DETAILED ACTION
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 .
Restriction/Election
Applicant’s election without traverse of Group I, drawn to a means for specifically binding the extracellular N-terminal domain 1, 2, and/or 3 of the human cation-independent mannose-6-phosphate (CI-M6PR) and corresponding to claims 28-43 and 47 in the reply filed 05/12/2026 is acknowledged.
Applicant has further elected examination of the following species: (a) ISVD set forth in SEQ ID NO:8 having the CDRs CDR1=SEQ ID NO:107; CDR2=SEQ ID NO:114; and CDR3=SEQ ID NO:121 and (b) fusion protein SEQ ID NO: 32.
Claim Status
The amendment filed 05/12/2026 is acknowledged. Claims 28-48 are pending. Claims 44-46 and 48 are withdrawn for being directed to non-elected inventions. Claim 33 is withdrawn for being drawn to a non-elected species.
Claims 28-32, 34-43, and 47 are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. The sequence identifiers for the sequences in Fig. 22, 46, 47, 52, and 64 are not identified in the drawings or Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities:
Pg. 2, Line 9 – “manoose” should be corrected to --mannose--
Starting on Pg. 44, the reference citations within the parentheses have an error warning instead of the citation, see for example Pg. 44, Line 13. These error notices are present on Pg. 44-104.
Appropriate correction is required.
Claim Objections
Claim 41 is objected to because of the following informalities: “alfa” should be corrected to --alpha--. Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 41 and 43 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 41 recites functional homologues of alpha-glucosidase and Cathepsin D. As there are no art recognized classes of naturally occurring or recombinant molecules that are considered homologues of either enzyme, the metes and bounds of the claim are indefinite.
Claim 43 depends from a cancelled claim. The metes and bounds of the claimed invention cannot be determined and the claim is indefinite. In the interest of compact prosecution, claim 43 will be interpreted as being dependent on independent claim 28.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 28-32, 35-43, and 47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, 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, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
The teachings of the specification and the claimed invention
The instant invention is directed to means for specifically binding the extracellular N-terminal domains 1, 2 and/or 3 of the human CI-M6PR, wherein the means shows internalization upon binding CI-M6PR-expressing cells. The means provided in the specification are immunoglobulin single variable domain molecules (ISVD, also referred to as VHH).
The specification discloses at least 16 VHH molecules that bind epitopes within the domain 1-3 region of CI-M6PR (VHH1-11 shown in Fig. 3 with additional VHH shown in Fig. 51). Importantly, the claimed means requires internalization upon binding CI-M6PR-expressing cells, but this property is not demonstrated for every ISVD disclosed in the specification. For example, Fig. 11 provides data for internalization of VHH1, VHH5, VHH7, and VHH8. Therefore, not all means for binding CI-M6PR provided in the specification meet the limitations of claim 28.
The state of the prior art
While ISVs are structurally distinct from “conventional,” four chain antibodies as found in humans, many principals of adaptive immunity are shared, and thus the knowledge in the art of conventional antibodies is also relevant to the claimed molecules. Muyldermans et al., Annu. Rev. Biochem. 2013. 82:775–97, (2013) teaches the use of an immunoglobulin fold comprising CDRs that contributes the majority of antigen binding residues supported by framework domains that contribute to both antigen binding residues and residues critical for the proper positioning of the CDRs, the use of recombination to produce CDR3 loops of diverse structure and length, and the presence of somatic hypermutation affinity maturation (for example, Pg. 783, Promiscious VH Genes Contribute to the VHH Repertoire).
Almagro et al. (Front. Immunol. 2018; 8:1751) teach that while affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
The prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, the unpredictability of single amino acid changes in an antibody is underscored by Winkler (J Immunol. 2000 Oct 15;165(8):4505-14) who teaches that a single amino acid change in a CDR can result in unpredictable and substantial changes in antibody specificity; see entire document (e.g., the abstract).
Similarly, Herold et al. (Sci Rep. 2017 Sep 25;7(1):12276) performed single- and double-point mutations in exemplary antibodies and found that a single point mutation in the VH CDR region can completely abolish antigen binding (Page 8, Paragraph 1, Line 11).
Pertaining to defining binding molecules based on the epitope they bind, it is known that antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156, page 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3.
Further, it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements, such as linear and discontinuous epitopes that is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al., Benchmarking B cell epitope prediction: Underperformance of existing methods, Protein Science (2005), 14:246–248 pg. 246). 3D structural analyses of antibody-epitope binding highlighting that the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al.,3D-Epitope-Explorer (3DEX): Localization of Conformational Epitopes within Three-Dimensional Structures of Proteins, Wiley Interscience, 2005 42–44, 60596, page 879).
