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 .
Response to Amendment/Disposition of Claims
Applicant’s Amendment filed on 16 March 2026 has been received and entered. Claims 1-2, 6, 8-12, 17-18, 20, 23-24, 26, 28-29, 40, 49, 52, and 54 were pending. Claims 1-2, 6, 9-12, 17-18, 20, 28-29, 40, 49, 52, and 54 have been amended. Claims 3-5, 7, 13-16, 19, 21-22, 25-27, 30-39, 41-48, 50-51, 53, and 55 have been cancelled. New Claim 56 has been added.
Accordingly, Claims 1-2, 6, 8-12, 17-18, 20, 23-24, 28-29, 40, 49, 52, 54, and 56 are currently pending and will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US 2023/0265455 A1, Published 24 August 2023. Applicant’s amended Specifications as presented on 16 March 2026 and 24 January 2023 are acknowledged and entered.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Response to Arguments
Applicant's arguments filed 16 March 2026 regarding the previous Office action dated 16 December 2025 have been fully considered. If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn. If the arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
Information Disclosure Statement
The information disclosure statements (IDSes) submitted on 16 March 2026 and 19 July 2023 have been considered by the examiner.
Specification
(Objection Withdrawn) – The objection to the Specification for failing to comply with Sequence Disclosure Requirements is withdrawn in light of the amendments to the Specification.
(Objection Withdrawn) – The objection to the disclosure for containing possible minor errors is withdrawn in light of the amendments to the Specification.
Claim Objections
(Objection Withdrawn) – The objection to Claims 10 and 17 for containing minor informalities is withdrawn in light of the amendments to the claims.
Claim Rejections - 35 USC § 112(b); Second Paragraph
Withdrawn Rejections
(Rejection Withdrawn) – The rejection of Claim 9 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claim.
(Rejection Withdrawn) – The rejection of Claims 40 and 49 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(Rejection Withdrawn) – The rejection of Claims 52 and 54 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
New Rejections
Claim Rejections - 35 USC § 112(b)
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.
(New Rejection – necessitated by amendment) – Claims 1, 12, 17, and 56, and dependent claims 2, 6, 8-11, 18, 20, 23-24, 28-29, and 40 thereof, 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, claims 1 and 17 recite the broad recitation “wherein the polynucleotide does not comprise the 5' untranslated region (UTR) of the human retinoschisin protein”, and the claims also recite “SEQ ID NO: 39”, which is the narrower statement of the range/limitation. Claims 12 and 56 recite the broad recitation “wherein the polynucleotide does not comprise the 3' untranslated region (UTR) of human retinoschisin”, and the claims also recite “SEQ ID NO: 40”, which is the narrower statement of the range/limitation. The claims 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. It is suggested that the claims be amended to recite these separate limitations as Markush groups where the recited limitations are claimed in the alternative or that the claims be amended to recite only one (1) of the possible limitations for each respective claim, but Applicant is free to amend the claims as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 1, 12, 17, and 56 are rejected on the grounds of being indefinite. Claims 2, 6, 8-11, 18, 20, 23-24, 28-29, and 40 are also rejected, since they depend upon Claims 1 and 17 but do not remedy the deficiencies of Claims 1 and 17.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim Rejections - 35 USC § 112(a); First Paragraph
(Rejection Withdrawn) – The rejection of Claims 17-18, 20, 23-24, 26, 28-29, and 40 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in light of the amendments to the claims and the cancellation of one of the claims.
Claim Rejections - 35 USC § 102
(Rejection Withdrawn) – The rejection of Claims 17-18, 20, 26, and 28-29 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Sieving et al. (US 2016/0002666 A1, Published 07 January 2016) (cited on IDS filed on 19 July 2023 by Applicant as U.S. Patent No. 9,873,893 B2) is withdrawn in light of the amendments to the claims.
