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 .
Remarks
The amendments and remarks filed on 07/07/2026 have been entered and considered. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior office action. The rejections and/or objections presented herein are the only rejections and/or objections currently outstanding. Any previously presented objections or rejections that are not presented in this Office Action are withdrawn. Claims 1, 2, 11-26, 28, and 29 are pending; Claims 3-10 and 27 are cancelled; Claims 1, 2, 11, 12, 16-22, and 26 are amended; and Claims 1, 2, 11-26, 28, and 29 are under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/19/2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97 and has been considered by the examiner.
Withdrawal of Objections
The objection to Claims 17 and 19-22 in the prior office action is withdrawn due to the amendment to the claims filed on 07/07/2026.
Withdrawal of Rejections
The rejection of claims 11, 16-19, and 26 under 35 U.S.C. 112(b) is withdrawn due to the amendment to the claims filed on 07/07/2026.
Claim Objections
Claim 2 is objected to due to the recitation of “wherein the coordinates correspond to said SEQ ID NO: 2”. Given at least one additional mutation is further included in the GCase of claim 2, it is suggested to change the phrase to “wherein the coordinates with the at least one additional mutation from (i) – (ix) correspond to said SEQ ID NO: 2”. Appropriate correction is required.
Claim 16 is objected to due to the recitation of “at least about 0.2 x 106 kcat/Km M-1min-1”. Given M-1min-1 is the unit of the recited “at least about 0.2 x 106”, the “M-1min-1” should directly follows the value of “at least about 0.2 x 106”. Appropriate correction is required.
Claim 26 is objected to because of the recitation of “the genetically modified human GCase claim 1”. The phrase should be corrected to ““the genetically modified human GCase of claim 1”. Appropriate correction is required.
Claim Interpretation
Claims 1 and 2 recite the mutation limitations of “K224N/G”, “H145K/R”, “T334F/Y/K”, “N102D/E”, “L103N/E/R”, “I406T/A”, “L420M/I”, and/or “D104N/G”. The forward slash (/) in the limitations is interpreted as an alternative term "or" based on the disclosure of the specification. For example, the mutation “K224N/G” is interpreted as substituting K at the position of 224 with N or G.
Claim Rejections - 35 USC § 112(a) or 112, First Paragraph
Claims 1, 2, 11, 16-20, 22-26, and 28-29 are 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention. This rejection is maintained.
The claims are directed in part to: (a) a genetically modified human beta-glucocerebrosidase (GCase): (i) comprising an amino acid sequence at least 95 % identical to SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27, (ii) comprising mutations L34P, K224N/G, T369E and N370D at coordinates correspond to SEQ ID NO: 2 (wild type GCase’s sequence), and (iii) being capable of catalyzing hydrolysis of a glycolipid glucosylceramide (GlcCer); (b) an isolated polynucleotide comprising a nucleic acid encoding the GCase as defined in (a); (c) a nucleic acid construct comprising the polynucleotide/nucleic acid encoding the GCase defined in (a); (d) an isolated cell comprising the polynucleotide/nucleic acid encoding the GCase defined in (a); (e) a pharmaceutical composition comprising as the GCase defined in (a) as an active ingredient; and (f) a method of treating a disease associated with GCase deficiency or Gaucher disease in a subject, comprising administering to the subject a therapeutically effective amount of the GCase defined in (a) or isolated polynucleotide encoding the GCase defined in (a) or cells comprising the polynucleotide. The dependent claims 16-18 further define that the GCase has catalytic activity at a kcat/Km level of at least 0.2 x 106 M-1min-1, has a higher thermal stability compared to a wild-type GCase, or is expressed in eukaryotic cells at a level two times higher than that of a wild type GCase.
