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 .
Claims 1-6 are pending in the present application, and they are examined on the merits herein.
Claim Objections
Claim 5 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claim 5 has not been further treated on the merits.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1 and 3-6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Feinsod (WO 2017/070491; IDS).
The instant claims are directed to a method of treating X-linked juvenile retinoschisis (XLRS) in a human subject, comprising subretinally delivering to the human subject a therapeutically effective amount of an rAAV vector, the rAAV vector comprising a nucleic acid sequence comprising coding sequence for human RS1 protein (e.g., rAAV2tYF-CB-hRS1).
Feinsod already disclosed at least a method of treating X-linked retinoschisis (XLRS) by administering (e.g., intravitreal injection or sub-retinally delivering) an effective amount of an ophthalmic formulation comprising a rAAV-based gene therapy vector (e.g., AAV2tYF-based gene therapy vector) comprising a Retinoschisin (RS1) gene or a fragment thereof (e.g., SEQ ID NO: 2 or a codon optimized version of SEQ ID NO: 2) into the eye of a patient in need thereof (a human patient), wherein the formulation comprises a density modifying agent (e.g., about 5% dextrose (v/v), about 5% glucose(v/v), about 5% sucrose (v/v), or about 50% D2O (v/v)) and a balanced salt solution (see at least Abstract; Summary of the Invention; particularly page 3, lines 1-15, lines 25-33; page 3, lines 4-14; page 10, lines 7-16, lines 24-33; and page 11, lines 29-31; Example 2 and Table 3). Feinsod taught specifically a patient in need thereof can be a patient suffering from a retinal disease such as X-linked Retinoschisis that includes juvenile X-linked retinoschisis (page 16, lines 9-17); and the gene therapy vector is present in a concentration of about 1 x 1011 to about 1x 1013 vg/mL (page 2, lines 30-31). Feinsod also taught a promoter to be employed in the rAAV vector includes the chicken beta-actin (CBA) promoter, and the immediate early CMV enhancer coupled with the CBA promoter (page 14, lines 27-32), with the exemplary AAV2tYF-CB-GFP vector was intravitreally or subretinally injected into cynomolgus macaques (Example 2 and Table 3).
Since Feinsod also stated “Still other dosages in these ranges may be selected by the attending physician, taking into account the physical state of the subject, preferably human, being treated, the age of the subject, the particular ocular disorder and the degree to which the disorder, if progressive, has developed” (page 19, lines 29-32); “An artificial AAV serotype may be, without limitation, a pseudotyped, a chimeric AAV, a chimeric AAV capsid, a recombinant AAV capsid, or a “humanized” AAV capsid” (page 11, lines 14-15), along with referencing to the RS1 gene (NG_008659.3 RefSeqGene which is a human RS1 gene) codes for the retinoschisin protein, which normally provides lateral adhesion that holds retinal cells together, and RS1 gene mutations alter the protein and thereby interfere with the ability of cells to maintain proper structure of the retina (page 17, lines 3-6), the provided SEQ ID NO: 2 or a codon optimized version of SEQ ID NO: 2 in the form of an AAV2tYF-based gene therapy vector for the treatment of a human patient must necessarily encodes a human RS1 protein.
Accordingly, the teachings Feinsod meet every limitation of the instant claims. Therefore, the reference anticipates the instant claims.
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.
Alternatively, claims 1 and 3-6 are rejected under 35 U.S.C. 103 as being unpatentable over Feinsod (WO 2017/070491; IDS) in view of Boye et al (WO 2022/026632).
