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
Claims 1-6 and 8-15 are pending and under examination herein.
The objection to claims 7, 11 and 13 is withdrawn in light of the cancellation of claim 7 and the correction of the informalities for claims 11 and 13 in the amendment dated 9/23/2026.
The rejection of claim 2 under 35 U.S.C. 112(d) is withdrawn in light of the amendment narrowing the scope to 25% of the N-linked glycans on glucocerebrosidase are bis-phosphorylated in the amendment dated 9/23/2026.
The rejection of claims 1-2, 4 and 8-15 under 35 U.S.C. 102(a)(1) and 102(a)(2) is withdrawn in light of the claim amendment to claim 1 adding the limitation “wherein the composition comprises less than 5 nanomolar affinity for cation-independent mannose 6-phosphate receptor (CIMPR)”. Vervecken does not teach wherein the composition comprises less than 5 nanomolar affinity to CIMPR.
The rejection of claim 7 under 35 U.S.C. 103 is withdrawn in light of the cancellation of the claim in the amendment dated 9/23/2026.
Priority
This application, filed on 8/5/2024, is a 371 of PCT/US2023/012523 filed on 2/7/2023. The effective filing date of the current application is February 7, 2023.
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.
Claims 1-4, 8-10, 12, and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Vervecken et al. (WO 2020/157248 A1, published on August 6, 2020; previously cited) in view of Zhou et al. (“Glycan Structure Determinants for Cation-Independent Mannose 6-Phosphate Receptor Binding and Cellular Uptake of a Recombinant Protein”, Bioconjugate Chemistry, 2013, Vol. 24, Issue 12, pp.2025-2035; previously cited).
Regarding claim 1, Vervecken teaches a glucocerebrosidase (GCase) preparation, wherein at least 50% of the glycans comprised by said glucocerebrosidase comprise at least one mannose-6-phosphate moiety (i.e. phosphorylated) (p.11, lines 1-7).
Vervecken does not teach wherein the composition comprises less than 5 nanomolar affinity to CIMPR.
However, Zhou teaches the cation-independent Man-6-P receptor (CI-MPR) is essential for update and lysosomal delivery of many endogenous as well as recombinant lysosomal enzymes (p.2025, 2nd column). Zhou teaches that the receptor contains 15 homologous extracytoplasmic domains involved in high affinity interactions with various ligands including Man-6-P containing glycans (p.2025, 2nd column). Zhou further teaches there is high sequence homology among the receptors from bovine, mouse and human, suggesting similar substrate specificities, and indeed glycan-binding properties are evolutionarily conserved in vertebrates (p.2025, 2nd column). Zhou teaches the affinity of human acid α-glucosidase to CI-MPR can vary based on the type of glycans conjugated (p.2033, 2nd column, conclusion). Zhou teaches that a high affinity interaction with CI-MPR can be observed for rhGAA [recombinant human acid α-glucosidase] conjugated to simple glycans containing a dimannose glycan with a single phosphate (p.2033, 2nd column conclusion).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the type of glycans bound to glucocerebrosidase of Vervecken as suggested by Zhou such that the affinity of the enzyme to the CI-MPR receptor changes based on the type of glycans bound to the enzyme. One of ordinary skill in the art would have been motivated to select glycans based on the desired affinity to the receptor because Zhou teaches that particular glycan structures affected the strength of the enzyme affinity to the CI-MPR receptor. One of ordinary skill in the art would have found it beneficial to modify the glycan composition to obtain a desired receptor affinity.
Regarding claim 2, Vervecken teaches a glucocerebrosidase (GCase) preparation, wherein at least 30% of glycans comprised by the glucocerebrosidase comprise at least one mannose-6-phosphate moiety (p.11, lines 1-2). Vervecken teaches that for Fig. 4 in the top panel, representing an embodiment of the presently described GCase, substantially all detectable N-glycans were phosphorylated, with 46% bi-phosphorylated N-glycans (i.e. at least 25%) and 54% monophosphorylated N-glycans (p.60, lines 24-29; Fig. 4 top panel).
