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 .
DETAILED ACTION
This application is a 371 of PCT/US2021/035154.
The amendment filed on March 5, 2026 has been entered.
Election/Restrictions
Applicant elected without traverse of Group II with a species election of SEQ ID NO:3 as the encoded polypeptide in the reply filed on November 17, 2025.
Claims 14-15, 50-53, 58-61, 67, 71, and 73 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species (claims 14-15, 67, 71, and 73) and invention (claims 50-53 and 58-61), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on November 17, 2025.
Status of Claims
Claims 11-15, 21-23, 40, 48-53, and 58-73 are pending.
Claims 14-15, 50-53, 58-61, 67, 71, and 73 are withdrawn.
Claims 11-13, 21-23, 40, 48-49, 62-66, 68-70, and 72 are under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on March 5, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 11-13, 21-22, 40, and 48-49 is/are rejected under 35 U.S.C. 102(a)(1) or 102(a)(2) as being anticipated by Kyostio-Moore (WO 2020/077250 - form PTO-1449).
Regarding claims 11-13 and 21-22, Kyostio-Moore discloses a mRNA comprising an ORF encoding a PAH variant (M180T), wherein the PAH variant consists/comprises an amino acid sequence having 100% sequence identity to the PAH variant of SEQ ID NO:3 of the instant application ([0154]-[0155] and Table 1 variant #14 at page 90 and see the sequence alignment below).
Regarding claim 40, Kyostio-Moore discloses a vector comprising the mRNA encoding the PAH variant (abstract, [0016], and [0157]).
Regarding claims 48-49, Kyostio-Moore discloses a pharmaceutical composition comprising mRNA encoding the M180T PAH variant and a pharmaceutically acceptable excipient (abstract, [0153] and [0160]).
Therefore, the reference of Kyostio-Moore anticipates claims 11-13, 21-22, 40, and 48-49.
Applicant's arguments filed March 5, 2026 have been fully considered but they are not persuasive.
Applicant argues that the sequence shown at pages 11-12 (sequence alignment between the PAH mutant having the amino acid sequence of SEQ ID NO:3 of the instant application and the M180T PAH mutant of Kyostio-Moore) of the Office Action is incorrect because variant #14 at Table 1 of Kyostio-Moore includes N- and C-terminal truncations, yield a polypeptide consisting of amino acids 103-428 of SEQ ID NO:1 (except for the recited substitution) as evidenced by paragraphs [0048], [0050, [0361]-[0363], and Figures 7 and 9A-9C of Kyostio-Moore. Therefore, Applicant argues that Kyostio-Moore does not teach a polypeptide comprising or consisting of SEQ ID NO:3 of the instant application.
This is not found persuasive.
Kyostio-Moore clearly discloses a PAH mutant (M180T) of 452 amino acids in length and having 100% sequence identity to SEQ ID NO:3 (452 amino acids in length) of the instant application as shown in the sequence alignment below.
Therefore, the rejection has been maintained.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 11-13, 21-22, 40, 48-49, 64-65, and 68-69 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kyostio-Moore (WO 2020/077250 - form PTO-1449) and Rajendran (WO 2019/104160 – form PTO-1449).
Regarding claims 11-13 and 21-22, Kyostio-Moore discloses a mRNA comprising an ORF encoding a PAH variant (M180T), wherein the PAH variant consists/comprises an amino acid sequence having 100% sequence identity to the PAH variant of SEQ ID NO:3 of the instant application ([0154]-[0155] and Table 1 variant #14 at page 90 and see the sequence alignment below).
Regarding claim 40, Kyostio-Moore discloses a vector comprising the mRNA encoding the PAH variant (abstract, [0016], and [0157]).
Regarding claims 48-49, Kyostio-Moore discloses a pharmaceutical composition comprising mRNA encoding the M180T PAH variant and a pharmaceutically acceptable excipient (abstract, [0153] and [0160]).
Kyostio-Moore does not disclose the 5’UTR of SEQ ID NO:56, 3’UTR of SEQ ID NO:108, 5’terminal cap, nor N1-methylpseudoruacils.
