DETAILED OFFICE ACTION
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment to the claims, filed on November 7, 2025 is
acknowledged. This listing of the claims replaces all prior versions and listings of the
claims.
Claims 1-18, 20-22 and 27-32 are pending.
Claims 19 and 23-26 are cancelled.
Applicant’s remarks filed November 7, 2025 in response to the non-final rejection mailed August 19, 2025, are acknowledged and have been fully 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.
Election/Restrictions
In response to a requirement for restriction/election mailed May 27, 2025, applicant elected with traverse Group 3, corresponding to pending claims 22 and 27-32, drawn to a recombinant glycoprotein produced by the cell line of claim 1, in the reply filed July 22, 2025. The restriction requirement was deemed proper and made FINAL in the Office action mailed August 19, 2025.
Claims 1-18 and 20-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 22 and 27-32 are under examination on the merits.
Information Disclosure Statement
The newly submitted information disclosure statement (IDS) submitted on November 7, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner and those references therein have been indicated as such.
Claim Rejections - 35 USC § 103
The rejection of claims 22 and 27-32 under 35 U.S.C. 103 as being unpatentable over Chang et al. (US 2014/0127227 A1; cited on Form PTO-892 mailed August 19, 2025; hereafter “Chang”) in view of Neelon et al. (US 2016/0129028 A1; cited on Form PTO-892 mailed August 19, 2025; hereafter “Neelon”), Kaisheva et al. (US 2006/0008415 A1; cited on Form PTO-892 mailed August 19, 2025; hereafter “Kaisheva”), and de Villiers (A Practical Guide to Contemporary Pharmacy Practice, published 2009, Third Edition, p. 224-230; cited on Form PTO-892 mailed August 19, 2025; hereafter “de Villiers”) and as evidenced by PubChem (Trisodium citrate, PubChem, published 8/8/2005; cited on Form PTO-892 mailed August 19, 2025; hereafter “PubChem’19”) and PubChem (Sucrose, PubChem, published 9/16/2004; cited on Form PTO-892 mailed August 19, 2025; hereafter “PubChem’20”) is withdrawn because the combination of cited references does not teach or suggest the newly added limitation to claim 22 to recite “wherein the β-glucocerebrosidase comprises a N-glycan containing one or more terminal mannose residues.”
Claims 22 and 27-32 are newly rejected under 35 U.S.C. 103 as being unpatentable over Chang in view of Neelon, Kaisheva, de Villiers, and Jung et al. (Protein Expression and Purification, published 2019, Vol. 158, p. 81-88; cited on the attached Form PTO-892; hereafter “Jung”), and as evidenced by PubChem’19, PubChem’20, and NCBI Gene ID: 2529 (NCBI, available September 13, 2019 from < https://web.archive.org/web/20190913095014/https://www.ncbi.nlm.nih.gov/gene/2629>; cited on the attached Form PTO-892; hereafter “NCBI’2529”).
The new rejection is necessitated by Applicant’s amendment to claim 22 to recite the new limitation “wherein the β-glucocerebrosidase comprises a N-glycan containing one or more terminal mannose residues.”
The claims are drawn to a pharmaceutical formulation comprising a therapeutically effective amount of β-glucocerebrosidase, a buffer, an osmoregulator and a surfactant, wherein the β-glucocerebrosidase is present in an amount of 50-150 U/mL, the buffer is a citrate buffer present in an amount of 2-10 g/L, the osmoregulator is sucrose present in an amount of 40-120 g/L, and the surfactant is polysorbate 80 present at an amount of 0.1-1 g/L, and wherein the β-glucocerebrosidase comprises a N-glycan containing one or more terminal mannose residues.
Regarding claims 22 and 27-32,
Chang teaches a pharmaceutical formulation comprising 100 U/ml β-glucocerebrosidase, 14 g/L sodium citrate buffer (70 mg/ 5 ml = 14 mg/ml; 14 mg/ml * (1 g/ 1000mg) * (1000 ml/ 1 L) = 14 g/L), 0.106 g/L polysorbate 80 (0.53 mg/ 5 ml = 0.106 mg/ml; 0.106 mg/ml * (1 g/ 1000mg) * (1000 ml/ 1 L) = 0.106 g/L) (para [0061, 0068, 0132]), and the polyol mannitol (para [0123, 0222]).