Regarding claim 3, Vervecken teaches that a representative DSA-FACE electropherogram of the isolated N-glycans of one of the uncapped and demannosylated GCase polypeptides is shown in Fig. 2, where substantially all detectable N-glycans were phosphorylated, with a very high proportion being bi-phosphorylated (M5P2, M6P2) (p.60, lines 17-21). Vervecken teaches a representative DSA-FACE electropherogram of the isolated N-glycans of one of the uncapped and demannosylated OxyGCase polypeptides (top panel), including annotation of peaks corresponding to bi-phosphorylated (2P), monophosphorylated (1P) and non-phosphorylated (neutral) N-glycans (p.5, lines 8-12; Fig. 4). Vervecken teaches that for Fig. 4 in the top panel, representing an embodiment of the presently described GCase, substantially all detectable N-glycans were phosphorylated, with 46% bi-phosphorylated N-glycans and 54% monophosphorylated N-glycans (p.60, lines 24-29; Fig. 4 top panel).
Vervecken does not teach wherein at least 50% of the N-linked glycans on glucocerebrosidase are bis-phosphorylated.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the conditions of bis-phosphorylation taught by Vervecken to increase the percentage of N-linked glycans from 46% to 50% to arrive at the claimed invention. One of ordinary skill in the art would reasonably expect that varying the phosphorylation conditions would predictably result in optimizing the desired level of bi-phosphorylated N-glycans, because Vervecken teaches 46% of N- glycans were bi-phosphorylated and 54% were monophosphorylated. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature 100°C and an acid concentration of 10%). See MPEP §2144.05.
Regarding claim 4, Vervecken teaches a representative DSA-FACE electropherogram of the isolated N-glycans of one of the uncapped and demannosylated OxyGCase polypeptides (top panel), including annotation of peaks corresponding to bi-phosphorylated (2P), monophosphorylated (1P) and non-phosphorylated (neutral) N-glycans (p.5, lines 8-12; Fig. 4). Vervecken teaches that for Fig. 4 in the top panel, representing an embodiment of the presently described GCase, substantially all detectable N-glycans were phosphorylated (p.60, lines 24-29; Fig. 4 top panel). Thus, in teaching that substantially all detectable N-glycans being phosphorylated (46% + 54% phosphorylated = 100% phosphorylated), Vervecken teaches that less than 10% of the N-linked glycans are non-phosphorylated glycans.
Regarding claims 8-9, Vervecken teaches GCase activity in brain hemispheres or liver of OxyGCase variants (i.e. glucocerebrosidase) and Cerezyme® (i.e. imiglucerase) (p.6, lines 7-16; Figure 14 and Figure 15). Vervecken teaches that compared to OxyGCase, ICV delivered Cerezyme® performed significantly worse in terms of increasing GCase activity, displaying only marginal improvements in the brain and the liver (3.5-fold of KI levels for GCaseMutl-H8 versus 1.5-fold of KI levels for Cerezyme®, both determined 48 hours after the last of 4 weekly ICV injections with 70 μg, Fig. 15A) (i.e. at least 2-fold greater) and the liver (25-fold of KI levels 25 for GCaseMutl-H8 versus 5-fold of KI levels for Cerezyme®, both determined 48 hours after the last of 4 weekly ICV injections with 70 μg, Fig. 15B) (p.69, lines 21-26).
Regarding claim 10, Vervecken teaches that HexSph levels consist of two epimers, GlcSph and Galactosylsphingosine (GalSph) of which only GlcSph is a substrate for GCase (p.70, lines 21-22). Vervecken teaches that all OxyGCase variants outperformed Cerezyme® when administered at an identical dose and regimen (p.70, lines 25-26). Vervecken teaches that 4 weekly bolus ICV treatments with 70 µg of CGaseMut1-H8, GCaseMut1 or huGCase(K32IN) resulted in a statistically significant reduction of HexSph levels compared to vehicle-treated KI mice, while this was not the case for Cerezyme® (p.70, lines 26-28).
Regarding claim 12, Vervecken teaches substrate levels were efficiently reduced in all brain regions (p.71, line 23). Vervecken teaches that substrate reduction upon 8 bi-weekly treatments with GCaseMutl-H8 occurred in all regions, to a higher extend in striatum, hippocampus and cerebellum compared to midbrain and cortex (p.71, lines 25-27). Vervecken further teaches that this is again in line with the enzyme levels measured through activity, and importantly, 4 weekly ICV infusions with 70 μg of Cerezyme® did not or only slightly reduced GlcSph in the analyzed regions (p.71, lines 27-29).
Regarding claim 14, Vervecken teaches a mouse model for neuronopathic Gaucher disease (p.62, Example 6, lines 19-29). Vervecken teaches intracerebroventricular (ICV) delivery of recombinant human glucocerebrosidase (GCase) polypeptides in mice (p.62, Example 7, lines 30-31). Vervecken teaches that mice were treated weekly, bi-weekly, or every other day with a bolus or a slow infusion of test article for 1-12 weeks (p.63, lines 1-3).
