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 .
Status of Application/Amendments/Claims
Applicant’s response filed on 8/4/2025 has been considered.
Claim 1 has been amended. Claims 1, 3-4 and 6-13 are pending. Claims 4 and 6-12 are currently withdrawn with traverse from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1, 3 and 13 are the subject of the present Official action. All previous rejections have been withdrawn and the following action is made nonfinal. 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
Applicant’s claim for the benefit of a prior-filed application PRO 62/476,290 and PCT/US2018/024305 filed on 3/24/2017 and 3/26/2018, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 3/24/2017.
Withdrawn Rejections
The 35 U.S.C. 112(b) rejections of claims 1, 3 and 13 have been withdrawn in light of applicants claim amendments canceling language directed to a comparison between the visceral fat transduction of the claimed AAV vector as compared to an AAV2/8 based vector.
The 35 U.S.C. 103 rejection of claims 1, 3 and 13 is withdrawn since During does not teach the use of a liver specific promoter.
The nonstatutory double patenting rejection of claim 1 over co-pending Application No: 18/024,806 has been withdrawn in light of applicant’s arguments stating that the instant case has an earlier filing date and non-overlapping subject matter.
Claim Interpretation
Claim 1 describes a second cassette comprising a liver specific promoter operatively linked to a RNA silencing element. It is emphasized that the liver is a metabolic organ comprised of numerous cell types including hepatocytes, cholangiocytes adipocytes and various progenitor cells. Thus, the liver specific promoter described is not necessarily limited to hepatocyte specific promoters (albumin or hATT) but may also include other cell types found in the liver.
New 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 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.
Claims 1, 3 and 13 are newly rejected under 35 U.S.C. 103 as being unpatentable over During et al. US 2011/0288160, published 11/24/2011 (hereinafter During, reference of record) in view of O'Neill et al. "Targeting adipose tissue via systemic gene therapy." Gene therapy 21.7 (2014): 653-661 (hereinafter O'Neill, reference of record) and Oka et al. "Recent advances in liver-directed gene therapy: implications for the treatment of dyslipidemia." Current Opinion in Lipidology 11.2 (2000): 179-186 (hereinafter Oka). This rejection is newly applied.
Claims 1 and 3: During describes an engineered AAV vector comprising two expression cassettes, wherein the first cassette comprises a regulatory element and a transgene operatively linked to a promoter and wherein the second cassette comprises a promoter operatively linked to miRNA silencing element that targets the regulatory element in the first expression cassette (During, para 3, 17, 61 and 90). During presents this dual expression cassette strategy as an effective method to regulate a given functional transgene of interest, wherein the transgene is self-regulated by a miRNA driven by one or more promoters activated, in turn, by a physiological change induced by the transgene of interest (During, para 61). During describes experimental data showing the advantages of such a dual expression system, wherein a “negative feedback like regulation of transgene expression responsive to physiological changes” can be achieved (During, para 266 and Example 2). During outlines the dual expression cassette system in Fig 4a (shown below). During states that the second expression cassette uses a promoter (AGRP484) which is responsive to BDNF-induced physiological changes (During, para 90). During describes the use of a woodchuck posttranscriptional regulatory element (WPRE) sequence as the regulatory element controlling the transgene expression for the first expression cassette (During, para 189).
During does not describe the use of a liver specific promoter operatively linked to the microRNA in the second expression cassette. Although the majority of During’s disclosure focuses on BDNF transgene expression for treating metabolic disorders, During does mention that BDNF expression led to a sharp decrease in leptin and insulin, which are known correlates with fat mass (During, para 132 and 215-216). During does not expressly describe the transgene of the first expression cassette as a leptin gene.
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Claim 13: During describes microRNA encoded by the second expression cassette including SEQ ID NO: 3 miR-XVPRE (mature miR seq: CTATGTGGACGCTGCTTTA, corresponding to SEQ ID NO: 1 of the instant application; sequence search results shown below) which acts on the WPRE regulatory element in the first expression cassette (During, Fig 14, para 123 and example 2).
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Claims 1 and 3: O'Neill describes an adipose-targeting AAV expression vector encoding a leptin transgene as a gene therapy for metabolic diseases (O'Neill, abstract). O'Neill experimented with multiple vector formulations and found that AAV2/8 vectors containing an adiponectin promoter/enhancer element had selective leptin expression in adipose tissue (O'Neill, abstract). O'Neill describes improved adipose specificity and reduced immune response against the transgene by incorporating a synthetic liver-specific miRNA (miR-122) target site into the 3’ UTR of the expression cassette (O'Neill, intro last para). O'Neill describes the AAV construct in Fig 1, showing preferential expression in subcutaneous fat and liver tissue by implementing adiponectin distal enhancer and proximal promoter elements (O'Neill, Fig 1).
It would have been prima facie obvious to one of ordinary skill in the art to substitute the leptin transgene as described by O'Neill into the dual expression cassette AAV vector as described by During. It would have been a matter of simply substituting one known transgene for another (BDNF for leptin) to obtain predictable results since both are known therapeutic proteins associated with treating metabolic disorders. One would have been motivated to make this substitution given that leptin is a known protein hormone which regulates food intake, enhances thermogenesis and metabolic rates (O'Neill, pg 658). Although the majority of During’s disclosure focuses on BDNF transgene expression for treating metabolic disorders, During does mention that BDNF expression led to a sharp decrease in leptin and insulin, which are known correlates with fat mass (During, para 132 and 215-216). Thus, one would have a reasonable expectation of success given that During was well aware of the important role leptin expression plays in metabolic disorders and there exists predictable means for substituting one therapeutic transgene for another in AAV vectors.
Although it is argued in the claim interpretation section that “liver specific promoter” as recited in claim 1 is not necessarily limited to hepatocyte specific promoters (albumin or hATT) but may also include other cell types found in the liver like adipocytes, neither During nor O'Neill expressly describe the use of liver specific promoters which may conventionally be defined as hepatocyte specific promoters.
Claim 1: However, liver specific promoters are known in the art and routinely used to direct AAV expression for liver-directed gene therapy. Oka describes the use of albumin promoters to drive AAV expression in the liver and cites numerous supporting studies (Oka, pg 180 col 2; Ref 14).
It would have been prima facie obvious to one of ordinary skill in the art to substitute the adiponectin promoter as described by O'Neill into the dual expression cassette AAV vector as described by During. It would have been a matter of simply substituting one known promoter for another (WPRE for albumin) to obtain predictable results. One would have been motivated to make this substitution given that albumin is a liver specific promoter which would result in higher microRNA expression in the liver and thus inhibit leptin expression in the liver. One would have a reasonable expectation of success given that O'Neill used a similar approach to incorporate a synthetic liver-specific miRNA (miR-122) target site into the 3’ UTR of the expression cassette in order to eliminate hepatic transgene expression (O'Neill, intro last para). Furthermore, Oka shows that promoter choice is a known variable in directing AAV expression to the liver (Oka, pg 180 col 2). Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Conclusion
No claims allowed.
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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634