Chang teaches the formulation can comprise tonicity modifiers to alter osmolality of the formulation and sucrose (para [0123, 0127]).
Chang teaches a stable protein composition comprising Inflixamab and 50 g/L sucrose (50 mg/ml * (1 g/ 1000mg) * (1000 ml/ 1 L) = 50 g/L) (Abstract; para [0062]).
The difference between Chang’s β-glucocerebrosidase pharmaceutical composition and the claimed invention is that Chang does not teach wherein the β-glucocerebrosidase composition comprises 2-10 g/L citrate buffer and 40-120 g/L sucrose as well as that the β-glucocerebrosidase does not explicitly comprise a N-glycan containing one or more terminal mannose residues.
Neelon teaches a protein-based pharmaceutical composition (Abstract; para [0004]; Claim 1) comprising 5-50 mM sodium citrate buffer (para [0002, 0004, 0042, 0044, 0147]; Claim 12), 0.1-10 g/L of the surfactant polysorbate 80 (0.1 mg/ml * (1 g/ 1000 mg) * (1000 ml/ 1 L) = 0.1 g/L; 10 mg/ml * (1 g/ 1000 mg) * (1000 ml/ 1 L) = 10 g/L) (para [0158]), and a tonicity agent comprising sucrose to adjust the osmolality to produce an isotonic composition (para [0065-0066, 0135, 0159]). The pH of the pharmaceutical composition is pH 5.5-6.5 (para [0046]; Claim 12).
Neelon teaches that mannitol and mannose are polyols are tonicifier/tonicity-agents and added to the composition to produce a desired isotonicity in order to obtain the same osmotic pressure as human blood (para [0065-0067, 0159]).
PubChem’19 is cited as an evidentiary reference to indicate the molar mass of sodium citrate is 258.07 g/mol (p. 1 – “Molecular Weight: 258.07 g/mol”). Therefore, 5-50 mM sodium citrate buffer taught by Neelon is inherently equivalent to approximately 1.29-12.9 g/L sodium citrate (5 mM sodium citrate * (1 M/1000 mM) * (258.07 g / 1 mol) = 1.29 g/L sodium citrate; 50 mM sodium citrate * (1 M/1000 mM) * (258.07 g / 1 mol) = 12.9 g/L sodium citrate).
Kaisheva teaches a stable pharmaceutical protein formulation (Abstract) comprising a sodium citrate buffer (para [0037, 0102, 0114]), polysorbate 80 (para [0080]), and a tonicity modifier of 100-300 mM sucrose (para [0044, 0115, 0118]). Kaisheva teaches surfactants are added to formulations to reduce aggregation of protein, minimizes the formation of particulates in the formulation, and/or reduces adsorption to the container containing the formulation (para [0103]).
PubChem’20 is cited as an evidentiary reference to indicate the molar mass of sucrose is 342.3 g/mol (p. 1 – “Molecular Weight: 342.3 g/mol”). Therefore, the 100-300 mM sucrose taught by Kaisheva is inherently equivalent to approximately 34.23-102.69 g/L sucrose (100 mM sucrose * (1 M/1000 mM) * (342.3 g / 1 mol) = 32.23 g/L sucrose; 300 mM sucrose * (1 M/1000 mM) * (342.3 g / 1 mol) = 102.69 g/L sucrose). de Villiers teaches that buffering capacity is related to the concentration of the buffer; the greater the concentration of the buffer, the greater the resistance to a change in pH (p. 225 – “Buffer capacity is related to the concentration of the buffer; the greater the concentration of the buffer, the greater the resistance to a change in pH.”).