Rajendran discloses mRNA therapy comprising an mRNA comprising PAH (abstract and [0001]). Rajendran discloses efficient delivery of the mRNA to cells and/or tissues of subjects and increased expression of mRNA in cells and/or subjects (abstract).
Regarding claims 64-65, Rajendran discloses an mRNA comprising an ORF encoding PAH, wherein the mRNA comprises a 5’UTR of SEQ ID NO:39 ([0049]) and 3’UTR of SEQ ID NO:175 ([0047]). The 5’UTR of SEQ ID NO:39 and 3’UTR of SEQ ID NO:175 of Rajendran have 100% sequence identity to the 5’UTR of SEQ ID NO:56 and 3’UTR of SEQ ID NO:108 of the instant application (see the sequence alignments below).
Regarding claim 68, Rajendran discloses an mRNA comprising an ORF encoding PAH, wherein the mRNA has a 5’terminal cap, such as Cap0, Cap1, ARCA, inosine, N1- methyl-guanosine, 2′-fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2- amino-guanosine, LNA-guanosine, 2-azidoguanosine, Cap2, Cap4, 5' methylG cap, or an analog thereof ([0030]).
Regarding claim 69, Rajendran discloses an mRNA comprising an ORF encoding PAH, wherein the all of the uracils of the mRNA are N1-methylpeudoruacils [0032]).
Therefore, combining the teachings of Kyostio-Moore and Rajendran, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to enhance the mRNA of Kyostio-Moore by modifying the mRNA by using the 5’UTR, 3’UTR, 5’terminal caps, and N1-methylpeudoruacils disclosed by Rajendran. One having ordinary skill in the art would have been motivated to do so in order to for efficient delivery of the mRNA to cells and/or tissues of subjects and increased expression of mRNA in cells and/or subjects. One having ordinary skill in the art would have had a reasonable expectation of success since Kyostio-Moore discloses an mRNA comprising an ORF encoding a PAH variant and Rajendran discloses mRNA comprising an ORF encoding PAH, wherein the mRNA is efficiently delivered to and expressed in cells or subjects.
Therefore, the above references render claims 11-13, 21-22, 40, 48-49, 64-65, and 68-69 prima facie obvious.
Applicant's arguments filed March 5, 2026 have been fully considered but they are not persuasive.
Applicant argues that since Kyostio-Moore does not teach or suggest a polypeptide comprising the amino acid sequence of SEQ ID NO:3, the Office Action fails to provide any reason the skilled artisan would have been motivated to modify the teachings of Kyostio-Moore to add human PAH amino acids 1-102 and 429-452 to Kyostio-Moore’s V14 construct to arrive at SEQ ID NO:3 of the claimed invention.
This is not found persuasive.
Kyostio-Moore clearly discloses a PAH mutant (M180T) of 452 amino acids in length and having 100% sequence identity to SEQ ID NO:3 (452 amino acids in length) of the instant application as shown in the sequence alignment below.
Applicant argues that the skilled artisan would not have been motivated to modify the teachings of Kyostio-Moore because Kyostio-Moore teaches that an M180T substitution alone does not provide any improvement.
This is not found persuasive.
The PAH mutant of Kyostio-Moore maintains PAH activity. Therefore, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to enhance the mRNA of Kyostio-Moore by modifying the mRNA by using the 5’UTR, 3’UTR, 5’terminal caps, and N1-methylpeudoruacils disclosed by Rajendran. One having ordinary skill in the art would have been motivated to do so in order to for efficient delivery of the mRNA to cells and/or tissues of subjects and increased expression of mRNA in cells and/or subjects.
Applicant argues that Rajendran does not cure the deficiencies of Kyostio-Moore since Rajendran does not recite the M180T substitution presently claimed SEQ ID NO:3.
This not found persuasive.
Kyostio-Moore clearly discloses a PAH mutant (M180T) of 452 amino acids in length and having 100% sequence identity to SEQ ID NO:3 (452 amino acids in length) of the instant application as shown in the sequence alignment below. Rajendran is relied upon for its disclosure of improving mRNA expression.
