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/RCE 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1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 7/23/2026 has been entered. No claims have been amended and the claim sets are interpreted as being patentably indistinct from those submitted on 12/18/2025. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b).
Claims 104, 107, 110, 120, 129, 135, 139-143, 147-162 are the subject of the present office action. 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 62/744,944 and PCT/US2019/055917, filed on 10/12/2018 and 10/11/2019, 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 10/12/2018.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 7/23/2026 were received. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement was considered by the examiner.
Withdrawn Rejections
The 35 U.S.C. 112(a) rejection of claims 104, 107, 110, 120, 129, 135, 139-143, 147-157 and 159 has been withdrawn in light of applicant’s arguments which argue that the genus of transgenes that could be included in the expression cassette were well-known to a person of ordinary skill in the art at the time of filing.
Maintained 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 104, 107, 110, 120, 129, 135, 139-143 and 147-162 stand rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al. US 2019/0336550, published 11/7/2019, priority date 12/30/2016 (hereinafter Wilson, reference of record), in further view of Lahusen et al. US 2020/0318081, published 10/8/2020, priority date 10/2/2017 (hereinafter Lahusen, reference of record), Delabar et al. FR2978457, published 7/27/2011(hereinafter Delabar, reference of record), Fontanellas et al. WO 2016/037931, published 3/17/2016 (hereinafter Fontanellas, reference of record), Kim et al. US 2019/0343864, published 11/14/2019 (hereinafter Kim, reference of record), Doering et al. US 2017/0326256, published 11/16/2017 (hereinafter Doering, reference of record), Kyostio-Moore et al. US 2019/0048362, published 2/14/2019, priority date 9/17/2015 (hereinafter Kyostio-Moore, reference of record), Minshull et al. US 2020/0283798, published 9/10/2020 (hereinafter Minshull, reference of record), Flotte et al. WO 99/55564, published 11/4/1999 (hereinafter Flotte, reference of record), Alam et al. US 2017/0342441, published 11/30/2017 (hereinafter Alam, reference of record) and Vance et al. "AAV gene therapy for MPS1-associated corneal blindness." Scientific reports 6.1 (2016): 1-10 (hereinafter Vance, reference of record). This rejection is repeated for the same reasons of record as set forth in the Official action dated 4/3/2026. A response to applicant’s traversal follows the rejection below.
Claim 104: Wilson describes the development and use of recombinant adeno-associated virus (rAAV) with transthyretin enhancers for driving the expression of human phenylalanine hydroxylase as a therapy for phenylketonuria (PKU) (Wilson, para 3, 6-10 and 28). Wilson describes the use of liver-specific expression control elements including the use of a mouse transthyretin enhancer (mTTR) (Wilson, para 59 with reference to SEQ ID NO: 5). Wilson describes the use of liver-specific enhancers including alpha 1-microbikunin enhancers (mA1MB2) and modified shortened versions thereof (Wilson, para 59). Wilson does not use the specific enhancer sequences identified in SEQ ID NOs 7-11 with at least 95% identity. Wilson does not use the specific mTTR482 promoter.
Claims 107 and 110: Wilson describes the use of liver-specific promoters and 3’ elements including alpha 1 anti-trypsin (A1AT) promoters and modified versions thereof (Wilson, para 60, SEQ ID NO: 10 and Fig 1). Wilson describes other suitable promoters and 3’ elements including hum Alb (Wilson, para 60). Wilson does not use the a 3’Alb/SMAR sequences comprising SEQ ID Nos 12 and 13.
Claim 120, 129 and 135: Wilson describes rAAV particles and vector compositions comprising the expression cassette (Wilson, para 6-10, claim 1 and Example 2). Wilson describes expression cassettes with 5’ to 3’ arrangements of enhancers, promoters, introns and transgenes (Wilson, para 28, 59 and Fig 1). Wilson describes a total rAAV vector genome from about 2-5.5 KB in size, indicating that the encoded transgene would be smaller than 5KB (Wilson, para 61).
However, each of the recited expression cassette elements were known in the art and it would have been prima facie obvious to one of ordinary skill to select the corresponding promoters, enhancers, introns and 3’ elements to meet the limitations of claims 104, 107, 110, 120, 129, 135, 139-143 and 147-162 based on substituting equivalents. For instance, MPEP 2144.07 states that “the selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carrol Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitutions obvious, see MPEP 2144.06.
Claim 139: Lahusen describes a viral vector expression cassette for treating PKU in a subject by expressing PAH (Lahusen, abstract). Lahusen describes the use of liver-specific enhancers including a prothrombin enhancer (Lahusen, example 4, SEQ ID NO: 65, sequence alignment shown below).
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Claim 158 and 160-162: Lahusen describes a viral vector expression cassette for treating PKU in a subject by expressing PAH (Lahusen, abstract).
Claim 140: Delabar describes an adenoviral vector comprising an alpha 1 microbikunin enhancer to deliver liver specific expression (Delabar abstract, Example 1, SEQ ID NO: 13, sequence alignment shown below).
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Claim 141: Fontanellas describes expression constructs using a mouse albumin gene enhancer element (Fontanellas, claim 8, SEQ ID NO: 7, sequence alignment shown below).
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Claim 142: Kim describes a pharmaceutical composition comprising a liver specific hepatitis B virus enhancer (Kim, claim 39, SEQ ID NO: 19, sequence alignment shown below).
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Claim 143: Doering describes the use of a liver-directed CRM8 enhancer (Doering, para 358 and SEQ ID NO: 100, sequence alignment shown below).