Jung teaches β-glucosidase hydrolyzes glucosylceramide (also termed glucocerebroside) (p. 82, col 1, para 1). Jung teaches Gaucher disease is caused by accumulation of glucocerebroside in cells, especially macrophages, due to a deficiency in acid β-glucosidase (Abstract; p. 82, col 1, para 1). Jung teaches enzyme replacement therapy that results in beta-glucosidase uptake in macrophages requires the beta-glucosidase to carry terminal mannose residues on their N-glycans (Abstract; p. 82, col 1, para 1 – p. 82, col 2, para 1).
NCBI’2629 is cited as an evidentiary reference to indicate acid beta-glucosidase is synonymous with beta-glucocerebrosidase (p. 7 – “General protein information… Names… acid beta-glucosidase… beta-glucocerebrosidase…”).Therefore, the beta-glucosidase taught by Jung is inherently beta-glucocerebrosidase, so hereafter the beta-glucosidase is referred to as beta-glucocerebrosidase.
In view of the combined teachings of Chang, Neelon, Kaisheva, de Villiers, and Jung, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the pharmaceutical formulation comprising 100 U/ml β-glucocerebrosidase taught by Chang to comprise β-glucocerebrosidase with an N-glycan with terminal mannose residues taught by Jung as well as by substituting the buffer system and excipient composition, and concentrations thereof, for those taught by Neelon. Through routine optimization of the modified composition an ordinary artisan could have arrived at a 100 U/ml β-glucocerebrosidase-based pharmaceutical composition with a pH of 5.5-6.5 comprises 5-6 g/L sodium citrate buffer, 0.2 g/L of the surfactant polysorbate 80, and 80 g/L of the tonicity agent sucrose. Thereby arriving at the invention of claims 22, 27-29, and 31.
An ordinary artisan would have been motivated to modify the pharmaceutical formulation comprising 100 U/ml β-glucocerebrosidase taught by Chang by making a simple substitution of the buffer system and excipient composition, and concentrations thereof, for those taught by Neelon. Thereby the modified the 100 U/ml β-glucocerebrosidase-based pharmaceutical composition (Meeting claim limitations of independent claim 22 and dependent claims 28 and 32) has a pH of 5.5-6.5 (Meeting claim limitations of dependent claims 27 and 32) as well as comprises 1.29-12.9 g/L sodium citrate buffer (Meeting claim limitations of independent claim 22), 0.1-10 g/L of the surfactant polysorbate 80 (Meeting claim limitations of independent claim 22), and a tonicity agent comprising sucrose. This is because a simple substitution of one known element for another to obtain predictable results is considered obvious. Both compositions from Chang and Neelon comprise the same buffer, the same surfactant, and a tonicity modifier/agent of either mannitol or mannose, respectively. Furthermore, the claimed ranges for citrate buffer and polysorbate 80, with regard to claim 22, lie inside or substantially overlap the ranges disclosed by Neelon. Therefore, the limitations of those composition components are obvious with regard to claim 22 (See MPEP 2144.05.I).
de Villiers teaches buffering capacity, and therefore a system’s ability to resist changes in pH, is dependent on the concentration of a buffer and generally increases as the buffer concentration increase. Therefore, an ordinary artisan could have optimized the concentration of sodium citrate in the composition to adjust the buffering capacity of the composition and through the course of routine experimentation arrived at a 5-6 g/L sodium citrate (Meeting claim limitations of independent claim 22 and dependent claims 29 and 32) (See MPEP 2144.05.II).
Kaisheva teaches that the aggregation of proteins in a composition are dependent on the surfactants, like polysorbate 80, added to the composition such that adding surfactants reduces protein aggregation. Therefore, an ordinary artisan could have optimized the concentration of polysorbate 80 to minimize protein aggregation in the composition and through the course of routine experimentation arrived at a 0.2 g/L polysorbate 80 (Meeting claim limitations of independent claim 22 and dependent claims 31- 32) (See MPEP 2144.05.II).