Applicant argues that the working examples of the PAH of SEQ ID NO:3 has unexpected results of increased expression (relative to wildtype control, Examples 15-16) and a greater sustained reduction in phenylalanine levels over time (relative to wild type control, Example 19 and Figure 9).
This is not found persuasive.
“Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.”, see MPEP 716.02. “Whether the unexpected results are the result of unexpectedly 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). In the instant case, Example 15 discloses expression levels of mRNA constructs encoding truncated forms of the PAH variants (page 286, lines 6-7). However, the PAH mutant of SEQ ID NO:3 of the instant application is a full length PAH. Example 16 discloses expression of SEQ ID NO:3 from mRNA constructs modified with poly(A) tail. However, not all pending claims recite mRNA modified with poly(A) tail. Further, the increased expression of SEQ ID NO:3 from mRNA having a poly(A) tail is not unexpected because poly(A) tails stabilize mRNA. Example 19 and Figure 9 discloses PAH activity expressed from mRNA having a stable tail. However, not all pending claims recite mRNA modified with a stable tail. Further, the increased PAH activity of SEQ ID NO:3 expressed from mRNA having a stable tail is not unexpected due to the stabilizing tail. Therefore, the asserted unexpected results are insufficient to rebut the prima facie case because the alleged unexpected results are not unexpected and/or are not commensurate in scope with the claims.
Therefore, the rejection has been maintained.
Double Patenting
Claims 11-13, 21-23, 48-49, and 62-63 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 7-22, and 38-41 of copending Application No. 18/282,639 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the instant application and the claims of the reference application are directed to mRNA encoding a PAH variant having the amino acid sequence of SEQ ID NO:3 (M180T). The PAH variant of SEQ ID NO:3 of the instant application is identical to the PAH variant of SEQ ID NO:3 of the reference application.
Regarding claims 11-13 and 21-22 of the instant application, claims 1 and 11 of the reference application recites an mRNA comprising an ORF encoding a PAH variant having the amino acid sequence of SEQ ID NO:3. Therefore, claims 11-13 and 21-22 of the instant application are anticipated by claims 1 and 11 of the reference application.
Regarding claims 23 and 62-63 of the instant application, claims 1 and 19 of the reference application recites that the mRNA comprises the nucleotide sequence of SEQ ID NO:15. The mRNA of SEQ ID NO:15 of the reference application is identical to the mRNA of SEQ ID NO:22 of the instant application. Therefore, claims 23 and 62-63 of the instant application are anticipated by claims 1 and 19 of the reference application
Regarding claims 48-49 of the instant application, claims 1, 11, and 39 of the reference application recites administering an effective amount of a lipid nanoparticle comprising PAH variant to a human, which reads on a pharmaceutical composition comprising said PAH variant and a pharmaceutically acceptable excipient. Therefore, claims 48-49 of the instant application are anticipated by claims 1, 11, and 39 of the reference application.
Regarding claims 64-65 of the instant application, claim 20 of the reference application recites that the mRNA comprises a 5’UTR comprising the nucleic acid sequence of SEQ ID NO:55 or 56 and claim 21 of the reference application recites that the mRNA comprises a 3’UTR comprising the nucleic acid sequence of SEQ ID NO:108 or 112. The 5’UTR of SEQ ID NO:55 and 56 of the reference application are identical to the 5’UTR of SEQ ID NO:55 and 56, respectively, of the instant application. The 3’UTR of SEQ ID NO:108 and 112 of the reference application are identical to the 3’UTR of SEQ ID NO:108 and 112, respectively, of the instant application. Therefore, claims 64-65 of the instant application are anticipated by claims 20-21 of the reference application.
Therefore, the conflicting claims are not patentably distinct from each other
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant's arguments filed March 5, 2026 have been fully considered but they are not persuasive.
Applicant argues that since the present application has an earlier effective filing date, the rejection should we withdrawn if the only remaining rejection is the nonstatutory double patenting rejection.
While the present application has the earlier patent term filing date, the provisional nonstatutory rejection is not the only remaining rejection.
Therefore, the rejection has been maintained.
Claim Objections
Applicant’s arguments, see pages 11-12 of the Remarks, filed March 5, 2026, with respect to claim 13 have been fully considered and are persuasive. Claim 13 has been amended to recite “consisting of” and is no longer a duplicate of claim 12.
