DETAILED ACTION
Claims 1-29 are pending and under examination in the instant application. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
37 CFR 1.821-1.825
This application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth on the attached Notice To Comply With Requirements For Patent Applications Containing Nucleotide Sequence And/Or Amino Acid Sequence Disclosures. Specifically, Figure 3 and Figure 61, and at least specification page 139 each contain one or more amino acid sequence disclosure(s) that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821 (a)(1) and (a)(2) and which are not identified by SEQ ID NO. Applicant is encouraged to further review the specification for additional sequences which are not identified by SEQ ID NO. Note that the Brief Description of the Drawings present in the specification also does not provide SEQ ID NOS for any of the amino acid sequences present in Figures 3 and 61. Compliance with 37 CFR 1.821-1.825 requires that the specification be amended to recite SEQ ID NOS. for each recitation of a sequence in the specification, including the drawings. Further, it is unclear whether these sequences are present in the paper copy and CRF of the sequence listing filed in this application on 4/8/22. If the sequences are present in the paper and CRF listings, applicant may fully comply with 37 CFR 1.821 by amending the specification for page 139, or both of the drawings and brief description of the drawings for Figures 3 and 61 to include the appropriate SEQ ID NOS present in each of Figures 3 and 61. If the sequences are not present on the filed paper and CRF listings, then new paper and CRF sequence listings are required as set forth in the attached Notice to Comply.
Claim Objections
Claims 13, 15, and 16 are objected to because of the following informalities: the claims recite the proteins PPT1 and TPP1 without providing name of the proteins associated with these abbreviations. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 13 is 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.
In claim 13, the recitation of the phrase "e.g.", which is a Latin abbreviation which means “for example”, renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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 1-29 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.
A patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Further, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features if there are any. See University of Rochester, 358 F.3d at 927, 69USPQ2d at 1895. Applicant must instead convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention.
In the instant application, the claims encompass a large genus of variant IGF2 (vIGF2) peptides that bind to the CI-MPR and are capable of mediating uptake of a vIGF2-enzyme fusion protein where the vIGF2 variants are at least 95% identical to one of SEQ ID NOS:90-103, or at least 98% identical to one of SEQ ID NOS 106, 109, 111, 119, 120, or 121. The claims further recite specific functional activities for the variants, such as where the vIGF2 peptide is capable of increasing expression and/or secretion of a therapeutic protein compared to a vIGF2 peptide having the amino acid sequence of SEQ ID NO:80, or where the vIGF2 peptide has increased affinity for the CI-MPR as compared to a vIGF2 peptide having the amino acid sequence of SEQ ID NO:80, or where the vIGF2 peptide is capable of improving uptake of the therapeutic protein into a cell. The 20 specific SEQ ID NOS recited in the claims are themselves variants of an earlier disclosed variant which applicant identifies as SEQ ID NO:80. However, the claimed variants set forth in SEQ ID NOS 90-103, 106, 109, 111, 119, 120, and 121 do not, for the most part, share at least 95% sequence identity with each other. The specification further does not identify any specific shared structure or functional motif between the variants of SEQ ID NOS 90-103, 106, 109, 111, 119, 120, and 121 which define their functional activity either alone or in comparison to SEQ ID NO:80. As stated in Eli Lilly, “Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement”. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Looking more closely at the disclosure of the working examples, the specification teaches that 34 different IGF2 variant peptides based on a vIGF2 with the sequence of SEQ ID NO:80 were tested as part of a vIGF-GAA fusion protein. The 34 different IGF2 variants included sequence with one or more single amino acid substitutions, N- or C-terminal deletions, internal deletions, or combinations of both substitutions and deletions. Constructs encoding fusion protein between the variant IGF2 peptides and GAA were created and tested for expression of the fusion protein in transfected cells. While most of the 34 variant IGF2-GAA fusion proteins were detected in the cell lysates- with substantial variance in expression, several of the fusion proteins, labeled variants 1, 2, 3, and 8, were barely detected/not detected as being secreted by the transfected cells (see