)–green fluorescent protein (GFP) and TFEB(S467A) Flag–IRES–GFP vectors showed that the mutant TFEB protein was more stable than WT TFEB (Supplementary Fig. 14). Palmieri teaches TFEB(S467A) showed increased ability to induce the expression of TFEB target genes compared to WT TFEB (Fig. 7e). TFEB(S467A) showed diminished co-localization and interaction with the 14-3-3 proteins likely due to its increased nuclear localization (Fig. 7f,g).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art to combine the teachings of prior art to modify the method of administering the vector comprising a nucleic acid encoding a constitutively active form of a serine mutant form of TFEB as disclosed in Trapani/Hose, TFEB Uniport PTM, Groendahl by further including another serine mutant form of TFEB(S467A) as disclosed in Palmieri (TFEB), in a method of restoring lysosomal function of retinal pigment epithelial (RPE) cells, as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant application. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of skill in the art would have had a reasonable expectation of success in combining the teachings of prior art because prior art teaches serine mutant form of TFEB with other known serine mutation at phosphorylation site of TFEB including at position S455 and S467 were known for treating RPE associated with an eye disorder. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf). Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art at the time of the invention.
Conclusion
No claims allowed.
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.
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/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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