Conclusion
Claims 11-15, 21-23, 40, 48-53, and 58-73 are pending.
Claims 14-15, 50-53, 58-61, 67, 71, and 73 are withdrawn.
Claims 11-13, 21-23, 40, 48-49, 62-65, and 68-69 are rejected.
Claims 66, 70, and 72 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to YONG D PAK whose telephone number is (571)272-0935. The examiner can normally be reached M-Th: 5:30 am - 3:30 pm.
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, Robert Mondesi can be reached on 408-918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/YONG D PAK/Primary Examiner, Art Unit 1652
Sequence alignment between the PAH variant of SEQ ID NO:3 of the instant application (“Qy”) and the PAH variant M180T of Kyostio-Moore (“Db”)
BHQ69639
ID BHQ69639 standard; protein; 452 AA.
XX
AC BHQ69639;
XX
DT 28-MAY-2020 (first entry)
XX
DE Human PAH mutant M180T.
XX
KW PAH protein; enzyme engineering; enzyme production; metabolic-gen.;
KW mutein; nephrotropic; phenylalanine hydroxylase; phenylketonuria;
KW protein therapy; therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
XX
CC PN WO2020077250-A1.
XX
CC PD 16-APR-2020.
XX
CC PF 11-OCT-2019; 2019WO-US055917.
XX
PR 12-OCT-2018; 2018US-0744944P.
XX
CC PA (GENZ ) GENZYME CORP.
XX
CC PI Kyostio-Moore S, Manavalan P;
XX
DR WPI; 2020-29701C/035.
XX
CC PT New variant phenylalanine hydroxylase (PAH) polypeptide comprising 2-4
CC PT amino acid substitutions, for treating phenylketonuria in individual, and
CC PT for reducing level of phenylalanine in blood of in individual.
XX
CC PS Example 5; Page; 153pp; English.
XX
CC The present invention relates to a novel variant phenylalanine
CC hydroxylase (PAH) polypeptide comprising 2-4 amino acid substitutions,
CC useful for treating phenylketonuria in individual, and for reducing the
CC level of phenylalanine in blood of in individual. The invention also
CC provides: a composition comprising the variant PAH polypeptide; an
CC isolated nucleic acid encoding the variant PAH polypeptide; a vector
CC comprising the nucleic acid; a recombinant adeno-associated virus (rAAV)
CC vector comprising the nucleic acid flanked by one or more AAV inverted
CC terminal repeat (ITR) sequences or comprising the expression cassette
CC that is flanked by one or more AAV inverted terminal repeat (ITR)
CC sequences; a rAAV particle comprising the rAAV vector; a cell comprising
CC the nucleic acid or the vector or the rAAV vector; a method for producing
CC variant PAH polypeptide; a method for treating phenylketonuria in an
CC individual; a method for reducing the level of phenylalanine in the blood
CC of in an individual; a kit comprising the variant PAH polypeptide, the
CC nucleic acid, the rAAV vector, the rAAV particle, or the composition; and
CC a rAAV particle comprising the rAAV vector. Note: The present sequence is
CC not shown in the specification, but it is derived from a parent sequence
CC (BHQ69608), and the information is given in example 5.