Kaisheva taught a stable pharmaceutical protein composition comprising 34.23-102.69 g/L sucrose of the tonic modifier sucrose. Since Chang taught the osmolality of a pharmaceutical formulation is dependent on the concentrations of components in a composition - such as tonicity modifiers like sucrose. Therefore, an ordinary artisan could have optimized the concentration of sucrose and through the course of ordinary experimentation and arrived at 80 g/L sucrose to adjust the osmolality and in order to produce an isotonic composition with respect to the site of administration in a subject (Meeting claim limitations of independent claim 22 and dependent claims 30 and 32) (See MPEP 2144.05.II).
An ordinary artisan would have had a reasonable expectation of success of substituting the pharmaceutical formulation comprising 100 U/ml β-glucocerebrosidase taught by Chang by making a simple substitution of the buffer system and excipient composition, and concentrations thereof, for those taught by Neelon with predictable and expected results due to the similar content. This is because Chang and Neelon both teach protein-based pharmaceutical compositions with a sodium citrate buffer and similar excipients. An ordinary artisan would have had a reasonable expectation of success of modifying the sucrose content in the modified protein composition to comprise 80 g/L because Kaisheva taught a stable pharmaceutical protein composition comprising 34.23-102.69 g/L of the tonicity modifier sucrose.
An ordinary artisan would have had a reasonable expectation of success of substituting the β-glucocerebrosidase in the composition Chang for a β-glucocerebrosidase with an N-glycan with terminal mannose residues taught by Jung in order to treat Gaucher disease caused by a β-glucocerebrosidase deficiency. This is because Jung taught: β-glucosidase hydrolyzes glucosylceramide (also termed glucocerebroside); Gaucher disease is caused by accumulation of glucocerebroside in cells, especially macrophages, due to a deficiency in β-glucocerebrosidase; and enzyme replacement therapy that results in β-glucocerebrosidase uptake in macrophages requires the β-glucocerebrosidase to carry terminal mannose residues on their N-glycans.
Consequently, the invention of claims 22 and 27-32 would have been obvious to one of ordinary skill in the art before the effective filing date.
Applicant’s Arguments and Examiner’s Response
ARGUMENT: Applicant submits that there is no prima facie case of obviousness for the combination of Chang in view of Neelon, Kaisheva, and de Villiers and as evidenced by PubChem’19 and PubChem’20 with regard to claims 22 and 27-32 when claim 22 is currently amended as follows:
A pharmaceutical formulation comprising a therapeutically effective amount of β-glucocerebrosidase, a buffer, an osmoregulator and a surfactant, wherein the glucocerebrosidase is present in an amount of 50-150 U/mL, the buffer is a citrate buffer present in an amount of 2-10 g/L, the osmoregulator is sucrose present in an amount of 40-120 g/L, and the surfactant is polysorbate 80 present at an amount of 0.1-1 g/L, and wherein the β-glucocerebrosidase comprises a N-glycan containing one or more terminal mannose residues.
RESPONSE TO REMARKS: Applicant’s arguments are not found persuasive. The Examiner agrees that combination of Chang in view of Neelon, Kaisheva, and de Villiers and as evidenced by PubChem’19 and PubChem’20 does not teach or suggest the newly added limitation to claim 22 “wherein the β-glucocerebrosidase comprises a N-glycan containing one or more terminal mannose residues” and therefore does not teach all of the limitations for claims 22 and 27-32 as currently amended. However, for the reasons set forth in the new rejection above, it would have been obvious for an ordinary artisan to have modified the β-glucocerebrosidase composition taught by Chang in view of Neelon, Kaisheva, de Villiers, and Jung and as evidenced by PubChem’19, PubChem’20, and NCBI’2629 to include a β-glucocerebrosidase that comprises a N-glycan containing terminal mannose residues in order to treat Gaucher disease.
Conclusion
No claims are in condition for allowance.
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 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 SCOTT E. MULDER whose telephone number is (571)272-2372. The examiner can normally be reached Monday - Friday 7:30 AM - 3:30 PM.
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/SCOTT E. MULDER/Examiner, Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656