DETAILED CORRESPONDENCE
Status of the Application
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 13, 2026 has been entered.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 156-158, 160-173, 175, and 176 are pending in the application.
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. Claim 173 has been amended without markings to show changes made and without being presented with the status identifier “Currently Amended.” Applicant is reminded of the manner of making amendments under 37 CFR 1.121, which requires an amended claim to have the status identifier “Currently Amended” and to include markings to show changes made.
Applicant’s remarks filed February 13, 2026 in response to the final rejection filed August 13, 2025 have been fully considered.
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
In response to a requirement for an election of species mailed on June 15, 2023, applicant elected without traverse species 5), the rhα-Gal protein has at least 4 moles of sialic acid residues per mole of rhα-Gal A homodimer as measured by liquid chromatography.
By the amendment to claim 156 filed June 20, 2025, the elected species 5) has been deleted from the claims and the search and examination has been extended to species 6), the rhα-Gal protein has at least 50% of total N-linked oligosaccharides that contain sialic acid as measured by liquid chromatography, and species 7), the rhα-Gal protein has at least 25% of total N-linked oligosaccharides that are mono-mannose-6-phosphate and at least 6% of total N-linked oligosaccharides that are bis-mannose-6-phosphate as measured by liquid chromatography, as set forth in the Office action filed June 15, 2023. Accordingly, the requirement for an election of species among species 5) to 7) as set forth in the Office action mailed June 15, 2023 is withdrawn.
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, 164-173, 175, and 176 are being examined on the merits.
Claim Objections
The objection to claim 173 for not ending with a period is withdrawn in view of applicant’s amendment to add a period at the end of the claim.
Claim Rejections - 35 USC § 112(a)
The rejection of claims 156, 161, and 164-173 under 35 U.S.C. 112(a) as failing to comply with the written description requirement is withdrawn in view of applicant’s amendment to claim 156 to delete the phrase “the rhα-Gal A has at least 25% of total N-linked oligosaccharides contain at least one mannose-6-phosphate (M6P) residue.”
Claims 175 and 176 are rejected under 35 U.S.C. 112(a) 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 or a joint inventor, at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims.” See also MPEP 714.02. MPEP § 2163.II.A.3.(b) further states, “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112, para. 1, as lacking adequate written description.” According to MPEP § 2163.I.B, “While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure” and “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.”
New claim 176 recites “the rhα-Gal A has at least 25% of total N-linked oligosaccharides that are…bis-mannose-6-phosphate” and amended claim 175 recites “wherein at least 35% of total N-linked oligosaccharides are…bis-mannose-6-phosphate.” According to applicant’s instant remarks, “[s]upport for the amendments can be found throughout the original application as filed, including at least paragraph [00205]” (p. 6, top). However, while the disclosure at paragraph [00205] of the specification provides descriptive support for at least 20% of total N-linked oligosaccharides are bis-mannose-6-phosphate, there is no apparent descriptive support for the limitations “the rhα-Gal A has at least 25% of total N-linked oligosaccharides that are…bis-mannose-6-phosphate” and “wherein at least 35% of total N-linked oligosaccharides are…bis-mannose-6-phosphate” in the original application as filed. Applicant is invited to show support for the limitations at issue.
Claim Rejections - 35 USC § 103
Claims 156, 161, 169, 171, and 172 are newly rejected 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”).
This rejection is necessitated upon further consideration of the prior art of record.
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, 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 explicitly teach the claim 156 limitation that the rhα-Gal A has 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 silalylated 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 silalylated glycans greater than 50% or 55%.
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 rejected 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”).
The relevant teachings of Lee, Soh, and Treco 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, and Treco 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, 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 rejected 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”).
The relevant teachings of Lee, Sohn, and Treco as applied to claims 156, 161, 169, 171, and 172 are set forth above.
Regarding claim 170, Lee 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, and Treco 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, 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.
Claims 175 and 176 are rejected 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 Zhou et al. (Bioconjug. Chem. 24:2025-2035, 2013; cited on the attached Form PTO-892; hereafter “Zhou”).
The relevant teachings of Lee, Soh, and Treco as applied to claims 156, 161, 169, 171, and 172 are set forth above.
Regarding claims 175 and 176, 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).
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]).
While Lee teaches an increased percentage of N-linked oligosaccharides that are bis-mannose-6-phosphate, Sohn acknowledges a correlation between superior activity of a recombinant human α-galactosidase A protein and higher contents of mannose-6-phosphate, and Treco suggests selective isolation of glycoforms using a chromatography column, the combination of Lee, Sohn, and Treco does not teach
the rhα-Gal A has at least 25% or 35% of total N-linked oligosaccharides that are bis-mannose-6-phosphate.
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 25% or 35% 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 additional teachings of Lee and the teachings of 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 25% or 35% 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.
Therefore, the method of claims 175 and 176 would have been obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Status of the claims:
Claims 156-158, 160-173, 175, and 176 are pending.
Claims 157, 158, 160, 162, and 163 are withdrawn from consideration.
Claims 156, 161, 164-173, 175, and 176 are rejected.
No claim is in condition for allowance.
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.
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, MANJUNATH N. RAO can be reached on 571-272-0939. 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 http://pair-direct.uspto.gov. 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.
/David Steadman/Primary Examiner, Art Unit 1656