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
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Applicant’s response filed on 12/18/2025 has been considered. Rejections and/or objections not reiterated from the previous office action mailed 9/18/2025 are hereby withdrawn.
Claims 104, 110, 129, 155 and 158 are amended. Claims 160-162 are newly added.
Claims 104, 107, 110, 120, 129, 135, 139-143, 147-162 are the subject of the present Official action. Claims 104, 107, 110 and 160 are independent claims.
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 9/16/2025 and 12/18/2025 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Withdrawn Rejections
35 USC § 103
The 35 U.S.C. 103 rejection of claims 104, 107, 110, 120, 129, 135, 143 and 147-150 has been withdrawn and applied in modified form to address applicants claim amendments filed on 12/18/2025 to address the increase to 95% identity for several SEQ IDs.
Maintained Claim Rejections in response to Applicants’ amendments–
35 USC § 112a, Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 104, 107, 110, 120, 129, 135, 139-143, 147-157 and 159 stand rejected 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. This rejection is supported by Wilson et al. US 2019/0336550, published 11/7/2019, priority date 12/30/2016 (hereinafter Wilson, reference of record). This rejection is repeated for the same reasons of record as outlined in the Office Action mailed on 9/18/2025. A response to applicant’s traversal follows the rejection below.
The genus of “transgene” refers to a genus that is considered extraordinarily broad. It is thought to encompass ANY transgene both known and yet to be discovered. It encompasses transgenes at any length, which is particularly problematic given that the claimed expression system will have a maximum packing capacity. It is noted that claims 158 and 160-162 are excluded from the instant rejection given that a particular transgene phenylalanine hydroxylase (PAH) is described.
For each claim drawn to a genus, the written description requirement may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant identifying characteristics, i.e. structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in procession of the claimed genius. If a representative number of adequately descried species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, para. 1.
The instant specification exemplifies the expression of phenylalanine hydroxylase (PAH) and “variants” in liver cells (Spec, para 8). The instant specification provides embodiments to PAH variants with N-terminal truncation and specific amino acid mutations/substitutions (Spec, para 10). This is not considered a representative number of samples to support the claim to all transgenes, in part because the specification is entirely directed to the expression of PAH as a treatment of severe PKU by liver-directed gene replacement, but also because of the genus which encompasses all transgenes. Given the breadth of the genus to all imagined transgenes in contrast to the exemplified and prophetic proportions of the specification, which are largely drawn only PAH, the instant specification does not adequately disclose a sufficient number of adequately described species of the genus of all transgenes.
Furthermore, the prior art does not support the breadth of applicants claim to all transgenes. In particular, the prior art reveals that recombinant expression vectors have a maximum packing capacity which can accommodate transgenes of less than 5 kB (Wilson, para 62). Regulatory sequences are carefully selected so that the entire rAAV genome is ideally 2-5 kB. Thus, the prior art shows that regulatory and transgene expression cassette elements are carefully selected towards a particular therapeutic goal wherein there exists a great deal of unpredictability in substituting large or uncharacterized transgenes.
Thus, although the specification prophetically considers and discloses expression cassettes for expressing PAH and particular PAH humanized variants, the instant specification does not disclose a sufficient number of adequately described species to support the claim to all transgenes.
Response to Traversal
Applicant traverses the rejection by arguing that the claimed expression vector can accommodate transgenes of various sizes, including greater than 5 KB (exhibit a). Applicant argues that the claims do not recite a specific vector and points to amendments to claim 129 which limit the transgene to no greater than 5 KB. Applicant argues that the invention is directed to an expression vector which will drive the expression of any transgene in a liver cell and are thus not limited to a particular transgene.