Claim Rejections - 35 USC § 103
Withdrawn Rejections
(Rejection Withdrawn) – The rejection of Claims 1-2, 6, and 8-12 under 35 U.S.C. 103 as being unpatentable over LaCroix-Desmazes et al. (US 2021/0228738 A1, earliest Priority Date 17 July 2018) and O’Riordan and Adamowicz (US 2017/0173183 A1, Published 22 June 2017) is withdrawn in light of the amendments to the claims.
(Rejection Withdrawn) – The rejection of Claims 23-24 and 40 under 35 U.S.C. 103 as being unpatentable over Sieving et al. (US 2016/0002666 A1, Published 07 January 2016) (cited on IDS filed on 19 July 2023 by Applicant as U.S. Patent No. 9,873,893 B2) as applied to claims 17-18, 20, 26, and 28-29 above, and further in view of Gray (US 2018/0305715 A1, Published 25 October 2018), Xie and Guo (US 2022/0403417 A1, earliest Priority Date 20 November 2019), LaCroix-Desmazes et al. (US 2021/0228738 A1, earliest Priority Date 29 July 2021), and Dyka and Hauswirth (US 2022/0175969 A1, earliest Priority Date 04 March 2019) is withdrawn in light of the invocation of the 102(b)(2)(C) exception regarding Dyka and Hauswirth (US 2022/0175969 A1).
Maintained Rejections
(Rejection Maintained) – The rejection of Claims 49, 52, and 54 under 35 U.S.C. 103 as being unpatentable over by Sieving et al. (US 2016/0002666 A1, Published 07 January 2016) (cited on IDS filed on 19 July 2023 by Applicant as U.S. Patent No. 9,873,893 B2), Boye et al. (Boye SL, Choudhury S, Crosson S, Di Pasquale G, Afione S, Mellen R, Makal V, Calabro KR, Fajardo D, Peterson J, Zhang H, Leahy MT, Jennings CK, Chiorini JA, Boyd RF, Boye SE. Novel AAV44.9-Based Vectors Display Exceptional Characteristics for Retinal Gene Therapy. Mol Ther. 2020 Jun 3;28(6):1464-1478.) (cited on IDS filed on 19 July 2023 by Applicant), and Dyka and Hauswirth (US 2022/0175969 A1, earliest Priority Date 04 March 2019) is maintained.
Response to Arguments
Applicant's arguments filed with respect to the rejection of rejection of Claims 49, 52, and 54 under 35 U.S.C. 103 have been fully considered but they are not persuasive.
In their Response, Applicant invoked the 102(b)(2)(C) exception regarding Dyka and Hauswirth (US 2022/0175969 A1) to overcome the obviousness rejection (see Pages 8-9 of Remarks). Applicant also argues that the “other cited references, Sieving and Boye, do not teach or suggest the subject matter of Dyka” (see Page 9, Paragraph 2).
Examiner does not find this argument persuasive. While the invocation of the 102(b)(2)(C) exception does disqualify Dyka and Hauswirth (US 2022/0175969 A1) from being used as prior art, the other references cited still meet the limitations of the instant claims. As noted in the previous Office Action, Sieving et al. teach a method of treating X-linked retinoschisis (XLRS) in a human comprising administering to said human a therapeutically effective amount of an expression vector comprising: a capsid protein from AAV and an expression cassette encoding retinoschisin protein, wherein the vector is administered subretinally (see Abstract; Paragraphs 0014, 0017, 0020). Sieving et al. also teach a method wherein the rAAV vector is administered to one or both eyes and wherein administration results in preserved retinal function and structure (see Paragraphs 0042, 0084, 0098-0101). Boye et al., as noted in the previous Office Action, teach a method for treating inherited retinal diseases (IRDs) in a subject using gene therapy, including rAAV vectors (see Page 1464, Left Column, Last Paragraph), which reads on instant Claim 49. Boye et al. also teach a method wherein administering a vector, specifically AAV44.9 (E531D), subretinally to a fovea of one or both eyes of a mammal resulted in restoration of both cone and rod function (see Abstract; Page 1465, Left Column, Paragraph 2). As such, the combination of these two references still renders obvious the limitations of the instant claims, even with the exclusion of Dyka and Hauswirth (US 2022/0175969 A1), as the capsid variant disclosed by Boye et al. would enable better expression in the eye for retinoschisin, as disclosed by Sieving et al., using an eye-specific promoter, also disclosed by Sieving et al. This capsid variant would also allow for better transduction of the eyes, which would greatly enhance the therapeutic effect of the rAAV expressing retinoschisin of Sieving et al. and make it more cost effective to use in gene therapy. Therefore, for at least these reasons, the rejection of Claims 49, 52, and 54 under 35 U.S.C. 103 as being unpatentable over the prior art is maintained.