Regarding claim 15, Vervecken teaches that there is currently no cure for Gaucher disease, although enzyme replacement therapy (ERT) in which intravenously administered recombinant GCase is partially supplementing the deficient enzyme, is an approved treatment to alleviate the symptoms of type 1 Gaucher disease (p.2, lines 27-29).
Claims 11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Vervecken et al. (WO 2020/157248 A1, published on August 6, 2020; previously cited) in view of Zhou et al. (“Glycan Structure Determinants for Cation-Independent Mannose 6-Phosphate Receptor Binding and Cellular Uptake of a Recombinant Protein”, Bioconjugate Chemistry, 2013, Vol. 24, Issue 12, pp.2025-2035; previously cited) as applied to claim 1 above, as evidenced by Revel-Vilk et al. (“Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review”, International Journal of Molecular Sciences, 2020, Vol. 21, No. 19, article 7159; 35 pages; previously cited).
Regarding claims 11 and 13, Vervecken teaches accumulation of GCase substrates glucosylsphingosine (GlcSph) and glucosylceramide (GlcCer) is an important cause of pathological symptoms in Gaucher patients (p.70, lines 13-14). Vervecken further teaches that the superior therapeutic potential of ICV injected OxyGCase variants for treating Gaucher compared to Cerezyme® was demonstrated by assessing the reduction of GlcSph levels in brain and liver. As evidenced by Revel-Vilk, glucosylsphingosine is also known as (lyso-GB1), and is considered to be the most reliable biomarker currently available for the diagnosis, prognosis, and disease/treatment monitoring of patients with Gaucher disease (abstract).
Claims 5 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Vervecken et al. (WO 2020/157248 A1, published on August 6, 2020; previously cited) in view of Zhou et al. (“Glycan Structure Determinants for Cation-Independent Mannose 6-Phosphate Receptor Binding and Cellular Uptake of a Recombinant Protein”, Bioconjugate Chemistry, 2013, Vol. 24, Issue 12, pp.2025-2035; previously cited) as applied to claim 1 above, and further in view of Brumshtein et al. (“Characterization of gene-activated human acid-β-glucosidase: Crystal structure, glycan composition, and internalization into macrophages”, Glycobiology, 2010, Vol. 20, No.1, pp.24-32; previously cited).
The teachings of Vervecken et al. and Zhou et al. are discussed above.
Regarding claims 5-6, Vervecken teaches that N-glycans are divided into three main classes, (i) high-mannose, (ii) complex, and (iii) hybrid types (p.15, lines 7-8).
Vervecken and Zhou do not disclose less than 50% of the N-linked glycans on glucocerebrosidase are complex type N-glycans (claim 5) or wherein less than 5% of the N-linked glycans on glucocerebrosidase are hybrid type N-glycans (claim 6).
However, Brumshtein teaches Gaucher disease, the most common lysosomal storage disease, can be treated with enzyme replacement therapy, ERT, in which defective acid-β-glucosidase (GlcCerase) is supplemented by a recombinant, active enzyme (abstract). Brumshtein teaches that analysis of glycosylation patterns shows that velaglucerase alfa displays distinctly different structures from imiglucerase and prGCD (abstract). Brumshtein teaches observing mono-sialyated mono antennary hybrid and complex-type structures with core fucosylation, which were quantified by glycan map analysis (p.27, 2nd column, 2nd paragraph). Brumshtein teaches that estimates from glycan map analysis show that mono-sialylated mono-antennary hybrid structures account for ~2% of the total glycan pool (p.27, 2nd column, 3rd paragraph). Brumshtein further teaches that high-mannose type glycans form the majority of the glycans, and as shown in the glycan map analysis, less than 50% of the N-linked glycans are complex type N-glycans (p.29, Fig. 8).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to obtain a glucocerebrosidase having less than 50% complex type N-glycans and less than 5% hybrid type N-glycans, because Brumshtein teaches that the majority of the glycans correspond to high-mannose type neutral glycans, with less than 50% complex type N-glycans and ~2% hybrid type N-glycans. One of ordinary skill in the art would reasonably expect that a glucocerebrosidase would predictably result in the desired distribution of complex type and hybrid type N-glycans, because Brumshtein teaches this distribution of N-glycans in glucocerebrosidase.
