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 1-15 are pending and under examination herein.
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.
Information Disclosure Statement
The information disclosure statement filed on 8/5/2024 complies with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. All references were considered.
Claim Objections
Claims 7, 11 and 13 are objected to because of the following informalities:
Claim 7 recites “composition of any of claim 1” in line 1, which contains an extraneous phrase “any of” and should be amended to “composition of claim 1”. The acronym “CIMPR” in line 2 is not preceded by the full name of the receptor at first recitation. The full name of the receptor should be recited, followed by CIMPR in parentheses.
Claim 11 recites “the group consisting of is Lyso-GL1” in lines 1-2, which contains an extraneous verb and should be amended to recite “The group consisting of Lyso-GL1”.
Claim 13 recites “the group consisting of is Lyso-GL1” in lines 1-2, which contains an extraneous verb and should be amended to recite “The group consisting of Lyso-GL1”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 recites “wherein at least 25% of the N-linked glycans on glucocerebrosidase are phosphorylated”. Claim 2 depends from claim 1, which recites “wherein at least 50% of the N-linked glycans on glucocerebrosidase are phosphorylated”. The scope of claim 2 is broader than the scope of claim 1. Thus, claim 2 does not further limit claim 1 from which it depends, and therefore is an improper dependent claim.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 4, and 8-15 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being clearly anticipated by Vervecken et al. (WO 2020/157248 A1, published on August 6, 2020). The rejection of claims 11 and 13 are further 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).
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).
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).
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 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).
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).
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.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Vervecken et al. (WO 2020/157248 A1, published on August 6, 2020).
The teachings of Vervecken et al. are discussed above.
Regarding claim 3, Vervecken teaches that a representative DSA-FACE eletropherogram 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 percent 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.
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) 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).
The teachings of Vervecken 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 does 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.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Vervecken et al. (WO 2020/157248 A1, published on August 6, 2020) as applied to claim 1 above, and further 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).
The teachings of Vervecken et al. are discussed above.
Regarding claim 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.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DEEPA MISHRA whose telephone number is (571) 272-6464. The examiner can normally be reached Monday - Friday 9:30am - 3:30pm EST.
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/DEEPA MISHRA/Examiner, Art Unit 1657
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
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