New Rejections
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.
(New Rejection – necessitated by amendment) – Claims 1-2, 6, 8-12, 17-18, 20, 23-24, 28-29, 40, and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Sieving et al. (US 2016/0002666 A1, Published 07 January 2016) (cited on IDS filed on 19 July 2023 by Applicant as U.S. Patent No. 9,873,893 B2) (cited in the previous Office Action), in view of LaCroix-Desmazes et al. (US 2021/0228738 A1, earliest Priority Date 29 July 2021) (cited in the previous Office Action), O’Riordan and Adamowicz (US 2017/0173183 A1, Published 22 June 2017) (cited in the previous Office Action), Xie and Guo (US 2022/0403417 A1, earliest Priority Date 20 November 2019) (cited in the previous Office Action), and Beltran et al. (US 2015/0202269 A1, Published 23 July 2015), Boye et al. (Boye SL, Choudhury S, Crosson S, Di Pasquale G, Afione S, Mellen R, Makal V, Calabro KR, Fajardo D, Peterson J, Zhang H, Leahy MT, Jennings CK, Chiorini JA, Boyd RF, Boye SE. Novel AAV44.9-Based Vectors Display Exceptional Characteristics for Retinal Gene Therapy. Mol Ther. 2020 Jun 3;28(6):1464-1478.) (cited on IDS filed on 19 July 2023 by Applicant), and TarMart (2018).
Sieving et al. still teach the limitations of the instant claims, namely an scAAV expressing a heterologous nucleic acid encoding a human retinoschisin protein which consists of reference SEQ ID NO: 2, which is 100% identical and the exact same length as instant SEQ ID NO: 12 (see Sequence Listing), wherein said heterologous nucleic acid comprises an intron (see Paragraphs 0050-0051), under the control of an eye-specific promoter, such as a rhodopsin kinase promoter, which allows for expression of the therapeutic protein in cells such as photoreceptor cells of a mammalian eye (see Paragraphs 0012-0013, 0042, 0046, 0078, 0102-0103, 0105, 0107), and wherein said heterologous nucleic acid is a cDNA of the human retinoschisin protein under control of non-native promoters for use in the disclosed expression vectors, including a rhodopsin promoter and a rhodopsin kinase promoter (see Paragraph 0046), which reads on instant Claims 17 and 29. Sieving et al. also teach wherein said scAAV expressing said heterologous nucleic acid also further comprises a post-transcription regulatory element positioned downstream, or 3’, of the heterologous nucleic acid encoding a human retinoschisin protein and a polyadenylation site (see Paragraphs 0102 and 0104), which reads on instant Claims, 6, 9, 18. Additionally, Sieving et al. teach that the polynucleotide comprises the human β-globin 3’ UTR, and therefore does not comprise the 3’ UTR of the human retinoschisin protein (see Paragraphs 0102 and 0104), which reads on instant Claims 1, 11-12, 56. Furthermore, Sieving et al. teach a vector comprising a 3.5-kb human retinoschisin promoter and a human retinoschisin cDNA containing a truncated retinoschisin first intron (see Paragraph 0009), wherein the intron is positioned upstream, or 5’, of the heterologous nucleic acid (see Figure 1), which reads on instant Claim 2.