XX
SQ Sequence 452 AA;
Query Match 100.0%; Score 2382; Length 452;
Best Local Similarity 100.0%;
Matches 452; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSTAVLENPGLGRKLSDFGQETSYIEDNCNQNGAISLIFSLKEEVGALAKVLRLFEENDV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSTAVLENPGLGRKLSDFGQETSYIEDNCNQNGAISLIFSLKEEVGALAKVLRLFEENDV 60
Qy 61 NLTHIESRPSRLKKDEYEFFTHLDKRSLPALTNIIKILRHDIGATVHELSRDKKKDTVPW 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NLTHIESRPSRLKKDEYEFFTHLDKRSLPALTNIIKILRHDIGATVHELSRDKKKDTVPW 120
Qy 121 FPRTIQELDRFANQILSYGAELDADHPGFKDPVYRARRKQFADIAYNYRHGQPIPRVEYT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 FPRTIQELDRFANQILSYGAELDADHPGFKDPVYRARRKQFADIAYNYRHGQPIPRVEYT 180
Qy 181 EEEKKTWGTVFKTLKSLYKTHACYEYNHIFPLLEKYCGFHEDNIPQLEDVSQFLQTCTGF 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 EEEKKTWGTVFKTLKSLYKTHACYEYNHIFPLLEKYCGFHEDNIPQLEDVSQFLQTCTGF 240
Qy 241 RLRPVAGLLSSRDFLGGLAFRVFHCTQYIRHGSKPMYTPEPDICHELLGHVPLFSDRSFA 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 RLRPVAGLLSSRDFLGGLAFRVFHCTQYIRHGSKPMYTPEPDICHELLGHVPLFSDRSFA 300
Qy 301 QFSQEIGLASLGAPDEYIEKLATIYWFTVEFGLCKQGDSIKAYGAGLLSSFGELQYCLSE 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 QFSQEIGLASLGAPDEYIEKLATIYWFTVEFGLCKQGDSIKAYGAGLLSSFGELQYCLSE 360
Qy 361 KPKLLPLELEKTAIQNYTVTEFQPLYYVAESFNDAKEKVRNFAATIPRPFSVRYDPYTQR 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 KPKLLPLELEKTAIQNYTVTEFQPLYYVAESFNDAKEKVRNFAATIPRPFSVRYDPYTQR 420
Qy 421 IEVLDNTQQLKILADSINSEIGILCSALQKIK 452
||||||||||||||||||||||||||||||||
Db 421 IEVLDNTQQLKILADSINSEIGILCSALQKIK 452
Sequence alignment between the 5’UTR of SEQ ID NO:56 of the instant application (“Qy”) and the 5’UTR of SEQ ID NO:39 of Rajendran (“Db”)
BGJ91551
ID BGJ91551 standard; mRNA; 57 BP.
XX
AC BGJ91551;
XX
DT 25-JUL-2019 (first entry)
XX
DE Modified mRNA construction related 5' untranslated region, SEQ ID 39.
XX
KW 5'-utr; metabolic-gen.; nanotechnology; nephrotropic; phenylketonuria;
KW prophylactic to disease; protein expression; protein therapy; ss;
KW therapeutic.
XX
OS Unidentified.
XX
CC PN WO2019104160-A2.
XX
CC PD 31-MAY-2019.
XX
CC PF 21-NOV-2018; 2018WO-US062237.
XX
PR 22-NOV-2017; 2017US-0590128P.
PR 01-JUN-2018; 2018US-0679081P.
XX
CC PA (MODR ) MODERNATX INC.
XX
CC PI Rajendran R, Finn P, Martini PGV, An D, Dousis A, Ravichandran K;
XX
DR WPI; 2019-491295/43.
XX
CC PT Pharmaceutical composition comprises mRNA comprising an open reading
CC PT frame encoding phenylalanine hydroxylase polypeptide, where composition
CC PT when administered as single intravenous dose to human subject in need is
CC PT sufficient.
XX
CC PS Disclosure; SEQ ID NO 39; 415pp; English.
XX
CC The present invention relates to a novel pharmaceutical composition
CC comprising a mRNA having an open reading frame (ORF) encoding a
CC phenylalanine hydroxylase (PAH) polypeptide. The mRNA is preferably
CC encapsulated in lipid nanoparticles (LNPs) to effect efficient delivery
CC to cells or tissues. The composition when administered as single
CC intravenous dose to a human subject in need is sufficient to increase the
CC level of PAH activity in liver tissue, reduce liver levels of
CC phenylalanine and reduce plasma, serum or urine levels of phenylalanine.
