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 .
Priority
Applicants’ claim for the benefit of a prior-filed application parent provisional application 63149122 filed on 02/12/2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) was filed before the mailing date of the non-final first action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Election/Restrictions
Applicant's election with traverse of claims 1-3,5,7-12,23 ,and 29 in the reply filed on 04/27/2026 is acknowledged. The traversal is on the ground(s) that examining one alleged species would necessarily involve review of issues relevant to the others, therefore examining
the non-elected subject matter/species would not impose a serious or undue search
or examination burden. This is not found persuasive because, as discussed previously, even if the species subjected to restriction share the technical feature of a viral vector comprising a transgene construct comprising a DNA segment of retinal genes longer than 10kb, this technical feature is not a special technical feature as it does not make a contribution over the prior art Liu et al in view of Brennan et al ( See rejection below).
Applicants also argue that there is no search burden to examine the nonelected species. This is not found persuasive, because search burden is not a consideration in the lack of unity practice.
Therefore, the requirement is still deemed proper and is therefore made FINAL.
Claims 4,6, 13-22, 24-28, and 30-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 04/27/2026. Claims 1-3,5,7-12,23, and 29 are under examination
Claim Objections
Claim 12 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 11. Applicant is advised that should claim 11 be found allowable, claim 12 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Interpretation
It is noted that the term "retinal gene’s" recited in claim 1 is unclear, since retinal cells have the same set of genes as any other somatic cell in the body. For examination purpose, the term “retinal gene’s” is interpreted to mean genes that are exclusively expressed in retinal cells.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3,5,10,23, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al (BMB Reports, 2020), in view of Brennan et al ( US 2010/0120155 A1)
Regarding claims 1-3,5, 10, 23, and 29, Liu et al disclose a third-generation adenoviral vector, referred to as gutless adenovirus (GLAd), wherein GLAd is constructed by deleting all the viral genes from an adenovirus, only leaving the ITRs and the ψ packaging signal in its genome backbone. ( See Fig. 2). Liu et al state that “ This structural characteristic eliminates the expression of viral proteins in transduced cells and only induces negligible immune responses, enabling high level and persistent transgene expression in host organism. Importantly, this large deletion also increases the cargo capacity for the transgene up to 36 kb, which allows the delivery of a large transgene or multiple transgenes”. ( See section “ The third-generation adenoviral vector: gutless adenovirus(GLAd), on page 567”. Liu et al teach that GLAd is a helper-dependent gutless adenovirus vector that can be used for gene delivery comprising a transgene construct. Liu et al state while the helper adenovirus efficiently provides helper functions, it remains as an unavoidable contaminant and also generates replication competent adenovirus (RCA) during the production of GLAd. Thus, Liu et al also teach a helper virus-free gutless adenovirus (HF-GLAd), a new version of GLAd, which is produced by a helper plasmid instead of a helper adenovirus. (See abstract, and Fig.4). Liu et al teach that HF-GLAd is an ideal vector to safely deliver large transgenes to treat inherited eye diseases such as retinitis pigmentosa 25 (with mutations involving the EYS gene ( also known as eyes shut homolog),~9.5 kb) , and retinitis pigmentosa 39 (associated with USH2A gene mutations,~15.6 kb) . ( See page 571, 2nd column, 1st paragraph).
Liu et al , on the other hand, do not explicitly state that the transgene construct comprises of a DNA sequence comprising a promoter and terminator elements (i.e. option (a) of instant claim 1 and claim 10).
Brennan et al supplement Liu et al by teaching how to construct a fully-deleted (i.e. gutless) adenovirus-based gene delivery vector that is packaged without helper adenovirus and can be used for gene therapies. According to Brennan et al, the fully-deleted/gutless adenovirus vector is engineered to comprise a promoter, a gene of interest, and a polyadenylation signal sequences (i.e. terminator sequence), the LITR ψ and RITR from Adenovirus, and two
regions of homology with the stuffer plasmid DNA sequence, together forming a gene-expression construct . ( See Fig.1, [0063], and [0108]). Brennan et al teach that the fully-deleted/gutless viral vectors are "high-capacity" Adenoviruses as they can accommodate up to 36 kilobases of DNA. ([0062]).
Taken together, the instant claims are combining prior art elements according to known methods to yield predictable results, namely the predictable result being the construction of a fully-deleted viral vector comprising a gene expression cassette comprising a promoter operably linked to a gene of interest (i.e.Ush2A) and a terminator sequence. Liu et al teach that HF-GLAd is being an ideal vector to safely deliver large transgenes to treat inherited eye diseases such as retinitis pigmentosa 39 (associated with USH2A gene mutations,~15.6 kb), and strongly suggest that the use of such vector would be advantageous for the delivery of a large transgene (i.e. transgene up to 36 kb), but fail to explicitly state the individual components of the transgene construct. Brennan et al supplement Liu et al by demonstrating how to construct a fully-deleted adenoviral vector comprising a transgene construct suitable for gene therapy. Brennan et al also teach the basic elements a transgene construct may include to facilitate gene expression (i.e. promoter, and terminator sequence). Thus, an ordinary skill in the art who had reviewed Liu et al, could have come across Brennan et al and immediately noticed the strong possibility that the construction of an HF-GLAd vector comprising a transgene construct encoding Ush2A according to Brennan et al’s teachings, would have the predictable result of generating an effective HF-GLAd vector for Ush2A delivery.
Claims 7,9, and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al and Brennan et al as applied to claims 1-3,5,10,23, and 29 above, and further in view of Khanna et al (WO 2020/214796 A1).