This argument has been fully considered, but is not found persuasive. Although the claims are not limited to a particular vector and loading capacity, the claims still generically describe the expression of a transgene which is considered extraordinarily broad. If a claim covers a wide genus of transgenes, the specification must provide a representative number of species within that genus or provide common structural features that would allow a person of ordinary skill in the art to visualize the members of the genus. The instant specification provides embodiments to PAH variants with N-terminal truncation and specific amino acid mutations/substitutions (Spec, para 10). This is not considered a representative number of samples to support the claim to all transgenes, in part because the specification is entirely directed to the expression of PAH as a treatment of severe PKU by liver-directed gene replacement, but also because of the genus which encompasses all transgenes. Although applicant has amended claim 129 to specify that the transgene is no greater than 5KB, this still reads on a vast number of transgenes both known and yet to be discovered which is not supported by the instant specification.
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 are rejected in modified form 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). This rejection is applied in modified form to address applicants claim amendments filed on 12/18/2025 and newly applied to claims 160-162. 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).
PNG
media_image1.png
187
518
media_image1.png
Greyscale
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).
PNG
media_image2.png
406
516
media_image2.png
Greyscale
Claim 141: Fontanellas describes expression constructs using a mouse albumin gene enhancer element (Fontanellas, claim 8, SEQ ID NO: 7, sequence alignment shown below).
PNG
media_image3.png
465
515
media_image3.png
Greyscale
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).
PNG
media_image4.png
236
521
media_image4.png
Greyscale
Claim 143: Doering describes the use of a liver-directed CRM8 enhancer (Doering, para 358 and SEQ ID NO: 100, sequence alignment shown below).
PNG
media_image5.png
189
514
media_image5.png
Greyscale
Claims 104, 107, 110: Kyostio-Moore describes 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.
PNG
media_image6.png
76
518
media_image6.png
Greyscale
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.
PNG
media_image7.png
73
523
media_image7.png
Greyscale
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
PNG
media_image8.png
79
518
media_image8.png
Greyscale
3’AlbSMAR = SEQ ID NO: 13
PNG
media_image9.png
79
532
media_image9.png
Greyscale
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
Although the rejection is applied in modified form, some of applicant’s arguments are relevant and discussed below.
Applicant traverses the rejection by pointing to claim amendments to increasing the sequence identity percentages from 90 to 95%. Furthermore, applicant argues that the independent claims specifying the use of mTTR482 as the promoter. Applicant points to Examples 1-2 and FIG 3A from the specification for support. Applicant argues that the cited art does not teach the instant claims, arguing that Wilson merely lists possible promoters and enhancers and fails to exemplify any of the possible combinations. Thus, one of ordinary skill would not look to combine the instantly claimed mTTR482 promoter with the claimed enhancer elements. Applicant argues that here is no reasonable expectation of success to achieve the level of expression observed from the applicant’s sequence-specific constructs.
This argument has been fully considered, but is not found persuasive. Although Wilson describes preferred embodiments to TBG promoters, patents are relevant as prior art for all they contain. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, see MPEP 2123. Thus, nonpreferred and alternative embodiments constitute prior art. Furthermore, Kyostio-Moore descries the use of an mTTR482 promoter in a liver-specific AAV vector (Kyostio-Moore, Fig 1A and para 138).
Applicant points to unexpected results in using the claimed expression construct. Applicant points to Fig 16A-B and Example 2 from the specification showing a robust decrease of brain Phe levels and subsequent enhancement of dopamine and serotonin synthesis in the brains of treated animals.
This argument has been fully considered, but is not found persuasive. Whether the unexpected results are the result of unexpected improved results or a property not taught by the prior art, the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support, see MPEP 716.02(d). The instant claims are generic to any transgene and applicants unexpected results appear to be directed to only PAH expression.
Conclusion
Claims 104, 107, 110, 120, 129, 135, 139-143, 147-162 are rejected.
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 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 Dr. 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.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see https://ppair-my.uspto.gov/pair/PrivatePair. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Alexander Nicol
Patent Examiner
Art Unit 1633
/ALEXANDER W NICOL/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
Prosecution Insights