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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 3, 2026, has been entered.
DETAILED ACTION
The amended claims filed on April 3, 2026, have been acknowledged. Claims 1-50 were cancelled. Claims 51-53 were amended. Claims 54-60 and 62-71 are new. Claims 51-60 and 62-71 are pending and examined on the merits.
Rejections and/or objections not reiterated from the previous office action mailed July 7, 2025, are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
Claims 51-71 find support in and receive domestic benefit from U.S. provisional application No. 62/726,184. Accordingly, the effective priority date of claims 1-7, 9-11, 13-20, 25 is granted as August 31, 2018.
Information Disclosure Statement
The information disclosure statements (IDS) filed on April 6, 2026, and July 10, 2026 have been considered.
Claim Objections
The numbering of claims is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not).
Claim 61 has been skipped. Misnumbered claims 62-71 should be renumbered, accordingly.
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.
Claims 64-66 are 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 64 recites the broad recitation “a viral vector”, and the claim also recites “optionally wherein the viral vector is a recombinant adeno-associated virus (rAAV) vector” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 65-66 are also rejected because of their dependency on claim 64.
Under the broadest reasonable interpretation, the claim is being interpreted to include any viral vector.
Claim Rejections - 35 USC § 102
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 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 54-57, 63-67, and 70 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Guziewicz et al. (PNAS 115: E2839-E2848. 2018. Published March 5, 2018. Referenced in IDS), as evidenced by Guziewicz et al. (PLoS One 8: 1-11. 2013) and Trubetskoy et al. (Journal of Virology 73: 3477-3483. 1999).
Regarding claims 54-57 and 63-66, Guziewicz 2018 teaches a method of treating canine bestrinopathies by sub-retinal injection of an AAV2 encoding canine BEST1 or human BEST1 under control of a human VMD2 promoter. Guziewicz 2018 teaches that they treated cBest canines exhibiting different stages of focal or multifocal retinal detachments. For example, they treated central retinal detachment retinal macrodetachments and focal macular lesions (such as a dog with compound heterozygous (R25*/P463fs) displaying advanced central retinal detachment in the right eye (EM356-OD) and a cBest dog (R25*/R25*) showed that the early bilateral lesions. Furthermore, Guziewicz 2018 teaches that they treated canines with retina wide microdetachments (a cBest (R25*/P463fs) dog showed homogeneous microdetachment covering all the imaged retina) and retina microdetachments (cBest-mutant dogs [cmr1 (R25*/R25*), cmr1/cmr3, (R25*/P463fs), or cmr3 (P463fs/P463fs)) (Figures 3-4 and page E2842, column 2, paragraph 3-page E2844, column 1, paragraph 2).
Guziewicz 2018 teaches that they used the AAV vector and vector production method of Guziewicz 2013 (Supporting Information page 1 (page 11 of pdf), column 2, paragraph 2).
Guziewicz 2013 evidences a nucleic acid vector comprising a VMD2 promoter, SV40 splice donor/acceptor sites (a synthetic intron), a recombinant human BEST1 sequence, and an SV40 polyadenylation signal, as can be seen in Supplemental Figure 1 (shown below) (page 7, column 1, paragraph 4-column 2, paragraph 1).
PNG
media_image1.png
268
320
media_image1.png
Greyscale
Regarding the synthetic intron, as stated supra, Guziewicz 2013 evidences they used an SV40 splice donor/acceptor sites. Trubetskoy evidences that splice donors/splice acceptors are part of introns (Figure 2). Furthermore, Figures 13-16 of the instant application use the SV40 splice donor/splice acceptor, as well, as the intron. As shown in Supplemental Figure 1 of Guziewicz 2013, the BEST1 coding sequence is preceded by the SV40 SD/SA intron and followed by the SV40 polyadenylation sequence. Guziewicz 2013 evidences that they generated plasmid constructs and rAAV2 constructs of the VMD2-BEST1 nucleic acid of Supplementary Figure 1. Guziewicz 2013 evidences that they confirmed their AAV vectors had capsids, affirming that the AAV vectors were comprised within a rAAV particle (abstract and page 7, column 1, paragraph 4-column 2, paragraph 1).
Regarding claim 67, Guziewicz 2018 teaches that their results can be translated to treat humans to reverse macro- and microdetachments in patients affected with bestrophinopathies (abstract).
Regarding claim 70, Guziewicz 2013 evidences that cmr1 is an autosomal recessive bestrophinopathy (page 1, column 2, paragraph 2-page 2, column 1, paragraph 1).
Claim Rejections - 35 USC § 103
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 54 and 58-59 are rejected under 35 U.S.C. 103 as being unpatentable over Guziewicz et al. (PNAS 115: E2839-E2848. 2018. Published March 5, 2018) as applied to claim 54 above, and further in view of United States Patent Application No. 2005/0049212 (Steuernagel), as evidenced by Guziewicz et al. (PLoS One 8: 1-11. 2013).
