DETAILED CORRESPONDENCE
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 February 13, 2026, is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Claims 156-158 and 160-173 are pending in the application.
Applicant’s remarks filed September 16, 2026 in response to the non-final rejection filed March 16, 2026 have been fully considered.
Claims 175 and 176 have been canceled by applicant’s claim amendment filed September 16, 2026 and rejections previously applied to claims 175 and 176 are withdrawn.
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in a prior Office action.
Election/Restrictions
Claims 157, 158, 160, 162, and 163 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim.
Claims 156, 161, and 164-173 are being examined on the merits.
Claim Rejections - 35 USC § 103
The rejection of claims 156, 161, 169, 171, and 172 under 35 U.S.C. 103 as being unpatentable over Lee et al. (WO 2015/061464 A2; cited on Form PTO-892 filed October 11, 2023; hereafter “Lee”) in view of Sohn et al. (BMB Rep. 46:157-162, 2013; cited on Form PTO-892 filed October 11, 2023; hereafter “Sohn”), and Treco et al. (US 2004/0071686 A1; cited on Form PTO-892 filed June 3, 2024; hereafter “Treco”),
the rejection of claims 164-168, 170, and 173 under 35 U.S.C. 103 as being unpatentable over Lee in view of Sohn and Treco as applied to claims 156, 161, 169, 171, and 172 above, and further in view of Warnock et al. (PLoS One 10:e013441, 2015, 17 pages; cited on Form PTO-892 filed October 11, 2023; hereafter “Warnock”), and
the rejection of claims 164-166, 170, and 173 under 35 U.S.C. 103 as being unpatentable over Lee in view of Sohn and Treco as applied to claims 156, 161, 169, 171, and 172 above, and further in view of Khanna et al. (US 2015/0174214 A1; cited on Form PTO-892 filed October 11, 2023; hereafter “Khanna”)
are withdrawn in view of applicant’s amendment to claim 156 to recite “wherein the rhα-Gal has at least 20% of total N-linked oligosaccharides that are mono-mannose-phosphate or bis-mannose-6-phosphate, wherein the rhα-Gal A has greater than 3 moles of mannose-6-phosphate (M6P) residues per mole of rhα-Gal A homodimer.”
Claims 156, 161, 169, 171, and 172 are newly rejected under 35 U.S.C. 103 as being unpatentable over Lee in view of Sohn, Treco, and Zhou et al. (Bioconjug. Chem. 24:2025-2035, 2013; cited on Form PTO-892 filed ; hereafter “Zhou”).
This rejection is necessitated by applicant’s amendment to claim 156.
As amended, the claims are drawn to a method for treating Fabry disease, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising a human recombinant α-galactosidase A (rhα-Gal A), wherein the rhα-Gal A comprises an amino acid sequence having at least 98% sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2, wherein the rhα-Gal A has less than 10% of total N-linked oligosaccharides that are neutral, wherein the rhα-Gal has at least 20% of total N-linked oligosaccharides that are mono-mannose-phosphate or bis-mannose-6-phosphate, wherein the rhα-Gal A has greater than 3 moles of mannose-6-phosphate (M6P) residues per mole of rhα-Gal A homodimer, wherein the rhα-Gal A has greater than 5 moles sialic acid residues per mole of rhα-Gal A homodimer, and the rhα-Gal A has at least 50% of total N-linked oligosaccharides that contain sialic acid, as measured by normal-phase liquid chromatography on an amino column.
Regarding claim 156, Lee generally teaches recombinant human α-galactosidase A protein that has altered glycosylation as compared to Fabrazyme® (p. 30, lines 13-14). Lee teaches the amino acid sequence of SEQ ID NO: 2 as being the sequence of the recombinant human α-galactosidase A protein (p. 29, lines 11-16). SEQ ID NO: 2 of Lee is identical to SEQ ID NO: 1 of this application (see Appendix at pp. 18-19 of the Office action filed October 11, 2023).
Lee teaches the N-linked glycosylation profile of the recombinant human α-galactosidase A protein was determined using liquid chromatography (paragraph bridging pp. 92-93). Lee teaches the recombinant human α-galactosidase A protein has a percentage of total N-linked oligosaccharides that are neutrally-charged oligosaccharides between about 0.1% and about 3.9% (paragraph bridging pp. 41-42; Figure 21A). Lee teaches the recombinant human α-galactosidase A protein has a mole/mole ratio of sialic acid to protein that is greater than 5.0 (p. 41, lines 13-18). Although Lee does not teach the liquid chromatography is “normal-phase liquid chromatography on an amino column”, it is presumed that the moles of N-linked oligosaccharides are encompassed by claim 156.
Lee teaches a method for treating Fabry disease in a subject by administering a pharmaceutical composition comprising the recombinant human α-galactosidase A protein to the subject (p. 82, lines 4-10).