Figure 38 and 39). The specification further shows that the majority of the variants exhibited less secretion/expression than the original variant (SEQ ID NO:80). The specification also further shows that the majority of the 34 variants exhibited substantially less uptake of the vIGF2-GAA fusion proteins and substantially less binding activity than a vIGF2-GAA fusion protein comprising SEQ ID NO:80. Of the 34 tested variants only vIGF2-7 (SEQ ID 96), vIGF2-10 (SEQ ID 99), vIGF2-17 (SEQ ID 106), vIGF2-18 (SEQ ID NO 107), vIGF2-20 (SEQ ID NO 109), vIGF2-22 (SEQ ID NO 111), and vIGF2-23 (SEQ ID NO 112) exhibited comparable or better PM25 cellular uptake than the original vIGF2 (SEQ ID NO:80) (specification paragraph 268, and Figures 40-47, more specifically Figures 46 and 47. Importantly, only vIGFs with SEQ ID NOS 106, 107, 109, 111, and 112 exhibited increased cellular uptake compared to SEQ ID NO:80. The working examples then repeated the experiments where the 34 variant IGF2 were fused to PPT1 and obtained different results than were obtained using vIGF2-GAA fusion proteins. Figures 48-51 shows highly variable expression and activity of the PPT1 fusion proteins. Based on these results, only a few of the 34 vIGF2-PPT1 fusion proteins were further tested CI-MPR binding and that of these vIGF2-2 (SEQ ID NO 91), vIGF2-32 (SEQ ID NO 121), v-IGF2-33 (SEQ ID NO 122) , v-IGF2-29 (SEQ ID NO 118), and vIGF2-30 (SEQ ID NO 119) bound CI-MPR (Figure 53). The working examples also tested fusions of SEQ ID NOS 106, 120, and 121 with NAGLU and showed increased binding of CI-MPR compared to WT IGF2, not vIGF2 comprising SEQ ID NO:80. Thus, the data provided in the working examples show a substantial level of variability in secretion, enzyme activity, CI-MPR binding and cellular uptake between the IGF2 variants and further between fusion proteins comprising different lysosomal enzymes. The examples clearly show that the majority of SEQ ID NOS 90-103, 106, 109, 111, 119, 120, and 121 exhibit less activity than SEQ ID NO:80 and that increased activity is not consistent between fusions with different enzymes. The specification further does not provide any particular description or evidence of activity of any variants of SEQ ID NOS 90-103, 106, 109, 111, 119, 120, and 121 with 95% or 98% identity to these sequences and which are capable of functional expression as a fusion protein with any enzyme, capable of CI-MPR binding, and capable of CI-MPR mediated uptake of the fusion protein and which may have up to 3 additional single amino acid substitutions of any of amino acid, or any deletion or additions of up to 3 amino acids.
As indicated in MPEP § 2163, 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, reduction to drawings, 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 that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. In the instant case, the specification clearly shows substantial variability in the activity of the disclosed variant IGF2 peptides including variant peptides as set forth in SEQ ID NOS 90-103, 106, 109, 111, 119, 120, and 121, and further does not disclose any particular additional variants of each of these sequences. In addition, as noted above, the specification does not disclose any required structural feature or particular domain motif shared by SEQ ID NOS 90-103, 106, 109, 111, 119, 120, and 121 or any subset of these sequences which define their activity. Also, as discussed in detail above, the specification clearly demonstrates that only a few of the disclosed variants have any activity greater than that observed with SEQ ID NO:80, and again the specification does not disclose the any required structural feature or particular domain motif shared by the few variants that did demonstrate increased secretion, and/or binding to CI-MPR, and/or increased uptake of the fusion protein by cells as compared to SEQ ID NO:80. Therefore, for the reasons set forth above, the skilled artisan would not have viewed the teachings of the specification as sufficient to show that the applicant was in possession of the claimed genus of variant IGF2 peptides or fusion proteins comprising these peptides.
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)(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, 4, 7-11, 13-14, and 18-29 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2022/0193261 (6/23/22), hereafter referred to as Wilson et al., with an effective filing date of 4/30/19.
Wilson et al. teaches expression vector comprising a nucleotide sequence encoding vIGF2 fusion protein comprising a nucleic acid sequence encoding human alpha-glucosidase (hGAA) and a nucleic acid sequence encoding a vIGF2 peptide (Wilson et al., page 1). Wilson et al. teaches that the vIGF2 peptide can be fused to the N-terminus or the C-terminus of the hGAA polypeptide (Wilson et al., page 6, paragraph 62, and Table on page 7). In particular, Wilson et al. teaches a vIGF2 peptide, SEQ ID NO:46, which is greater than 95% identical to instant SEQ ID NO:102 (Wilson et al., paragraph 62 and Table of vIGF2).