The teachings of Guziewicz 2018 are as discussed above. Furthermore, Guziewicz 2013 evidences that the BEST1 sequence is the wild-type human BEST1 sequence (page 2, column 2, paragraph 3).
Guziewicz 2018 and Guziewicz 2013 are silent as to the wild-type human BEST1 sequence.
However, Steuernagel teaches a wild type sequence of the human gene (SEQ ID NO: 1 of Steuernagel; also known as VMD2; Genbank Accession No. NP 004174) is 100% identical to SEQ ID NO: 9 of the instant claims.
As the wild-type human BEST1 sequence of SEQ ID NO: 1 of Steuernagel is known within the art and was already cloned into a plasmid, it would have been obvious that one could choose this as the sequence for the wild-type human BEST1 sequence of Guziewicz 2018. Furthermore, the successful cloning and sequencing of the nucleic acid sequence encoding a known wild-type coding sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 54, 60, and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Guziewicz et al. (PNAS 115: E2839-E2848. 2018. Published March 5, 2018) as applied to claim 54 above, and further in view of Chinese Patent Application No. 107287238.
The teachings of Guziewicz 2018 are as discussed above. Furthermore, Guziewicz 2018 teaches that their viral vector transduces RPE cells (page E2843, column 2, paragraph 3).
Guziewicz 2018 is silent as to the VMD2 sequence.
However, ‘238 teaches a VMD2 sequence for use in a viral vector gene therapy to treat an autosomal recessive disorder of the eye (Leber's congenital amaurosis type 2 (LCA2)) by overexpressing a gene in RPE cells (abstract). The VMD2 promoter sequence of ‘238 (SEQ ID NO: 4) is a specific promoter for RPE cells (page 2, paragraph 10-page 3, paragraph 1). SEQ ID NO: 4 of ‘238 comprises a sequence that is 100% identical to SEQ ID NO: 12 of the instant application.
As the VMD2 promoter sequence of SEQ ID NO: 4 of ‘238 is known within the art, was known to specifically target RPE cells (the cell transduced by Guziewicz 2018), and was already cloned into a plasmid, it would have been obvious that one could choose this as the sequence for the VMD2 sequence of Guziewicz 2018. Furthermore, the successful cloning and sequencing of the nucleic acid sequence encoding a known regulatory element is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 51-53, 68-69, and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Guziewicz et al. (PLoS One 8: 1-11. 2013) in view of United States Patent Application No. 2005/0049212 (Steuernagel) and Chinese Patent Application No. 107287238, as evidenced by Guziewicz et al. (PLoS One 8: 1-11. 2013) and Trubetskoy et al. (Journal of Virology 73: 3477-3483. 1999).
Regarding claims, 51, 68-69, and 71, Guziewicz 2018 teaches a method of treating canine bestrinopathies by sub-retinal injection of an AAV2 encoding canine BEST1 or human BEST1 under control of a human VMD2 promoter. Guziewicz 2018 teaches that they treated cBest canines exhibiting different stages of focal or multifocal retinal detachments. For example, they treated central retinal detachment retinal macrodetachments and focal macular lesions (such as a dog with compound heterozygous (R25*/P463fs) displaying advanced central retinal detachment in the right eye (EM356-OD) and a cBest dog (R25*/R25*) showed that the early bilateral lesions. Furthermore, Guziewicz 2018 teaches that they treated canines with retina wide microdetachments (a cBest (R25*/P463fs) dog showed homogeneous microdetachment covering all the imaged retina) and retina microdetachments (cBest-mutant dogs [cmr1 (R25*/R25*), cmr1/cmr3, (R25*/P463fs), or cmr3 (P463fs/P463fs)) (Figures 3-4 and page E2842, column 2, paragraph 3-page E2844, column 1, paragraph 2).
Guziewicz 2018 teaches that they used the AAV vector and vector production method of Guziewicz 2013 (Supporting Information page 1 (page 11 of pdf), column 2, paragraph 2).
Guziewicz 2013 evidences a nucleic acid vector comprising in order a 5’ ITR (TR before VMD2 promoter), a VMD2 promoter, SV40 splice donor/acceptor sites (a synthetic intron), a recombinant human BEST1 sequence, an SV40 polyadenylation signal, and a 3’ ITR (TR after SV40 polyadenylation sequence), as can be seen in Supplemental Figure 1 (shown below) (page 7, column 1, paragraph 4-column 2, paragraph 1).