Pertaining specifically to single domain antibodies specific for CI-M6PR, WO2020185069A1 discloses 17 VHH, each with fully defined binding regions comprising three defined CDRs (Pg. 19, Table 2). The disclosure importantly shows that a subset of the disclosed VHH are internalized in multiple cell types (Fig. 16 and 17, Pg. 74, 10.1. Internalization of VHHs, see entire section).
In all, the art shows that in order to define a single domain antibody requires the identification of all 3 CDRs that define the binding regions.
Claim analysis
In light of the teachings of the specification and the state of the relevant art, the claims have the following written description issues:
Claim 28 is directed to a means for specifically binding the N-terminal domains 1, 2, or 3 of CI-M6PR that also has the function of internalization upon binding CI-M6PR-expressing cells. The means provided in the disclosure and in claim 29 are ISVD specific for the domains 1-3 of CI-M6PR. However, based on the specification, not all CI-M6PR ISVD are capable of internalization and while the disclosure provides exemplary ISVD that possess this function, the disclosure does not provide a minimal structure required for internalization.
Claims 30 and 31 define the means for binding CI-M6PR based on the epitope to which is binds. This defines the means by function only and does impart structure to the means.
Claim 32 only partially defines the binding region of the claimed means for binding CI-M6PR.
Claim 35 provides the three CDRs of the ISVD, but the claim as written allows for mixing and matching between the different CDRs. There is no indication in the speciation that the three CDRs can be mixed and matched to produce additional ISVD that bind CI-M6PR and internalize upon binding to a cell.
Claims 36 and 42 claim the ISVD and ISVD fusion protein based on percent identity, allowing for undefined amino acid substitutions within the CDRs of the binding regions.
Because these claims do not define 3 CDRs of the ISVD means for binding and provide evidence that all ISVD of the disclosure internalize upon binding of CI-M6PR, one of skill in the art would neither expect nor predict the appropriate functioning of the antibodies as broadly as is claimed. There is no disclosure of a correlation between structure and function that would allow those of skill in the art to recognize other members of the claimed genus from the disclosure. That is, the specification provides neither a representative number of the encompassed antibodies, nor does it provide a descriptive of structural features that are common to the encompassed antibodies.
Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, the artisan cannot envision the detailed structure of the encompassed antibodies and non-antibody proteins and therefore Applicant was not in possession of the instant claimed invention.
Dependent claims 37-41, 43, and 47 are also rejected under 35 U.S.C. 112(a) for being dependent on rejected claims and not providing limitations for overcoming the written description rejection.
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 28-29, 37-38, and 43 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Houthoff (WO2020/185069, published 09/17/2020, effectively filed 03/08/2019, IDS 08/18/2023).
The disclosure of Houthoff is directed to binding molecules comprising at least one single variable antibody domain that targets hepatic stellate cell or myofibroblasts through binding insulin-like growth factor receptor (IGF2R, alternate name for CI-M6PR).
Regarding claims 28 and 29, pertaining to a means for specifically binding the extracellular N-terminal domains 1, 2 and/or 3 of the human CI-M6PR, wherein the means shows internalization upon binding CI-M6PR-expressing cells (claim 28) and wherein the means is an ISVD, Houthoff discloses the VHH (alternate name for ISVD) clone name 13E8 which binds within domain 1-3 of IGF2R/CI-M6PR, as evidenced by the instant specification, which teaches the VHH 13E8 binds to an epitope on CI-M6PR hDom1-3His which is non-overlapping with the instant disclosure’s preferred embodiments VHH7 and VHH8 (Specification Pg. 83, Fig. 54). Pertaining to internalization upon binding CI-M6PR cells, Houthoff teaches the bivalent/biparatopic construct “13F11-13E8” comprising two IGF2R/CI-M6PR VHH binding domains with non-overlapping binding epitopes, internalizes in multiple cell types expressing human IGF2R/CI-M6PR (Figs. 16A and 16B). Houthoff further shows the two variations of the biparatopic VHH (“13F11-13E8” and “13E8-13F11”) internalize and accumulate into endosomes and lysosomes (Pg. 75, Lines 1-12, Fig. 18).