While Lee provides extensive teachings regarding N-linked sialylated oligosaccharides of the recombinant human α-galactosidase A protein (see, e.g., pp. 33-41, 45, and 46), teaches capping with sialic acid (see e.g., p. 27, line 19), and teaches altered glycosylation of the recombinant human α-galactosidase A protein relative to Fabrazyme to impart the advantage of decreased non-specific targeting to the liver by binding to the asialoglycoprotein receptor (p. 23, lines 15-19), Lee does not teach the limitation of at least 50% of total N-linked oligosaccharides that contain sialic acid.
Sohn teaches Fabry disease can be treated with enzyme replacement therapy by employing an injection of a recombinant enzyme with proper glycans for lysosomal targeting (p. 157, column 2, top). Sohn teaches successful targeting to lysozymes of tissues affected in Fabry disease patients requires terminal sialic acid capping as the asialoglycoprotein receptor in the liver rapidly removes the glycoprotein containing the exposed galactose residues from blood circulation (p. 157, column 2, bottom). Sohn teaches the increased level of sialic acids of glycoproteins is well known to correlate with the prolonged half-life in the serum (p. 157, column 2, bottom). Sohn teaches development and optimization of an in vitro glycosylation process designed to increase sialic acid content, which resulted in almost complete sialic acid capping (p. 161, column 1, bottom).
Treco teaches methods for increasing the sialic acid content of rhα-Gal A in order to increase the circulatory half-life of the rhα-Gal A, including (i) isolation of the highly charged and/or higher molecular weight rhα-Gal A glycoforms during or after the purification process; (ii) adding sialic acid residues using cells genetically modified (either by conventional genetic engineering methods or gene activation) to express a sialyltransferase gene or cDNA, or (iii) fermentation or growth of cells expressing the enzyme in a low ammonium environment (paragraphs [088] to [0093] and [0112]). According to Treco, an α-Gal A preparation having a high percentage of the oligosaccharides being negatively charged, primarily by the addition of one to four sialic acid residues on complex glycans, noting that capping of penultimate galactose residues by 2,3- or 2,6-linked sialic acid prevents premature removal from the circulation by the asialoglycoprotein receptor present on hepatocytes (paragraph [0096]). Although Treco does not elaborate as to what is a “high percentage” of complex glycans with added sialic acid residues, Treco teaches an α-Gal A preparation that has sialylated glycans greater than 50% or 55% (paragraph [0033]).
In view of the combined teachings of Lee, Sohn, and Treco, it would have been obvious to one of ordinary skill in the art before the effective filing date for the rhα-Gal A of Lee to have at least 50% of total N-linked oligosaccharides that contain sialic acid. One would have been motivated for the rhα-Gal A of Lee to have at least 50% of total N-linked oligosaccharides that contain sialic acid because of the teachings of Sohn and Treco regarding increasing terminal sialic acids in order to achieve successful targeting to lysozymes of tissues affected in Fabry disease patients and improve circulatory half-life of the rhα-Gal A. One would have expected success because Sohn taught a method that results in almost complete sialic acid capping and Treco taught methods to increase the sialic acid content of the rhα-Gal A and suggests an α-Gal A preparation having sialylated glycans greater than 50% or 55%.
Lee further teaches the recombinant human α-galactosidase A protein has an increased percentage of total N-linked oligosaccharides that are bis-mannose-6-phosphate oligosaccharides (as compared to Fabrazyme) that results in increased binding to the mannose-6-phosphate receptor, which in turn can increase the rate of endocytosis of the recombinant protein by a mammalian cell expressing mannose-6- phosphate receptor protein on its surface (p. 30, lines 14-20). Lee teaches the recombinant human α-galactosidase A protein can have greater than 11% of total N-linked oligosaccharides that are bis-mannose-6-phosphate (paragraph bridging pp. 35-36) and can have a mole to mole ratio of mannose-6-phosphate to protein of greater than 3 (p. 48, lines 1-14).
Lee does not teach the rhα-Gal A has at least 20% of total N-linked oligosaccharides that are bis-mannose-6-phosphate.
Sohn teaches mannoase-6-phosphate is an essential factor for targeting to lysozymes of tissues affected in Fabry disease patients and teaches a correlation between superior activity of a recombinant human α-galactosidase A protein and higher contents of mannose-6-phosphate (p. 157, column 2).
Treco teaches the proportion of charged α-Gal A can be increased by selective isolation of glycoforms during the purification process using a chromatography column (paragraph [0100]) and teaches that enzyme molecules with two Man-6-phosphate residues have a much greater affinity for the cation-independent Man-6-phosphate receptor (CI-MPR) than those with a single Man-6-phosphate (paragraph [0097]).