The teachings of Liu et al and Brennan et al are set forth above.
Regarding claims 7,9, and 11-12, the teachings of Liu et al in view of Brennan et al render obvious the use of a helper virus-free gutless adenovirus comprising a transgene construct encoding Ush2A. It is noted that neither Liu et al nor Brennan et al teach that the expression of the transgene is driven by the human rhodopsin kinase promoter, a viral vector encapsulated in a capsid based on adenovirus type 6, or adenovirus in families of A-G.
Khanna et al supplements Liu and Brennan by teaching a recombinant adeno-associated virus (rAAV) comprising a transgene and its regulatory sequences. According to Khanna et al, the transgene may comprise, one or more regions that encode one or more proteins (e.g., human USH2A, or a fragment thereof), and hence the viral vector can be used for treating Usher Syndrome in a subject in need. ( See abstract, page 8 lines 12-16, and claims 8,13-14). In one of the embodiments, Khanna et al teach that the AA V capsid protein can be selected from the serotypes that has tropism for the eye tissues, such as AAV 6, which is known to efficiently transduce ocular cells than other serotypes.( See page 10 lines 8-12). It should be noted that AAV6 belongs to AAV family A. In another embodiment, Khanna et al teach that the transgene further comprises a promoter, wherein the promoter is a tissue-specific promoter, specifically photoreceptor-specific promoter, such as a human rhodopsin kinase promoter, to drive transgene expression specifically in photoreceptor cells. ( See page 2 lines 1-3). Taken together, instant claims are clearly combining prior art elements according to known methods to yield predictable results, namely the predictable result being the utilization of a helper-free gutless AAV with a tropism to ocular cells, comprising a transgene under the control of a photoreceptor-specific promoter. Liu et al in view of Brennan et al render obvious helper-free gutless AAV as an ideal vector to safely deliver large transgenes to treat inherited eye diseases such as retinitis pigmentosa 39 (associated with USH2A gene mutations,~15.6 kb), and strongly suggest that the use of such vector would be advantageous for the delivery of a large transgene (i.e. transgene up to 36 kb), but fail to explicitly state the AAV serotype or the promoter type. Khanna et al supplement Liu and Brennan by teaching the utilization of a rAAV with a tropism to ocular tissue, such as AAV6, for the delivery of a transgene selectively to photoreceptor cells. Thus, an ordinary skill in the art who had reviewed Liu et al and Brennan et al, could have come across Khanna et al and immediately noticed the strong possibility that the construction of HF-GLAd vector with a capsid based on AAV6 and comprising a photoreceptor-specific promoter, as taught by Khanna et al, would have the predictable result of generating an effective HF-GLAd vector for the delivery of a transgene specifically to photoreceptor cells.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Liu et al and Brennan et al as applied to claims 1-3,5,10, 23, and 29 above, and further in view of Cushman et al (The American Society of Gene Therapy, 2007).
The teachings of Liu et al and Brennan et al are set forth above.
Regarding claim 8, the teachings of Liu et al in view of Brennan et al render obvious the use of a helper virus-free gutless adenovirus comprising a transgene construct encoding Ush2A. It is noted that neither Liu et al nor Brennan et al teach a modified AAV vector lacking RGD sequences form the capsid protein.
Cashman et al supplement the recited prior arts by demonstrating that modifying the adenovirus capsid by deleting the RGD domain in the penton base significantly improves retinal transduction, allowing for 700-fold more efficient photoreceptor targeting. According to Cashman et al, the RGD motif is important because adenoviruses normally uses this sequence to bind αvβ3/αvβ5 integrins during cell entry specifically into retinal pigmented epithelial cells (RPE) within the retina. Cashman et al demonstrate that deleting the RGD motif form the penton base greatly reduces the normal RPE bias, improves penetration into neural retina, and enhances photoreceptors transduction. Cushman et al further demonstrate that when an AVV capsid (e.g. Ad5) lacking RGD is combined with a rhodopsin promoter (i.e. photoreceptor- specific promoter), this modified vector achieves exclusive, high-efficiency gene expression in photoreceptors, providing a viable tool for treating retinal degeneration impacting photoreceptor cells. ( See abstract, section “ PR-specific transgene expression”, and Fig.5).
Therefore, instant claim 8 would have been obvious to one of ordinary skill in the art, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Liu et al in view of Brennan et al render obvious helper-free gutless AAV as an ideal vector to safely deliver large transgenes to treat inherited eye diseases such as retinitis pigmentosa 39 (associated with USH2A gene mutations,~15.6 kb), and strongly suggest that the use of such vector would be advantageous for the delivery of a large transgene (i.e. transgene up to 36 kb), but fail to teach a modified AAV lacking RGD motif. Cashman et al supplement the recited prior arts by teaching that capsid engineering, specifically the removal of RGD motifs from an adenovirus capsid, can be utilized to redirect retinal tropism. In other words, the teachings of Cashman et al provide an ordinary skill in the art with the knowledge that removing the RGD motif from an AAV capsid and combining that with a tissue-specific promoter changes which retinal cells are preferentially transduced. Thus, an ordinary skill in the art would be motivated to modify the capsid of the helper-free gutless AAV by removing the RGD motifs, as taught by Cashman, to redirect viral tropism toward photoreceptor cells. There is a reasonable expectation of success, when building a helper virus-free gutless adenovirus, that taking the vector described in Liu and Brennan, and modifying the capsid by removing the RGD motifs, that the vector of claim 8 could be successfully synthesized.
Conclusion
No claim is allowed.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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