Feinsod already disclosed at least a method of treating X-linked retinoschisis (XLRS) by administering (e.g., intravitreal injection or sub-retinally delivering) an effective amount of an ophthalmic formulation comprising a rAAV-based gene therapy vector (e.g., AAV2tYF-based gene therapy vector) comprising a Retinoschisin (RS1) gene or a fragment thereof (e.g., SEQ ID NO: 2 or a codon optimized version of SEQ ID NO: 2) into the eye of a patient in need thereof (a human patient), wherein the formulation comprises a density modifying agent (e.g., about 5% dextrose (v/v), about 5% glucose(v/v), about 5% sucrose (v/v), or about 50% D2O (v/v)) and a balanced salt solution (see at least Abstract; Summary of the Invention; particularly page 3, lines 1-15, lines 25-33; page 3, lines 4-14; page 10, lines 7-16, lines 24-33; and page 11, lines 29-31; Example 2 and Table 3). Feinsod taught specifically a patient in need thereof can be a patient suffering from a retinal disease such as X-linked Retinoschisis that includes juvenile X-linked retinoschisis (page 16, lines 9-17); and the gene therapy vector is present in a concentration of about 1 x 1011 to about 1x 1013 vg/mL (page 2, lines 30-31). Feinsod also taught a promoter to be employed in the rAAV vector includes the chicken beta-actin (CBA) promoter, and the immediate early CMV enhancer coupled with the CBA promoter (page 14, lines 27-32), with the exemplary AAV2tYF-CB-GFP vector was intravitreally or subretinally injected into cynomolgus macaques (Example 2 and Table 3). Feinsod also stated “Still other dosages in these ranges may be selected by the attending physician, taking into account the physical state of the subject, preferably human, being treated, the age of the subject, the particular ocular disorder and the degree to which the disorder, if progressive, has developed” (page 19, lines 29-32); “An artificial AAV serotype may be, without limitation, a pseudotyped, a chimeric AAV, a chimeric AAV capsid, a recombinant AAV capsid, or a “humanized” AAV capsid” (page 11, lines 14-15), along with referencing to the RS1 gene (NG_008659.3 RefSeqGene which is a human RS1 gene) codes for the retinoschisin protein, which normally provides lateral adhesion that holds retinal cells together, and RS1 gene mutations alter the protein and thereby interfere with the ability of cells to maintain proper structure of the retina (page 17, lines 3-6).
Feinsod did not teach explicitly at least that the provided SEQ ID NO: 2 or a codon optimized version of SEQ ID NO: 2 in the form of an AAV2tYF-based gene therapy vector for the treatment of a human patient encodes a human RS1 protein.
Before the effective filing date of the present application (11/03/2021), Boye et al already taught a method for treating a human subject with or suffering from X-linked retinoschisis (XLRS) with a recombinant AAV vector comprising a human RS1 transgene that encodes a human RS1 protein (see Summary of the Invention; particularly paragraphs [004]-[0005]). Boye et al also stated “The rarer form, X-linked retinoschisis (XLRS) is present at birth and affects boys and young men” (paragraph [0003]).
Accordingly, it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to modify the teachings of Feinsod by also utilizing an AAV2tYF-based gene therapy vector comprising a nucleic acid encoding a human RS1 protein for the treatment of a human patient with or suffering from XLRS, in light of the teachings of Boye et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modification because Boye et al already taught successfully a method for treating a human subject with or suffering from X-linked retinoschisis (XLRS) with a recombinant AAV vector comprising a human RS1 transgene that encodes a human RS1 protein.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Feinsod and Boye et al; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified method resulting from the combined teachings of Feinsod and Boye et al as set forth above is indistinguishable from and encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Feinsod (WO 2017/070491; IDS) in view of Boye et al (WO 2022/026632) as applied to claims 1 and 3-6 above, and further in view of Petrs-Silva et al (Molecular Therapy 19:293-301, 2011).
The combined teachings of Feinsod and Boye et al were presented above. However, none of the cited references teach specifically that the rAAV vector further comprising a mutated AAV2 VP3 capsid protein comprising phenylalanine (F) for tyrosine (Y) substitution at each of the positions corresponding to Y444, Y500 and Y730 in a wild type AAV2 VP3 capsid protein.