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Claims 104, 107, 110 and 145: Kyostio-Moore descries the use of an mTTR482 promoter in a liver-specific AAV vector (Kyostio-Moore, Fig 1A and para 138).
Claims 147-148: Minshull describes polynucleotide vectors comprising chicken beta actin/rabbit beta-globin hybrid introns (Minshull, claim 31, SEQ ID NO: 160, sequence alignment shown below). The small difference in sequence alignment may be attributed to codon degeneracy.
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Claims 149-150: Flotte describes recombinant viral vectors comprising A1AT intron stuffer sequences (Flotte, Claim 32, Figs 19A-C, sequence alignment shown below). The small difference in sequence alignment may be attributed to codon degeneracy.
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Claims 151-152: Alam discloses a liver-specific vector comprising a human albumin 3’ element and human albumin 3’ element linked to a human alpha 1 antitrypsin scaffold/matrix attachment region (Alam, claim 31, Fig 4, sequence alignment shown below respectively).
3’Alb= SEQ ID NO: 12
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3’AlbSMAR = SEQ ID NO: 13
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It would have been prima facie obvious to one of ordinary skill in the art to select and substitute the corresponding promoters, enhancers, introns and transgenes into the rAAV vector described by Wilson based on substituting equivalents with predictable results. The motivation to combine can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their commonly known purpose, see MPEP 2144. The rationale to modify or combine prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles or legal precedence established by case law, see MPEP 2144. One would have a reasonable expectation of success given that Wilson described similar embodiments using liver-specific expression control elements like the mouse transthyretin enhancer (Wilson, para 59 with reference to SEQ ID NO: 5) and liver-specific enhancers including alpha 1-microbikunin enhancers (mA1MB2) and modified shortened versions thereof (Wilson, para 59).
The collection of cited art does not describe sequences with at least 95% or 100% identity to those found in claims 104, 107, 110, 120, 129, 135, 139-143 and 147-162.
Claims 104, 107, 110, 120, 129, 135, 139-143 and 147-162: Vance describes an AAV expression vector which is codon optimized for expression in human cells (Vance, abstract). Vance outlines commercially available techniques provided by GenScript for the production of codon optimized open reading frames (Vance, results para 1). GenScript and many other companies provide free web-based codon optimization tools which serve to minimize sequence complexity, eliminate deleterious secondary structures and may improve overall protein expression.
It would have been prima facie obvious to one of ordinary skill in the art to use the codon optimization techniques outlined by Vance and the disclosures of Lahusen, Delabar, Fontanellas, Kim, Doering, Kyostio-Moore, Minshull, Flotte and Alam to create codon optimized sequences with at least 95% or 100% identity to those described in claims 104, 107, 110, 120, 129, 135, 139-143 and 147-162 using the sequences in the rAAV vector described by Wilson. It would have been a matter of combining prior art elements according to known methods to yield predictable results since codon optimization procedures are well-known in the art as shown by Vance. One would be motivated to make this combination in order to improve transgene expression in a target host cell along with minimizing sequence complexity. One would have a reasonable expectation of success given the close similarity (greater than 90%) of sequences disclosed by Lahusen, Delabar, Fontanellas, Kim, Doering, Kyostio-Moore, Minshull, Flotte and Alam to those sequences described in claims 139-142, 145 and 151-159, respectively. Furthermore, with respect to claims 155-160, since each of the recited expression cassette elements were known in the art and it would have been prima facie obvious to one of ordinary skill to select the corresponding promoters, enhancers, introns and transgene s to meet the limitations of claims 155-160 based on substituting equivalents. When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitutions obvious, see MPEP 2144.06. 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.
Response to Traversal
Applicant traverses the rejection by arguing that the instant claims require the specific mTTR promoter (mTTR482) with the specific enhancer sequences which are not taught by the prior art. Applicant points to the comparison of expression of murine phenylalanine hydroxylase (mPAH) from the mA1MB2-mTTR482 promoter to mPAH expression from a known liver-specific promoter (LP1) in a PKU mouse model and found that the mA1MB2-mTTR482 vector was more efficacious in reducing blood Phe levels over a course of a 56-day study with further references to Figs 3-4 and Example 2. Applicant emphasizes that the promoter and enhancer elements are critical to the invention and not the particular transgene.
This argument has been fully considered, but is not found persuasive. Although applicant has shown a comparison between the expression of murine phenylalanine hydroxylase (mPAH) from the mA1MB2-mTTR482 promoter to mPAH expression from a known liver-specific promoter (LP1) in a PKU mouse model, applicant has not demonstrated that the combination of the promoter mTTR482 and one or two modified enhancers pPrT2, mA1B2, mEalb, HE11 or CRM8 result in a synergistic outcome greater than what one of ordinary skill would predict based on substituting equivalent expression cassette elements with predictable results. Each of the recited expression cassette elements were known in the art and it would have been prima facie obvious to one of ordinary skill to select the corresponding promoters, enhancers, introns and 3’ elements to meet the limitations of claims 104, 107, 110, 120, 129, 135, 139-143 and 147-162 based on substituting equivalents. For instance, MPEP 2144.07 states that “the selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carrol Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitutions obvious, see MPEP 2144.06. Furthermore, one would have a reasonable expectation of success given that Wilson described embodiments using liver-specific expression control elements like the mouse transthyretin enhancer (Wilson, para 59 with reference to SEQ ID NO: 5) and liver-specific enhancers including alpha 1-microbikunin enhancers (mA1MB2) and modified shortened versions thereof (Wilson, para 59).
Conclusion
No claims allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 extension fee 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
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, Maria Leavitt can be reached on (571)272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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