PNG
media_image1.png
268
320
media_image1.png
Greyscale
Regarding the synthetic intron, as stated supra, Guziewicz 2013 evidences they used an SV40 splice donor/acceptor sites. Trubetskoy evidences that splice donors/splice acceptors are part of introns (Figure 2). Furthermore, Figures 13-16 of the instant application use the SV40 splice donor/splice acceptor, as well, as the intron. As shown in Supplemental Figure 1 of Guziewicz 2013, the BEST1 coding sequence is preceded by the SV40 SD/SA intron and followed by the SV40 polyadenylation sequence. Guziewicz 2013 evidences that they generated plasmid constructs and rAAV2 constructs of the VMD2-BEST1 nucleic acid of Supplementary Figure 1. Guziewicz 2013 evidences that they confirmed their AAV vectors had capsids, affirming that the AAV vectors were comprised within a rAAV particle (abstract and page 7, column 1, paragraph 4-column 2, paragraph 1).
Regarding the VMD2 promoter sequence, the teachings of Guziewicz 2018 are as discussed above. Furthermore, Guziewicz 2018 teaches that their viral vector transduces RPE cells (page E2843, column 2, paragraph 3).
Guziewicz 2018 is silent as to the VMD2 sequence.
However, ‘238 teaches a VMD2 sequence for use in a viral vector gene therapy to treat an autosomal recessive disorder of the eye (Leber's congenital amaurosis type 2 (LCA2)) by overexpressing a gene in RPE cells (abstract). The VMD2 promoter sequence of ‘238 (SEQ ID NO: 4) is a specific promoter for RPE cells (page 2, paragraph 10-page 3, paragraph 1). SEQ ID NO: 4 of ‘238 comprises a sequence that is 100% identical to SEQ ID NO: 12 of the instant application.
As the VMD2 promoter sequence of SEQ ID NO: 4 of ‘238 is known within the art, was known to specifically target RPE cells (the cell transduced by Guziewicz 2018), and was already cloned into a plasmid, it would have been obvious that one could choose this as the sequence for the VMD2 sequence of Guziewicz 2018. Furthermore, the successful cloning and sequencing of the nucleic acid sequence encoding a known regulatory element is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the BEST1 coding sequence, the teachings of Guziewicz 2018 are as discussed above. Furthermore, Guziewicz 2013 evidences that the BEST1 sequence is the wild-type human BEST1 sequence (page 2, column 2, paragraph 3).
Guziewicz 2018 and Guziewicz 2013 are silent as to the wild-type human BEST1 sequence.
However, Steuernagel teaches a wild type sequence of the human gene (SEQ ID NO: 1 of Steuernagel; also known as VMD2; Genbank Accession No. NP 004174) is 100% identical to SEQ ID NO: 9 of the instant claims.
As the wild-type human BEST1 sequence of SEQ ID NO: 1 of Steuernagel is known within the art and was already cloned into a plasmid, it would have been obvious that one could choose this as the sequence for the wild-type human BEST1 sequence of Guziewicz 2018. Furthermore, the successful cloning and sequencing of the nucleic acid sequence encoding a known wild-type coding sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 52, Guziewicz 2018 teaches that their results can be translated to treat humans to reverse macro- and microdetachments in patients affected with bestrophinopathies (abstract).
Regarding claim 53, Guziewicz 2013 evidences that cmr1 is an autosomal recessive bestrophinopathy (page 1, column 2, paragraph 2-page 2, column 1, paragraph 1).
Relevant Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Guziewicz et al. (Sustained Therapeutic Reversal of Canine Bestrophinopathy with Gene Therapy using Recombinant AAV2. Investigating Ophthalmology and Visual Science 54: ARVO Annual Meeting. June 2013).
Thirteen cmr-affected dogs carrying R25X, R25X/P463fs or P436fs mutations in BEST1 and exhibiting bilateral focal or multifocal lesions were subretinally injected with rAAV2 expressing either canine (0.136-1.59x1011vg/ml) or human (7.64-8.82x1011vg/ml) BEST1 regulated by the hVMD2 promoter. Each treated and control (non-injected or B55-injected) eye was monitored clinically and imaged serially in vivo using cSLO/5D-OCT.
United States Patent Application No. 20190307900 (Maclaren; Effective filing date of April 5, 2018).
The disclosure provides composition comprising a nucleic acid sequence comprising (a) a sequence encoding a vitelliform macular dystrophy-2 (VMD2) promoter, and (b) a sequence encoding a Bestrophin-1 (BEST1) protein as well as the use of these compositions for the treatment of macular dystrophy in a subject comprising administration of the composition to an eye of a subject via a subretinal or a suprachoroidal route.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEENAN A BATES whose telephone number is (571)270-0727. The examiner can normally be reached M-F 7:30-5:00.
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, Doug Schultz can be reached on (571) 272-0763. 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.
/KEENAN A BATES/Examiner, Art Unit 1631
Prosecution Insights