Regarding claims 37 and 38, wherein the means of claim 28 is comprised in a multispecific or multivalent binding agent (claim 37), and further comprising a bind agent specifically binding a cell surface or extracellular molecule (claim 38), Houthoff’s biparatropic 13F11-13E8 and 13E8-13F11 are multivalent with two distinct, non-overlapping binding sites for IGF2R/CI-M6PR. Houthoff teaches that IGF2R/CI-M6PR is a transmembrane glycoprotein and is classified as an extracellular agent (Pg. 8, Lines 3-9).
Regarding claim 43, wherein means further comprises a detectable label or a tag, Houthoff disclose conjugation of the IGF2R/CI-M6PR VHH with various detection moieties including Alexa Fluor 647 (Pg. 43, Line 11), IRDye800CW (Pg. 45, Lines 16-17), and pHrodo-red (Pg. 75, Lines 1-4).
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.
Claims 28-29, 37-41, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Houthoff (WO2020/185069, published 09/17/2020, effectively filed 03/08/2019, IDS 08/18/2023) as applied to claims 28-29, 37-38, and 43 above, and further in view of Baik (WO2018/226861A1, published 12/13/2018, effectively filed 06/07/2017, IDS 08/18/2023).
The disclosure of Houthoff teaches conjugation of the IGF2R/CI-M6PR VHH with a therapeutic payload, wherein binding of the VHH to the transmembrane receptor leads to receptor mediated internalization, endocytosis and release of the drug within the endolysosomal compartment (Pg. 31, Lines 2-6).
The disclosure of Houthoff does not teach the VHH is fused to the lysosome localized enzymes acid alpha-glucosidase or Cathepsin D.
These deficiencies are taught by Baik.
The disclosure of Baik is directed to compositions for treating enzyme-deficiency diseases comprising multidomain therapeutic proteins containing first, an internalization effector binding domain (“delivery domain”) and second, a lysosomal replacement enzyme (see Abstract). In the preferred embodiment of the disclosure, the lysosomal targeting molecule is an anti-CD63 scFv and the lysosomal enzyme is alpha-glucosidase (GAA), the full molecule is designated in the disclosure as “anti-hCD63 scFv-hGAA”. The disclosure shows the treatment with anti-hCD63 scFv-hGAA produced sustained levels of GAA in GAA KO mice ([0222], Lines 1-4 and Table 6).
Regarding claims 39-41, wherein the means of claim 28 is fused directly or via linker to an enzyme (claim 39), wherein the enzyme is a lysosome localized enzyme (claim 40), and wherein the enzyme is acid alpha-glucosidase (claim 41), Baik teaches a multidomain therapeutic protein comprising a delivery domain and an enzyme domain, wherein the delivery domain is an scFv that binds IGF2R/CI-M6PR (Pg. 89, claims 1-5), and the enzyme domain is alpha-glucosidase (Pg. 93, claim 33).
It would have been obvious to one having ordinary skill in the art to at the time of filing to modify the IGF2R/CI-M6PR VHH of Houthoff with conjugation to the lysosomal enzyme alpha-glucosidase as taught by Baik. One would have been motivated to do so because Houthoff provides IGF2R/CI-M6PR VHH with known ability to internalize and contemplates conjugation of therapeutic payloads to be delivered to lysosomal compartment. Baik teaches targeting of alpha-glucosidase to lysosomes to treat the lysosomal storage disease Pompe disease, which is caused by defective lysosomal enzyme alpha-glucosidase ([0005], Lines 1-3). There would have been an expectation of success in conjugating the alpha-glycosidase enzyme as taught by Baik to the VHH of Houthoff because Houthoff teaches moieties can be conjugated to the VHH of their disclosure and Baik demonstrates that alpha-glycosidase can be conjugated to known internalization effector molecules (i.e. CD63) for delivery into the lysosome.
Claims 28-29, 37-38, 43, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Houthoff (WO2020/185069, published 09/17/2020, effectively filed 03/08/2019, IDS 08/18/2023) as applied to claims 28-29, 37-38, and 43 above, and further in view of Meuris (Nat Biotechnol. 2014 May;32(5):485-9).
The disclosure of Houthoff teaches a means for specifically binding IGF2R/CI-M6PR, wherein the means is comprise VHH that specifically bind IGF2R/CI-M6PR and internalize into the lysosome of cells that express IGF2R/CI-M6PR.
Houthoff does not teach wherein the means comprises N-glycans selected from the group of a single GlcNAc, a GalGlcNAc and a SiaGalGlcNAc.
This deficiency is taught by Meuris.