Response to Arguments
Applicant argues that claim 7 has been canceled and its limitation incorporated into claim 1; the combination of Vervecken and Zhou fails to render the claimed CIMPR affinity limitation obvious (See Remarks dated 9/23/2026, p.5 last paragraph). Applicant argues that Zhou relates CIMPR binding for acid alpha glucosidase (GAA) not GCase, and Zhou does not disclose achieving a binding affinity of less than 5 nanomolar for any enzyme, let alone GCase (See Remarks dated 9/23/2026, p.6 1st paragraph). Applicant argues that Zhou teaches that affinity of GAA to CIMPR can vary based on the type of glycans conjugated, and that high affinity interactions can be observed for certain glycan structures, but does not provide any specific nanomolar binding affinity values and there is no basis to conclude that modifying Vervecken’s GCase glycans using Zhou’s teachings would predictably result in a composition having less than 5 nanomolar CIMPR affinity (See Remarks dated 9/23/2026, p.6 1st paragraph).
Applicant argues that one of ordinary skill in the art would recognize that GCase and GAA are different enzymes with different glycosylation sites, different 3-D structures and different glycan processing pathways (See Remarks dated 9/23/2026, p.6 2nd paragraph). Applicant argues that the CIMPR binding affinity is influenced not only by the type of glycans but also by the specific arrangement and presentation of those glycans on the enzyme surface; therefore the teachings of Zhou regarding GAA cannot be extrapolated to GCase to predict a specific CIMPR binding affinity (See Remarks dated 9/23/2026, p.6 2nd paragraph).
Applicant argues that the experimental data in the present application demonstrates that not all GCase compositions having phosphorylated N-linked glycans possess the claimed CIMPR binding affinity (See Remarks dated 9/23/2026, p.6 3rd paragraph). Applicant refers to the specification paragraph [000103] and FIG. 2, and states that comparative data conclusively demonstrates that CIMPR binding affinity is not an inherent property of phosphorylated GCase compositions and does not necessarily flow from having a GCase with some level of phosphorylation (See Remarks dated 9/23/2026, p.6 3rd paragraph).
Applicant argues that production lot data confirms this distinction and refers to paragraphs [000184]-[000186], FIG. 38A, FIGS 39A-C; stating that CIMPR affinity profiles have been consistent in demonstrating high CIMPR affinity regardless of the cell type used (See Remarks dated 9/23/2026, p.6 last paragraph). Applicant further argues that as demonstrated in the present application, M011 achieves a CIMPR binding affinity of less than 5 nanomolar through specific glycosylation features, including the claimed feature that at least 50% of the N-linked glycans on the GCase are phosphorylated, and this functional outcome is not taught or suggested by the combination of Vervecken and Zhou (See Remarks dated 9/23/2026, p.6 last paragraph – p.7 top 2 lines).
Applicant's arguments filed September 23, 2026 have been fully considered but they are not persuasive. Vervecken teaches a glucocerebrosidase (GCase) preparation, wherein at least 50% of the glycans comprised by said glucocerebrosidase comprise at least one mannose-6-phosphate moiety. Zhou teaches that CIMPR receptor contains 15 homologous extracytoplasmic domains involved in high affinity interactions with various ligands including Man-6-P containing glycans, and there is high sequence homology among the receptors from bovine, mouse and human, and that glycan-binding properties are evolutionarily conserved in vertebrates. Zhou further teaches that a high affinity interaction with CIMPR can be observed for rhGAA conjugated to simple glycans containing a dimannose glycan with a single phosphate. The function of the composition’s affinity for the CIMPR receptor is based on the structure of the glucocerebrosidase having at least 50% of the N-linked glycans phosphorylated. Vervecken teaches a glucocerebrosidase preparation having at least 50% of the glycans comprising at least one mannose-6-phosphate moiety. Thus, it would have been obvious to one of ordinary skill in the art to modify the type of glycans bound to glucocerebrosidase of Vervecken as suggested by Zhou such that the affinity of the enzyme to the CI-MPR receptor changes based on the type of glycans bound to the GCase. One of ordinary skill in the art would have been motivated to select glycans based on the desired affinity to the receptor because Zhou teaches that particular glycan structures affected the strength of the enzyme affinity to the CI-MPR receptor. One of ordinary skill in the art would have found it beneficial to modify the glycan composition of GCase to obtain a desired receptor affinity.
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 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.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/DEEPA MISHRA/Examiner, Art Unit 1657
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