Sieving et al. does not teach an AAV vector comprising a polynucleotide that comprises a heterologous nucleic acid encoding a human retinoschisin protein and an intron, wherein said intron comprises an SV40 intron, or a polynucleotide wherein said heterologous nucleic acid is operably linked to a rhodopsin kinase promoter corresponding to instant SEQ ID NO: 7.
LaCroix-Desmazes et al. teach a viral vector, such as AAV, comprising a heterologous polynucleotide encoding a therapeutic molecule, including human retinoschisin (see Paragraphs 0012, 0017, 0049), which reads on instant Claims 1 and 11. LaCroix-Desmazes et al. also teach wherein said viral vector comprises an expression cassette comprising elements such as an intron, a polyadenylation signal, and a WPRE post-transcription regulatory element (see Paragraphs 0096, 0114, 0128, 0212), which reads on instant Claims 1-2, 6, 8-9, and 20. LaCroix-Desmazes et al. also contemplates embodiments wherein the AAV vector comprises a heterologous nucleic acid encoding a therapeutic protein or polynucleotide cloned therein with or without 5’, 3’, and/or intron regions that the gene is normally associated with (see Paragraph 0096). Additionally, LaCroix-Desmazes et al. teach an AAV vector comprising a heterologous polynucleotide encoding polypeptides, wherein said polypeptides can comprise a tag, such as a myc tag (see Paragraphs 0049, 0194), which reads on instant Claim 24.
O’Riordan and Adamowicz teach an AAV comprising an intron and a polyadenylation signal (see Paragraphs 0119, 0122, 0138), which reads on instant Claims 1-2 and 9. O’Riordan and Adamowicz also teach AAV comprising stuffer sequences which are on the 3’ side of the heterologous nucleic acid and on the 3’ side of the polyadenylation signal, wherein said stuffer sequence corresponds to reference SEQ ID NO: 11 and is 2239 nucleotides long (see Paragraphs 0119, 0121; Sequence Listing), which reads on instant Claims 1 and 10.
Sieving et al. teach SEQ ID NO: 1, which is 90.8% identical to instant SEQ ID NO: 9 and 89.2% identical to instant SEQ ID NO: 10 (see Sequence Listing), which reads on instant Claims 23-24.
Xie and Guo teach codon optimization of a gene of interest being delivered by an rAAV vector in which the codon optimization reduces the number of CpG dinucleotide islands (see Paragraphs 0025, 0028-0029), which reads on instant Claim 23.
Beltran et al. teach methods for treating X-linked eye diseases using AAV vectors, wherein the AAV carries a nucleic acid sequence encoding the therapeutic protein under the control of regulatory sequences which express the protein in the photoreceptor cells of a subject (see Abstract). Specifically, Beltran et al. teach that said regulatory sequences comprise a promoter, such as the human G-protein-coupled receptor protein kinase 1 promoter, which corresponds to reference SEQ ID NO: 2 and is 100% identical to and the exact same length as instant SEQ ID NO: 7 (see Figure 1; Paragraph 0049), which reads on instant Claim 28. Beltran et al. also teach that said regulatory sequences may also contain an intron between the promoter/enhancer sequence and the gene encoding the therapeutic protein, meaning that it is 5’ of, or upstream of, said gene, and wherein said intron is derived from SV-40 (see Paragraph 0046), which reads on instant Claim 2.
Boye et al. teach a method for treating inherited retinal diseases (IRDs) in a subject using gene therapy, including rAAV vectors (see Page 1464, Left Column, Last Paragraph). Boye et al. also teach a method wherein administering a vector, specifically AAV44.9 comprising an E531D mutation, subretinally to a fovea of one or both eyes of a mammal resulted in restoration of both cone and rod function (see Abstract; Page 1465, Left Column, Paragraph 2), which reads on instant Claim 40.