Before the effective filing date of the present application (11/03/2021), Petrs-Silva et al already evaluated the transduction characteristics of AAV2 vectors containing combination of multiple tyrosine to phenylalanine mutations in seven highly conserved surface-exposed capsid tyrosine residues following subretinal or intravitreal delivery in adult mice; and they found that following subretinal delivery of various multiple tyrosine-mutant vectors, eyes treated with the triple mutant (Y444, 500,730F) virus displayed widespread and intense fluorescence, stronger than wild type and all other Y-F mutants examined; and GFP expression of the (Y444,500,730F) triple mutant was confined primarily to the photoreceptors and RPE cells (Abstract; section titled “Behavior of subretinal multiple Y-F mutated AAV2 vectors” at page 294; and Figures 2d and 3b). Although Petrs-Silva et al noted that in some eyes, triple mutant treatment caused significant photoreceptor cell loss, but they attributed this toxic effect to GFP overexpression rather than the vector itself; and the same phenomenon was reported when using a high-titer AAV preparation in combination with a strong promoter (page 297, right column, bottom of second paragraph). Petrs-Silva et al stated “[i]t is not always beneficial to overexpress large amounts of protein in some neuronal cells,35 and the choice of weaker, cell-specific promoters may be critical for future therapeutic applications” (page 297, right column, bottom of second paragraph). Petrs-Silva et al also disclosed that the 60-subunit icosahedral AAV capsid is assembled from the three overlapping viral proteins VP1 (87kd), VP2 (73kd), and VP3 (62kd) in a ratio 1:1:10, respectively (page 293, right column, first paragraph).
Accordingly, it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to further modify the combined teachings of Feinsod and Boye et al by also utilizing a rAAV vector comprising a mutated VP3 capsid protein comprising the triple Y444F, Y500F, Y730F substitutions, in light of the teachings of Petrs-Silva et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modification because Petrs-Silva et al demonstrated that following subretinal delivery of various multiple tyrosine-mutant vectors, eyes treated with the triple mutant (Y444, 500,730F) virus displayed widespread and intense fluorescence, stronger than wild type and all other Y-F mutants examined; and GFP expression of the (Y444,500,730F) triple mutant was confined primarily to the photoreceptors and RPE cells. Moreover, the primary Feinsod reference already taught using an AAV2tYF-based gene therapy vector for X-linked retinoschisis (XLRS) treatment in a human patient.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Feinsod, Boye et al and Petrs-Silva et al; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified method resulting from the combined teachings of Feinsod, Boye et al and Petrs-Silva et al as set forth above is indistinguishable from and encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 1-2 and 6 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-2 and 6 of copending Application No. 18/161,655 (reference application). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 3-5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3-5 and 7-8 of copending Application No. 18/161,655 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because a method of treating X-linked juvenile retinoschisis (XLRS) in a human subject, comprising: subretinally delivering to the human subject a therapeutically effective amount of an rAAV vector, the rAAV vector comprising a nucleic acid sequence comprising coding sequence for human RS1 protein, wherein the nucleic acid sequence of the rAAV vector further comprises a chicken beta actin promoter sequence (claim 3), or wherein the nucleic acid sequence of the rAAV vector further comprises a CMV enhancer (claim 4); or the method of any of the foregoing claims, wherein the rAAV vector is rAAV2tYF-CB-hRS1 (claim 5); or the method of claim 2, wherein the nucleic acid sequence of the rAAV vector further comprises a chicken beta actin promoter sequence (claim 7), or wherein the nucleic acid sequence of the rAAV vector further comprises a CMV enhancer (claim 8) in the copending Application No. 18/161,655 anticipates the method of treating XLRS in a human subject in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
1. Kotterman et al (Gene Therapy 22:116-126, 2015) disclosed antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates (Abstract).
2. Li et al (Molecular Vision 14:1760-1769, 2008) disclosed that intravitreal administration of AAV vectors generated a humoral immune response against AAV capsid that blocked vector expression upon re-administration via the same route into the partner eye; while subretinal administration of vector did not trigger any humoral immune response against AAV capsid, and had no effect on subsequent administration of vector either intravitreally or subretinally into the partner eye (Abstract).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., whose telephone number is (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/Primary Examiner, Art Unit 1631