It is noted that the amino acid sequences of SEQ ID NOs: 4, 6, 8, 10, 12, 14, 18, 20, 22, and 27 all have a total of 497 amino acids, just like that of SEQ ID NO: 2 (of wild type GCase), as evidenced by the disclosure of the specification (see Figs. 1, 5, and 7). The at least 95% identity to these amino acid sequences would allow up to 25 amino acids in the sequences to be mutated by amino acids substitution, deletion, and/or insertion, for generating the claimed genetically modified GCase having at least 95% identity to SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27. However, the claim 1 does not define any specific positions where the 25 mutations occur, although it defines mutations L34P, K224N/G, T369E, and N370D at positions 34, 224, 369, and 370, which are all comprised in SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, and 27 as disclosed in the specification. As such, the claim 1 allows up to 25 amino acids to be mutated at any of the remaining 493 positions (497 – 4 = 493) throughout the sequence of SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27 to arrive at the claimed at least 95% identity. Although Claim 2 further limits the GCase of claim 1 to contain at least one additional mutation, a single additional substitution mutation with a defined position can meet the claimed limitation. As such, even combining the claims 1 and 2 together, the claims still allow up to 24 amino acids to be mutated at any of the remaining 492 positions throughout the sequence of SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27. It is further noted that Claim 11 limits the GCase of claim 1 by defining a total of 13 positions where amino acids are unmodified. However, even combining the claims 1 and 11 together, the claims still allow up to 25 amino acids to be mutated at any of the remaining 480 positions throughout the sequence of SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27. Furthermore, the claims do not define which types of mutations the additional 25 mutations are. As such, the GCase may have any types of up to 25 additional mutations (substitution, deletion, and/or insertion of any amino acids) at any of remaining up to 493 positions throughout the sequence of SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27. As known to one of ordinary skill in the art, there are 20 different amino acids, which may be used to mutate amino acids at the 493 positions of the GCase enzyme. The claimed GCase mutants comprises up to 25 additional mutations, which have any different combinations of deletion, insertion, and substitutions with any amino acids at any of up to 473 positions throughout the entire GCase enzyme. Accordingly, the GCase mutants that meet the claimed at least 95% identity to SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27 encompasses an extremely large number of different variants and mutants derived from the wild type GCase enzyme.
The specification of the instant application does not provide any information about the structural - functional relationship for the 497 amino acids in the wild type GCase (having the sequence of SEQ ID NO: 2). Given the claims do not define specific structures at the remaining 493 amino acids of the GCase having at least 95 % identical to SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27, an extremely large numbers of polynucleotide comprising a nucleic acid encoding various different mutants that meet at least 95% identity must be constructed, each of them must be cloned into an expression construct and transformed into a host cell, and then further screened for identifying genetically modified GCase mutants that have the claimed characteristics including: being capable of catalyzing hydrolysis of GlcCer, having the catalytic activity at a kcat/Km level of at least 0.2 x 106 M-1min-1, having a higher thermal stability compared to a wild-type GCase, and being expressed in eukaryotic cells at a level two times higher than that of a wild type GCase. As such, an effective high-throughput process is necessary for mutating, cloning and expressing nucleic acids encoding various mutants having 95 % identical to SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27, as well as further screening genetically modified GCase mutant for identifying those having the claimed characteristics, so as to apply them to patients in the method for treating a disease associated with GCase deficiency or specifically Gaucher disease. However, the working examples 1-10 in the specification only constructed and analyzed 10 GCase mutants (D2-D7 and D13-D16). There is no disclosure in the specification or the prior art regarding how to carrying out a high-throughput process for effectively mutagenizing, cloning, and expressing GCase mutants, and then effectively screening these mutants and determining which substitutions, deletions or insertions in SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27 encompassed by the claimed scope, would result in GCase mutants having the claimed characteristics.
In order for the written description provision of 35 USC 112, first paragraph to be satisfied, Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed. For example, MPEP 2163 states in part,
An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “without such disclosure, the claimed methods cannot be said to have been described.”).