TarMart teaches both a plasmid and an AAV vector comprising an ORF/cDNA clone of human retinoschisin (RS1/RS/XLRS1), specifically products pGMAAV000362 and vGMAAV000362 (see attached product webpages and data sheets). Both the construct and the AAV vector contain the ORF protein sequence for retinoschisin that is 100% identical to and the same length as instant SEQ ID NO: 12 (see Sequence Alignment attached) and neither possesses either a 5’ UTR or a 3’ UTR, which reads on instant Claims 1, 11-12, 17, and 56.
A person having ordinary would have been motivated to modify the teachings of Sieving et al. with those of LaCroix-Desmazes et al., O’Riordan and Adamowicz, Xie and Guo, Beltran et al., Boye et al., and TarMart in order to generate an AAV or rAAV expressing retinoschisin. The regulatory elements disclosed by both LaCroix-Desmazes et al., O’Riordan and Adamowicz, and Beltran et al. would allow for proper expression of the human retinoschisin protein disclosed by Sieving et al, particularly the use of an eye-specific promoter, such as the one disclosed by Beltran et al. The use of stuffer sequences and/or cDNA encoding a therapeutic protein, such as retinoschisin, lacking the UTRs, as disclosed by LaCroix-Desmazes et al. and Sieving et al., would allow for the expression cassette of Sieving et al. to be the proper size for packaging in the disclosed AAV vector of Sieving et al., which would increase packaging efficiency and increase the number of AAV vectors produced containing the therapeutic protein. It would also be obvious to optimize the size of the insert size in order to maximize packaging efficiency. Routine optimization is not patentable. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). Since Applicant has not disclosed that the specific limitations recited in instant claims are for any particular purpose or solve any stated problem, and the prior art teaches that parameter magnitudes that are encompassed by instant claims, often vary according to the sample being analyzed and various matrices, solutions and parameters appear to work equally as well, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable ranges of the methods disclosed by the prior art by normal optimization procedures known in the art. Sieving et al. teach that intron sequences are included in the promoter because they increase mRNA export from the nucleus to the cytoplasm compared to an intron-less construct for most cDNAs (see Paragraph 0051). The codon optimization technique disclosed by Xie and Guo reduces the number of structural elements, such as CpG islands, which may be immunogenic in a mammalian host. This would make the polynucleotide encoding the therapeutic protein less immunogenic and thus safer for administration to subjects, and making a safer therapeutic would have been an obvious thing to do to a skilled artisan. The inclusion of a myc tag, as disclosed by LaCroix-Desmazes et al., would be useful in the potential purification and/or detection of the polypeptide. The combination of these references would lead a person having ordinary skill in the art to instant SEQ ID NOs: 9 and 10 and as such they would be rendered obvious over these prior art references as the modifications to SEQ ID NO: 1 of Sieving et al., which is 100% identical to instant SEQ ID NO: 8, and instant SEQ ID NOs: 9 and 10 are simply obvious variants of instant SEQ ID NO: 8. The capsid variant disclosed by Boye et al. would enable better expression in the eye for retinoschisin, as disclosed by Sieving et al., using an eye-specific promoter, also disclosed by Sieving et al. This capsid variant would also allow for better transduction of the eyes, which would greatly enhance the therapeutic effect of the rAAV expressing retinoschisin of Sieving et al. and make it more cost effective to use in gene therapy. The plasmid construct and AAV vector of TarMart demonstrate that it was well known in the prior art that human retinoschisin could be successfully expressed from an AAV vector without the presence of either UTR as these products were commercially available prior to the effective filing date of the instant application. The combination of these references renders the claimed invention obvious.