Zhou teaches a method for CI-MPR affinity chromatography to bind and elute a recombinant lysosomal enzyme comprising a bis-mannose-6-phosphate (paragraph bridging pp. 2026-2027).
In view of the combined teachings of Lee, Sohn, Treco, and Zhou, it would have been obvious to one of ordinary skill in the art before the effective filing date for the rhα-Gal A of Lee to have at least 20% of total N-linked oligosaccharides that are bis-mannose-6-phosphate. According to MPEP 2144.05.II.B, the presence of a known result-effective variable would be motivation for a person of ordinary skill in the art to experiment to reach another workable product. Lee taught the recombinant human α-galactosidase A protein can have greater than 11% of total N-linked oligosaccharides that are bis-mannose-6-phosphate. In view of the teachings of Lee and Sohn, one of ordinary skill would have recognized that the percentage of total N-linked oligosaccharides that are bis-mannose-6-phosphate oligosaccharides is a result-effective variable and would have been motivated to experiment to discover the optimum or workable ranges of the percentages of total N-linked oligosaccharides that are bis-mannose-6-phosphate oligosaccharides for the rhα-Gal A of Lee. One would have expected success for the rhα-Gal A of Lee to have at least 20% of total N-linked oligosaccharides that are bis-mannose-6-phosphate because Treco suggests selective isolation of glycoforms using a chromatography column and Zhou taught a method for CI-MPR affinity chromatography to bind and elute a recombinant lysosomal enzyme comprising a bis-mannose-6-phosphate.
Regarding claim 161, Lee teaches that the recombinant human α-galactosidase A protein has a mole to mole ratio of sialic acid to protein that is about the same or greater than Fabrazyme® and Sohn teaches that Fabrazyme® (i.e., Agalsidase beta) has 7.3 moles of sialic acid per mole of protein as measured by liquid chromatography (p. 158, Table 1).
Regarding claim 169, Lee teaches the recombinant human α-galactosidase A protein is administered in a dose of about 0.5 mg/kg body weight to about 2.0 mg/kg body weight (p. 12, lines 23-25).
Regarding claim 171, Lee teaches the doses of the recombinant human α-galactosidase A protein are administered two weeks apart (p. 12, lines 26-28).
Regarding claim 172, Lee teaches the recombinant human α-galactosidase A protein is administered in a dose of about 0.5 mg/kg body weight to about 2.0 mg/kg body weight (p. 12, lines 23-25).
Therefore, the method of claims 156, 161, 169, 171, and 172 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 164-168, 170, and 173 are newly rejected under 35 U.S.C. 103 as being unpatentable over Lee in view of Sohn, Treco, and Zhou as applied to claims 156, 161, 169, 171, and 172 above, and further in view of Warnock et al. (PLoS One 10:e013441, 2015, 17 pages; cited on Form PTO-892 filed October 11, 2023; hereafter “Warnock”).
The relevant teachings of Lee, Soh, Treco, and Zhou as applied to claims 156, 161, 169, 171, and 172 are set forth above.
Regarding claim 170, Lee further teaches the doses of the recombinant human α-galactosidase A protein are administered two weeks apart (p. 12, lines 26-28).
The combination of Lee, Sohn, Treco, and Zhou does not teach a pharmacological chaperone, dosage, and administration route as recited in claims 164-168 and 173.
Warnock teaches that following a single oral dose of 150 mg of migalastat HCl co-administered with α-galactosidase A, the activity of α-galactosidase A in plasma was significantly increased 1.2- to 5.1-fold compared to α-galactosidase A administration alone, in 22 of 23 patients (95.6%) (p. 1, Abstract). Warnock teaches that no migalastat HCl-related adverse events or drug-related tolerability issues were identified (p. 1, Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date to combine Lee, Sohn, Treco, Zhou, and Warnock to co-administer recombinant human α-galactosidase A protein and migalastat HCl. One would have been motivated to and would have had a reasonable expectation of success to do this because Warnock taught a single oral dose of 150 mg of migalastat HCl co-administered with α-galactosidase A had the effect of significantly increasing α-galactosidase A activity in 22 of 23 patients.
Therefore, the method of claims 164-168, 170, and 173 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 164-166, 170, and 173 are newly rejected under 35 U.S.C. 103 as being unpatentable over Lee in view of Sohn, Treco, and Zhou as applied to claims 156, 161, 169, 171, and 172 above, and further in view of Khanna et al. (US 2015/0174214 A1; cited on Form PTO-892 filed October 11, 2023; hereafter “Khanna”).
The relevant teachings of Lee, Sohn, Treco, and Zhou as applied to claims 156, 161, 169, 171, and 172 are set forth above.
Regarding claim 170, Lee further teaches the doses of the recombinant human α-galactosidase A protein are administered two weeks apart (p. 12, lines 26-28).