The disclosure of Meuris describes a glycoengineering strategy that reduces the heterogeneity of N-glycans on therapeutic proteins. The strategy comprises the use of a “GlycoDelete” cell which shortens the Golgi N-glycosylation pathway in mammalian cells and produces small, sialylated N-glycosylation with reduced complexity and heterogeneity compared to native mammalian cell glycoproteins (see Abstract). The glycoengineering strategy and anticipated results are shown in Fig. 1a.
Regarding claim 47, wherein the means of claim 28 comprises N-glycan structures wherein one or more glycans are selected from the group of a single GlcNAc, a GalGlcNAc and a SiaGalGlcNAc, Meuris teaches the antibodies generated from the cells of the disclosure have a single GlcNAc N-glycan “stump” that can be modified downstream in a pathway that results in substantially reduced heterogeneity of N-glycans (Pg. 485, Right column, paragraph 1, glycoengineering strategy described within the entire paragraph).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to generate the means of claim 28 in an engineered cells as taught by Meuris to produce a VHH with a single GlcNAc N-glycan. One would have been motivated to do so as part of a glycoengineering strategy to produce antibodies that are homogenous and less complex compared to traditional wild-type mammalian cell-based glycoprotein production. Meuris teaches that the “GlycoDelete” cells of the disclosure produce a restricted number of small glycan structures is in contrast to the dozens of glycan structures produced by wild-type mammalian cells, all while retaining folding and antigen specificity (Pg. 489, Left column, full paragraph 1, Lines 1-10. There would be an expectation of success in generating the VHH of Houthoff with a single glycan group as taught by Meuris because the VHH of Houthoff could readily be produced in the “GlycoDelete” cells of Meuris.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 28-32, 34-38, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 16, and 21 of copending Application No. 18/293,467 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference application discloses a means for specifically binding the extracellular domains 1, 2, and/or 3 of human CI-M6PR as claimed in the instant invention.
Regarding instant claims 28 and 29, pertaining to a means for specifically binding the extracellular N-terminal domains 1, 2 and/or 3 of the human cation-independent mannose-6-phosphate receptor (CI-M6PR),wherein the means shows internalization upon binding CI-M6PR-expressing cells (claim 28) and wherein the means is an immunoglobulin-single-variable domain (ISVD) (claim 29), ‘467 claim 1 discloses an immunoglobulin ISVD which specifically binds CI-M6PR on the N-terminal domains 1, 2, and/or 3, and ‘467 claim 21 discloses a method comprising cell surface molecule comprising the protein binding agent of claim 1, which indicates internalization of the protein binding agent.
Regarding instant claims 30 and 31, wherein the means specifically binds an epitope comprising the amino acid residues Lys191, Gly194, Ala195, Tyr196, Leu197, Phe208, Arg219, Gln224, Leu225, I1e297, Lys357, Gly408, Asp409, Asn431, Glu433, and Phe457as set forth in SEQ ID NO:20 (claim 30), or wherein the means specifically binds an epitope comprising the amino acid residues Lys59, Asn60, Met85, Asp87, Lys89, Ala146, Thr147, and Glu148 , and Asp118 or Gln119, as set forth in SEQ ID NO:20 (claim 31), ‘467 claim 2 discloses that the CI-M6PR -specific ISVD binds to the instantly claimed amino acids.
Regarding instant claims 32, and 34-36, wherein the means specifically binds to CI- M6PR via the paratope comprising residues 32, 52-57, 100-103, 108 as set forth in SEQ ID NO:8 (claim 32), the ISVD comprises the CDR regions of elected species SEQ ID NO: 8 (claim 34), the ISVD comprises the elected species CDRs set forth in SEQ ID NO: 107, 114, 121 (claim 35), the means comprises the elected sequence of SEQ ID NO:8 (claim 36), ‘467 claim 4 discloses SEQ ID NO:8, identical to the instant SEQ ID NO:8.
Regarding instant claim 37 and 38, wherein the means of claim 28 is comprised in a multi-specific or a multivalent binding agent (claim 37) and wherein the means of claim 37 further comprises a binding agent specifically binding a cell surface or extracellular molecule (claim 38), ‘467 claim 10 discloses the protein binding agent is multi-specific or multivalent and the CI-M6PR-specific ISVD fused to an extracellularly-accessible protein-specific binding agent.
Regarding instant claim 43, wherein the means further comprises a detectable label or a tag, ‘467 claim 11 discloses the protein binding agent further comprises a detectable label or a tag.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 28-32, 34-41, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 28-32, 34-38, and 43 of copending Application No. 18/293,467 in view of Baik (WO2018/226861A1, published 12/13/2018, effectively filed 06/07/2017, IDS 08/18/2023).