Such modifications, combining prior art elements according to known methods to yield predictable results, would have had a reasonable expectation of success and arrived at the claimed invention prior to the effective filing date of the instant application. For at least these reasons, instant Claims 1-2, 6, 8-12, 17-18, 20, 23-24, 28-29, 40, and 56 are rejected under 35 U.S.C. 103 as being unpatentable over the prior art.
Response to Arguments
Applicant's arguments filed 16 March 2026 have been fully considered. While the original rejections have been withdrawn in light of the amendments to the claims and the invocation of the 102(b)(2)(C) exception regarding Dyka and Hauswirth (US 2022/0175969 A1), a new rejection was warranted which utilizes the teachings of Sieving et al., LaCroix-Desmazes et al., O’Riordan and Adamowicz, Xie and Guo, and Boye et al., and the arguments presented regarding these teachings will be addressed as applicable herein in the interest of compact prosecution.
In their Response, Applicant argues “that amended claim 1 is not obvious in view of LaCroix-Desmazes and O’Riordan at least because a person of skill in the art would not be motivated to remove the 5’ UTR of the human retinoschisin gene with an AAV vector with an expectation that the vector would be suitable for gene expression” and that they show “unexpected results in that the claimed vector was able to restore vision in a mouse model of XLRS using a vector without the 5’ UTR of retinoschisin” (see Page 4, Paragraph 2). Applicant also argues that a “person of skill in the art presented with the combination of cited references would have no reason to remove the 5’ UTR and/or 3’ UTR of retinoschisin gene within an AAV vector” and that while LaCroix-Desmazes does describe retinoschisin within the context of a large list of at least 90 potential heterologous polynucleotides”, “it is silent regarding the regulatory regions that control or modify its expression, including the 5’ UTR, which comprises its native promoter” (see Page 4, Last Paragraph). Applicant then argues that although “O’Riordan discloses an entirely different gene, rhodopsin, that lacks 5’ and 3’ UTRs, the purpose for removing at least the 3’ UTR is to replace it with a miR-708 to suppress activity of mutant rhodopsin” (see Page 5, First Paragraph). Applicant next argues that “at the time of filing the application, retinoschisin was expressed using its endogenous regulatory system (i.e., maintaining the 5’ UTR comprising its native promoter) because it was unknown what promoter would be necessary for expression to restore functional vision” (see Page 5, Paragraph 2). Additionally, Applicant argues that “surprisingly, Applicant was able to produce an AAV vector without the 5’ untranslated region of human retinoschisin and the 3’ untranslated region of a non-native promoter, that not only expressed retinoschisin, but also had a functional effect on the retinas of retinoschisin knockout mice” (see Page 5, Last Paragraph and Page 6, First Paragraph). Furthermore, Applicant argues that a “person of skill in the art presented with the combination of cited references would have no reason to remove the 5’ UTR (and 3’ UTR, as recited in new claim 56) of a retinoschisin gene within an AAV vector”, that “Sieving describes the use of endogenous retinoschisin untranslated regions in the vector to mirror endogenous expression (the vector comprises the 3.5-kb human retinoschisin promoter and a human retinoschisin cDNA)” (see Page 7, Paragraph 3), and that, in “view of the combination of cited references, a person of skill in the art would not only have no reason to remove the endogenous 5’ UTR of retinoschisin, that person would not replace such region with a photoreceptor-specific promoter, with any expectation that the retinoschisin would be expressed in the appropriate cells for a therapeutic effect (see Page 7, Paragraph 4).
In their Response, Applicant invoked the 102(b)(2)(C) exception regarding Dyka and Hauswirth (US 2022/0175969 A1) to overcome the obviousness rejection (see Pages 8-9 of Remarks). Applicant also argues that the “other cited references, Sieving and Boye, do not teach or suggest the subject matter of Dyka” (see Page 9, Paragraph 2).