The combination of Lee, Sohn, Treco, and Zhou does not teach a pharmacological chaperone as recited in claims 164-166 and 173.
Khanna teaches that enzyme replacement therapy for the treatment of Fabry disease has limitations (paragraph [0006]), while 1-deoxygalactonojirimycin (abbreviated as “DGJ”) can alleviate cell stress and inflammatory responses that are contributing factors in Fabry disease (paragraph [0007]). Lee teaches a co-formulation of human α-galactosidase A (α-Gal A) and an active site-specific chaperone such as DGJ for the treatment of Fabry disease (paragraph [0011]). Khanna teaches the DGJ is DGJ hydrochloride, also known as migalastat hydrochloride (paragraph [0012]). Khanna teaches a dose-dependent and time-dependent increase of α-Gal A with co-administration of DGJ as compared with α-Gal A alone (paragraphs [0281] and [0283]).
It would have been obvious to one of ordinary skill in the art before the effective filing date to combine Lee, Sohn, Treco, Zhou, and Khanna to administer a co-formulation of the recombinant human α-galactosidase A protein and the active site-specific chaperone of Khanna. One would have been motivated to and would have had a reasonable expectation of success to do this because Khanna taught a dose-dependent and time-dependent increase of α-Gal A with co-administration of DGJ as compared with α-Gal A alone.
Therefore, the method of claims 164-166, 170, and 173 would have been obvious to one of ordinary skill in the art before the effective filing date.
RESPONSE TO REMARKS: Applicant argues that in view of Treco’s teachings to have a sialic acid content of greater than 50% and a neutral glycan content of at least 22%, Treco teaches away from the claimed invention.
Applicant’s arguments are not found persuasive. Lee is directed to an α-Gal A produced in CHO cells (see Lee's Example 1 beginning at p. 88) while Treco's α-Gal A is produced in human cells (p. 31, line 25). Each of Lee and Treco teaches that the glycosylation profile of α-Gal A is dependent upon whether α-Gal A is produced in CHO cells or human cells (see Lee at p. 31, lines 21-25; Treco at paragraph [0056]) with CHO cells producing an α-Gal A with less than 10% neutral glycans (Lee at Figure 21A comparing percentages of neutral glycans of Fabrazyme and FZ2G, which are both produced in CHO cells; Treco at Table 1 comparing percentages of neutral glycans of Treco's human cell-produced α-Gal A with Fabrazyme, which is produced in CHO cells). Given that Treco's methods for increasing the sialic acid content of rhα-Gal A are not disclosed as requiring expression using a human cell and are independent of the expression host cell, one would have recognized that methods for increasing the sialic acid content of rhα-Gal A are applicable to CHO cell-produced α-Gal A and would have been motivated to and would have had a reasonable expectation of success to increase the sialic acid content of the rhα-Gal A of Lee according to one or more of the methods taught by the prior art. In this case, Treco does not criticize, discredit, or otherwise discourage modifying the rhα-Gal A of Lee to have at least 50% of total N-linked oligosaccharides that contain sialic acid. Thus, contrary to the applicant's position, Treco does not teach away from increasing the sialic acid content of the rhα-Gal A of Lee according to one or more of the methods taught by the prior art.
Applicant argues that similar to Treco, the proteins of Sohn have higher neutral glycan content than the claimed range of less than 10% of total N-linked oligosaccharides that are neutral.
Applicant’s arguments are not found persuasive. Sohn does not report the percentage of total N-linked oligosaccharides that are neutral. Moreover, Sohn – like Treco – does not criticize, discredit, or otherwise discourage modifying the rhα-Gal A of Lee to have at least 50% of total N-linked oligosaccharides that contain sialic acid.
Applicant argues that modifying the rhα-Gal A of Lee to increase sialic acid according to paragraph [0112] of Treco would change the relative distribution of the other glycans – including reducing the M6P content – which is contrary to Lee’s teachings of increasing M6P content.
Applicant’s arguments are not found persuasive. There is no evidence of record to support applicant’s position that increasing sialic acid content according to the prior art would have had the effect of decreasing M6P content. To the contrary, increasing sialic acid content without using enzymes that alter other glycans, e.g., in vitro sialylation of a purified rhα-Gal A, would not have been expected to have the effect of decreasing M6P content.
For these reasons, it is the examiner’s position that the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Status of the claims:
Claims 156-158, and 160-173 are pending.
Claims 157, 158, 160, 162, and 163 are withdrawn from consideration.
Claims 156, 161, and 164-173 are rejected.
No claim is in condition for allowance.
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 DAVID J STEADMAN whose telephone number is (571)272-0942. The examiner can normally be reached on Monday to Friday, 7:30 AM to 4:00 PM.
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/David Steadman/Primary Examiner, Art Unit 1656
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