Without additional information, the skilled artisan cannot envision which substitutions, deletions or insertions of the polypeptide of SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27 would result in a genetically modified GCase encompassed by the claims, which is capable of catalyzing hydrolysis of GlcCer, having catalytic activity at a kcat/Km level of at least 0.2 x 106 M-1min-1 and a higher thermal stability compared to a wild-type GCase, and/or being expressed at a level higher than that of wild type GCase. Adequate written description requires more than a mere statement that it is part of the invention.
Therefore, the full breadth of “comprising an amnio acid sequence 95 % identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 6, 8, 10, 12, 14, 18, 20, 22, and 27” encompassed by the claims do not meet the written description provision of 35 USC 112, first paragraph.
Allowable Subject Matter
The subject matter of Claims 1, 2, 11-26, and 28-29 is not taught or suggested by the prior art for the reasons of record (see pages 10-16 of the previous office action dated 03/12/2026).
Claims 12-15 and 21 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.
Response to Arguments
Applicant's arguments about the objection to claims 17 and 19-22 and the rejection of claims 11, 16-19, and 26 under 35 U.S.C. 112(b) in the response filed on 7/7/2026 (page 6-7) have been fully considered, but they are moot because they have been withdrawn as indicated above.
Applicant's arguments about the rejection of claims 1-2, 11, 16-20, 22-26 and 28-29 under 35 U.S.C. 112(a) in the 7/7/2026 response (pages 7-8) have been fully considered but they are not persuasive.
In response to Applicant’s arguments in page 7/para 3 – page 8/para 1 of the response, Examiner reminds Applicant that the amino acid sequence of the modified GCase in the claim 1 is not limited to the amino acid sequence of SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27. Rather, it is any amino acid sequence having at least 95% identity to SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27 and being capable of catalyzing hydrolysis of GlcCer. Although the specification provides the specific sequences of SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, and 27 for 10 GCase mutants in working examples, the specification does not disclose any other amino acid sequences encompassed by the claimed limitations of at least 95% identity to SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27 and being capable of catalyzing hydrolysis of GlcCer. As such, the amended claims newly submitted on 7/7/2026 is not anchored directly to the specific mutants in the specification of the originally filed application.
In response to Applicant’s additional arguments in the para spanning pages 7 and 8 of the response, it is noted that providing definitions for the terms such as GCase enzyme and sequence identity in the specification does not mean Applicant possesses the functional GCase mutants encompassed by the limitation of having at least 95% identity to SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27, as of the filing date. It is further noted that the claim 1 does not recite any limitation to define specific positions where additional mutations are located, or to limit the additional mutations to be substitution mutations. As such, additional mutations in the amino acid sequences having at least 95% identity to SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27 can be anywhere in the 493 positions throughout the GCase enzyme; and they are not limited to conservative or non-conservative substitution mutations, rather can be any combination of deletion, insertion, and substitution. Thousands of millions of different GCase mutants can meet the claimed limitation of having at least 95% identity to SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27. However, the specification does not provide any information about the structural - functional relationship for the 497 amino acids in the wild type GCase; and the specification does not disclose any high-throughput process for effectively mutagenizing, cloning, and expressing GCase mutants, and then effectively screening these mutants and determining which substitutions, deletions or insertions in SEQ ID NO: 4, 6, 8, 10, 12, 14, 18, 20, 22, or 27 encompassed by the claimed scope, would result in GCase mutants having the claimed characteristics. The disclosure of the specification only let one of skill in the art carry out a process of trial and error by using a time- and labor-consuming conventional process to constructing and screening an infinite number of mutants for identifying GCase mutants having claimed structural and functional characteristics, which are not disclosed in the specification but encompassed by the claims.
Overall, it is Examiner’s position that the amended claims 1-2, 11, 16-20, 22-26 and 28-29 do not meet the written description provision of 35 USC 112(a) for all the reasons indicated above.
Conclusion
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 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.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Qing Xu, Ph.D., whose telephone number is (571) 272-3076. The examiner can normally be reached on Monday-Friday from 9:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath N. Rao, can be reached at (571) 272-0939. Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to the receptionist whose telephone number is (571) 272-1600.
/Qing Xu/
Patent Examiner
Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
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