Examiner does not find these arguments persuasive. In their Response, Applicant argues that “Applicant has amended claim 17 to recite “[a] recombinant (rAAV) vector…wherein the polynucleotide does not comprise the 5’ untranslated region of human retinoschisin (SEQ ID NO: 39)” and that the “vector disclosed in Sieving (SEQ ID NO: 16 of Sieving) comprises the 5’UTR of retinoschisin”. Applicant then provides a partial sequence alignment to illustrate the sequence homology (see Page 3 of Remarks, Paragraphs 2-4).
While it is true that Sieving et al. disclose reference SEQ ID NO: 16, which does indeed comprise a sequence that is 100% identical to instant SEQ ID NO: 39 (Examiner confirmed independently via sequence alignment), this is one specific embodiment that is disclosed in Sieving et al. This is not the only embodiment disclosed by Sieving et al. and any other embodiments taught cannot simply be ignored, even if they are not the preferred embodiment(s) of the prior art. Sieving et al. even states “In one embodiment, the vector comprises SEQ ID NO: 16” (see Paragraph 0016, at least) (emphasis added). Applicant is reminded that preferred embodiments are not the only teaching of a reference.
“The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)).
A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also > Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005)(reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); < Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. “The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.”).
Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). MPEP 2123.
Additionally, Sieving et al. still teach some of the limitations of the instant claims, namely an scAAV expressing a heterologous nucleic acid encoding a human retinoschisin protein which consists of reference SEQ ID NO: 2, which is 100% identical and the exact same length as instant SEQ ID NO: 12 (see Sequence Listing) under the control of an eye-specific promoter, such as a rhodopsin kinase promoter, which allows for expression of the therapeutic protein in cells such as photoreceptor cells of a mammalian eye (see Paragraphs 0012-0013, 0042, 0046, 0078, 0102-0103, 0105, 0107), and wherein said heterologous nucleic acid is a cDNA of the human retinoschisin protein under control of non-native promoters for use in the disclosed expression vectors, including a rhodopsin promoter and a rhodopsin kinase promoter (see Paragraph 0046). Sieving et al. also teach wherein said scAAV expressing said heterologous nucleic acid also further comprises a post-transcription regulatory element positioned downstream, or 3’, of the heterologous nucleic acid encoding a human retinoschisin protein and a polyadenylation site (see Paragraphs 0102 and 0104). Additionally, Sieving et al. teach that the polynucleotide comprises the human β-globin 3’ UTR, and therefore does not comprise the 3’ UTR of the human retinoschisin protein (see Paragraphs 0102 and 0104). With respect to the argument regarding the promoter used and the presence or absence of the untranslated regions in the constructs of Sieving et al., while Sieving et al. does contemplate an embodiment with the 3.5-kb human retinoschisin promoter and a human retinoschisin cDNA, this is one specific embodiment that is disclosed in Sieving et al., as noted previously. This is not the only embodiment disclosed by Sieving et al. and any other embodiments taught cannot simply be ignored, even if they are not the preferred embodiment(s) of the prior art, also as noted previously. Sieving et al. explicitly contemplates other promoters for use in the disclosed expression vectors, including a rhodopsin promoter and a rhodopsin kinase promoter (see Paragraph 0046), as claimed in instant Claim 28. This also rebuts Applicant’s arguments that the prior art references would not provide any motivation or suggestion of using the non-native promoter or 5’ UTR region for expressing human retinoschisin or that it would be unknown what promoter or promoters could be used to restore functional vision, which then calls into question how unexpected the instant results really are if the prior art had already contemplated the same or very similar constructs. Even if this embodiment was not the preferred embodiment, a skilled artisan would have had a reason to try this combination and arrived at the same combination as the instant invention. Also, Sieving et al. explicitly teach that the polynucleotide comprises the human β-globin 3’ UTR, and therefore does not comprise the 3’ UTR of the human retinoschisin protein (see Paragraphs 0102 and 0104), as noted previously.