CC The pharmaceutical composition further comprises a delivery agent. The
CC invention further claims: (1) a polynucleotide comprising the mRNA; (2) a
CC method for expressing a PAH polypeptide in a human subject in need; (3) a
CC method for treating, preventing, or delaying the onset or progression of
CC phenylketonuria (PKU) in a human subject; (4) a method for reducing
CC phenylalanine blood level in a human subject; and (5) a method for
CC increasing PAH activity in a human subject in need. The PAH coding mRNA,
CC PAH protein, its functional fragment (such as a catalytic domain or the
CC catalytic domain and tetramerization domains) or a fusion protein
CC comprising the PAH can be used for preventing and treating
CC hyperphenylalaninemia such as phenylketonuria. Note: SEQ ID NO: 4565 is
CC described in page 346 of the specification, but no further sequence has
CC been shown.
XX
SQ Sequence 57 BP; 26 A; 11 C; 16 G; 0 T; 4 U; 0 Other;
Query Match 100.0%; Score 56; Length 57;
Best Local Similarity 100.0%;
Matches 56; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 56
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 GGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGACCCCGGCGCCGCCACC 57
Sequence alignment between the 3’UTR of SEQ ID NO:108 of the instant application (“Qy”) and the 5’UTR of SEQ ID NO:175 Rajendran (“Db”)
BGJ91673
ID BGJ91673 standard; mRNA; 119 BP.
XX
AC BGJ91673;
XX
DT 25-JUL-2019 (first entry)
XX
DE Modified mRNA construction related 3' untranslated region, SEQ ID 175.
XX
KW 3'-utr; metabolic-gen.; nanotechnology; nephrotropic; phenylketonuria;
KW prophylactic to disease; protein expression; protein therapy; ss;
KW therapeutic.
XX
OS Unidentified.
XX
CC PN WO2019104160-A2.
XX
CC PD 31-MAY-2019.
XX
CC PF 21-NOV-2018; 2018WO-US062237.
XX
PR 22-NOV-2017; 2017US-0590128P.
PR 01-JUN-2018; 2018US-0679081P.
XX
CC PA (MODR ) MODERNATX INC.
XX
CC PI Rajendran R, Finn P, Martini PGV, An D, Dousis A, Ravichandran K;
XX
DR WPI; 2019-491295/43.
XX
CC PT Pharmaceutical composition comprises mRNA comprising an open reading
CC PT frame encoding phenylalanine hydroxylase polypeptide, where composition
CC PT when administered as single intravenous dose to human subject in need is
CC PT sufficient.
XX
CC PS Claim 12; SEQ ID NO 175; 415pp; English.
XX
CC The present invention relates to a novel pharmaceutical composition
CC comprising a mRNA having an open reading frame (ORF) encoding a
CC phenylalanine hydroxylase (PAH) polypeptide. The mRNA is preferably
CC encapsulated in lipid nanoparticles (LNPs) to effect efficient delivery
CC to cells or tissues. The composition when administered as single
CC intravenous dose to a human subject in need is sufficient to increase the
CC level of PAH activity in liver tissue, reduce liver levels of
CC phenylalanine and reduce plasma, serum or urine levels of phenylalanine.
CC The pharmaceutical composition further comprises a delivery agent. The
CC invention further claims: (1) a polynucleotide comprising the mRNA; (2) a
CC method for expressing a PAH polypeptide in a human subject in need; (3) a
CC method for treating, preventing, or delaying the onset or progression of
CC phenylketonuria (PKU) in a human subject; (4) a method for reducing
CC phenylalanine blood level in a human subject; and (5) a method for
CC increasing PAH activity in a human subject in need. The PAH coding mRNA,
CC PAH protein, its functional fragment (such as a catalytic domain or the
CC catalytic domain and tetramerization domains) or a fusion protein
CC comprising the PAH can be used for preventing and treating
CC hyperphenylalaninemia such as phenylketonuria. Note: SEQ ID NO: 4565 is
CC described in page 346 of the specification, but no further sequence has
CC been shown.
XX
SQ Sequence 119 BP; 15 A; 45 C; 30 G; 0 T; 29 U; 0 Other;
Query Match 100.0%; Score 119; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 UGAUAAUAGGCUGGAGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCC 60
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Db 1 UGAUAAUAGGCUGGAGCCUCGGUGGCCUAGCUUCUUGCCCCUUGGGCCUCCCCCCAGCCC 60
Qy 61 CUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 119
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Db 61 CUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGCGGC 119
Prosecution Insights