Copending Application No. 18/293,467 teaches an ISVD which specifically binds human CI-M6PR on the extracellular N-terminal domains 1, 2, and/or 3.
‘467 does not teach the VHH is fused to the lysosome localized enzymes acid alpha -glucosidase or Cathepsin D.
These deficiencies are taught by Baik.
The disclosure of Baik is directed to compositions for treating enzyme-deficiency diseases comprising multidomain therapeutic proteins containing first, an internalization effector (“delivery”) binding domain and second, a lysosomal replacement enzyme (see Abstract). In the preferred embodiment of the disclosure, the lysosomal targeting molecule is an anti-CD63 scFv and the lysosomal enzyme is alpha-glucosidase (GAA), the full molecule designated as “anti-hCD63 scFv-hGAA”. The disclosure shows the treatment with anti-hCD63 scFv-hGAA produced sustained levels of GAA in GAA KO mice ([0222], Lines 1-4 and Table 6).
Regarding claims 39-41, wherein the means of claim 28 is fused directly or via linker to an enzyme (claim 39), wherein the enzyme is a lysosome localized enzyme (claim 40), and wherein the enzyme is acid alpha-glucosidase (claim 41), Baik teaches a multidomain therapeutic protein comprising a delivery domain and an enzyme domain, wherein the delivery domain is an scFv that binds IGF2R/CI-M6PR (Pg. 89, claims 1-5), and the enzyme domain is alpha-glucosidase (Pg. 93, claim 33).
It would have been obvious to one having ordinary skill in the art to at the time of filing to modify the IGF2R/CI-M6PR VHH of ‘467 with conjugation to the lysosomal enzyme alpha-glucosidase as taught by Baik. One would have been motivated to do so because ‘467 provides IGF2R/CI-M6PR VHH with known ability to internalize and contemplates conjugation of therapeutic payloads to be delivered to lysosomal compartment. Baik teaches targeting of alph-glucosidase to lysosomes to treat the lysosomal storage disease Pompe disease, which is caused by defective lysosomal enzyme alpha-glucosidase ([0005], Lines 1-3). There would have been an expectation of success in conjugating the alpha-glycosidase enzyme as taught by Baik to the VHH of ‘467 because Baik demonstrates that alpha-glycosidase can be conjugated to known internalization effector molecules (i.e. CD63) for delivery into the lysosome.
This is a provisional nonstatutory double patenting rejection.
Claims 28-32, 34-38, 43, and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 28-32, 34-36,37-38, and 43 of copending Application No. 18/293,467 in view of Meuris (Nat Biotechnol. 2014 May;32(5):485-9).
Copending Application No. 18/293,467 teaches an ISVD which specifically binds human CI-M6PR on the extracellular N-terminal domains 1, 2, and/or 3.
‘467 does not teach wherein the means comprises N-glycans selected from the group of a single GlcNAc, a GalGlcNAc and a SiaGalGlcNAc.
This deficiency is taught by Meuris.
The disclosure of Meuris describes a glycoengineering strategy that reduces the heterogeneity of N-glycans on therapeutic proteins. The strategy comprises the use of a “GlycoDelete” cell which shortens the Golgi N-glycosylation pathway in mammalian cells and produces small, sialylated N-glycosylation with reduced complexity and heterogeneity compared to native mammalian cell glycoproteins (see Abstract). The glycoengineering strategy and expected results are shown in Fig. 1a.
Regarding claim 47, wherein the means of claim 28 comprises N-glycan structures wherein one or more glycans are selected from the group of a single GlcNAc, a GalGlcNAc and a SiaGalGlcNAc, Meuris teaches the antibodies generated from the cells of the disclosure have a single GlcNAc N-glycan “stump” that can be modified downstream in a pathway that results in substantially reduced heterogeneity of N-glycans (Pg. 485, Right column, paragraph 1, glycoengineering strategy described within the entire paragraph).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to generate the means of claim 28 in an engineered cells as taught by Meuris to produce a VHH with a single GlcNAc N-glycan. One would have been motivated to do so as part of a glycoengineering strategy to produce antibodies that are homogenous and less complex compared to traditional wild-type mammalian cell-based glycoprotein production. Meuris teaches that the “GlycoDelete” cells of the disclosure produce a restricted number of small glycan structures is in contrast to the dozens of glycan structures produced by wild-type mammalian cells, all while retaining folding and antigen specificity. There would be an expectation of success in generating the VHH of ‘467 with a single glycan group as taught by Meuris because the VHH of ‘467 could readily be produced in the “GlycoDelete” cells of Meuris.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646
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