With respect to the argument that the removal of the 3’ UTR in the constructs disclosed by O’Riordan and Adamowicz serve a different purpose than that of the instant claims, O’Riordan and Adamowicz is no longer being relied upon to provide that teaching. As such, this argument is no longer relevant.
With respect to the argument that LaCroix-Desmazes et al. is silent regarding the regulatory regions that control or modify its expression, including the 5’ UTR, which comprises its native promoter, LaCroix-Desmazes et al. explicitly contemplates embodiments wherein the AAV vector comprises a heterologous nucleic acid encoding a therapeutic protein or polynucleotide cloned therein with or without 5’, 3’, and/or intron regions that the gene is normally associated with (see Paragraph 0096).
Applicant did not present any specific arguments regarding Gray or Xie and Guo, so no specific rebuttals are required. Also, Gray has not been used in this new rejection.
While the invocation of the 102(b)(2)(C) exception does disqualify Dyka and Hauswirth (US 2022/0175969 A1) from being used as prior art, the other references cited still meet the limitations of the instant claims. As noted in the previous Office Action, Sieving et al. teach a method of treating X-linked retinoschisis (XLRS) in a human comprising administering to said human a therapeutically effective amount of an expression vector comprising: a capsid protein from AAV and an expression cassette encoding retinoschisin protein, wherein the vector is administered subretinally (see Abstract; Paragraphs 0014, 0017, 0020). Sieving et al. also teach a method wherein the rAAV vector is administered to one or both eyes and wherein administration results in preserved retinal function and structure (see Paragraphs 0042, 0084, 0098-0101). Boye et al., as noted in the previous Office Action, teach a method for treating inherited retinal diseases (IRDs) in a subject using gene therapy, including rAAV vectors (see Page 1464, Left Column, Last Paragraph). Boye et al. also teach a method wherein administering a vector, specifically AAV44.9 (E531D), subretinally to a fovea of one or both eyes of a mammal resulted in restoration of both cone and rod function (see Abstract; Page 1465, Left Column, Paragraph 2). As such, the combination of these two references still renders obvious the limitations of the instant claims, even with the exclusion of Dyka and Hauswirth (US 2022/0175969 A1), as the capsid variant disclosed by Boye et al. would enable better expression in the eye for retinoschisin, as disclosed by Sieving et al., using an eye-specific promoter, also disclosed by Sieving et al. This capsid variant would also allow for better transduction of the eyes, which would greatly enhance the therapeutic effect of the rAAV expressing retinoschisin of Sieving et al. and make it more cost effective to use in gene therapy.
Finally, with regard to Applicant’s claims of unexpected results, the teachings of the prior art references used suggest that these alleged unexpected results are in fact not unexpected as the prior art contemplates the same or similar constructs, vectors, and/or conditions. For instance, the teachings of TarMart in particular call into question how unexpected Applicant’s results really are, as such products should not have been commercially available prior to the effective filing date of the instant application, based on Applicant’s Arguments, if the prior art indeed had no indication that constructs and/or vectors comprising retinoschisin without either UTR would be viable. As such, it would be reasonable for a person having ordinary skill in the art to expect the same or similar results using the combination of the prior art references cited here. Even if the instant results are indeed unexpected and would justify patentability, the claims need to be drawn to the specific UTRs which were used by Applicant. As currently written, the claims are drawn to constructs with any UTRs, as long as they do not comprise instant SEQ ID NOs: 39 and/or 40. In fact, the claims currently read upon mutant retinoschisin UTRs, as a single base change in either or both UTRs would mean that neither would comprise instant SEQ ID NOs: 39 and/or 40. It is strongly suggested that Applicant amend the claims to explicitly recite the specific UTRs which were used. If no UTRs are present at all, then the claims should explicitly recite that. As such, the current claim set is not commensurate in scope with the arguments presented and the alleged unexpected results.
Conclusion
No claims are 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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/CAREY ALEXANDER STUART/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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