Query is SEQ ID NO:102 of this application, and Db is Wilson et al. SEQ ID NO:46.
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Wilson et al. teaches that the nucleotide sequence encoding the fusion protein may further comprise sequence encoding a signal peptide, where the signal peptide is from binding immunoglobulin protein (BiP), chymotrypsinogen B2, human alpha-1-antitrypsin, protease CI inhibitor, an immunoglobulin, and a cytokine (Wilson et al., page 5, paragraph 57). More specifically, Wilson et al. teaches signal peptides from BiP has the amino acid sequence in one of SEQ ID NOS 49-53, which are 100% identical to instant SEQ ID NOS 169-173 respectively (Wilson et al., pages 7-8 and Table of Signal peptides). In addition, Wilson et al. teaches a linker peptide between the vIGF2 and hGAA, and more specifically linker peptide with the amino acid sequence in one of SEQ ID NOS 55-60, which are 100% identical to instant SEQ ID NOS 181-186 (Wilson et al., page 8, paragraph 65 and Table of Linker sequences). Wilson et al. also teaches where the expression vector is a non-viral vector such as a plasmid, or viral vector, and more specifically a recombinant viral vector such adenovirus, lentivirus, retrovirus, herpesvirus, or adeno-associated virus (AAV) (Wilson et al., paragraph 89, and 92-93). Wilson et al. also teaches a pharmaceutical composition comprising the expression vector in a physiologically compatible liquid which may contain a buffer (Wilson et al., paragraph 134). Wilson et al. demonstrates that the vIGF2-hGAA fusion protein increases the uptake of GAA into target cells expressing CI-MPR (Wilson et al., Figure 9C). Wilson et al. also shows that administration of vector to a mouse model of Pompe disease corrected glycogen storage in quadriceps muscle, heart, and spinal cord (Wilson et al., Examples 2 and 4). Finally, Wilson et al. teaches a method of treating a patient having Pompe disease- a lysosomal storage disorder, or a patient having a deficiency in alpha-glucosidase (GAA) by administering the expression vector encoding the vIGF2-hGAA fusion protein to the subject by intravenous, intrathecal, intranasal, or intramuscular delivery (Wilson et al., page 2). Thus, by teaching all the limitations of the claims as written, Wilson et al. anticipates the instant invention as claimed in claims 1, 4, 7-11, 13-14, and 18-29.
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.
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 1-2, 4, 7-11, 13-14, and 18-29 are rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0193261 (6/23/22), hereafter referred to as Wilson et al., with an effective filing date of 4/30/19, in view of US 2016/0129126 (2016), hereafter referred to as Do et al.
Wilson et al. teaches expression vector comprising a nucleotide sequence encoding vIGF2 fusion protein comprising a nucleic acid sequence encoding human alpha-glucosidase (hGAA) and a nucleic acid sequence encoding a vIGF2 peptide (Wilson et al., page 1). Wilson et al. teaches that the vIGF2 peptide can be fused to the N-terminus or the C-terminus of the hGAA polypeptide (Wilson et al., page 6, paragraph 62, and Table on page 7). In particular, Wilson et al. teaches a vIGF2 peptide, SEQ ID NO:46, which is greater than 95% identical to instant SEQ ID NO:102 (Wilson et al., paragraph 62 and Table of vIGF2).
Query is SEQ ID NO:102 of this application, and Db is Wilson et al. SEQ ID NO:46.
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Wilson et al. teaches that the nucleotide sequence encoding the fusion protein may further comprise sequence encoding a signal peptide, where the signal peptide is from binding immunoglobulin protein (BiP), chymotrypsinogen B2, human alpha-1-antitrypsin, protease CI inhibitor, an immunoglobulin, and a cytokine (Wilson et al., page 5, paragraph 57). More specifically, Wilson et al. teaches signal peptides from BiP has the amino acid sequence in one of SEQ ID NOS 49-53, which are 100% identical to instant SEQ ID NOS 169-173 respectively (Wilson et al., pages 7-8 and Table of Signal peptides). In addition, Wilson et al. teaches a linker peptide between the vIGF2 and hGAA, and more specifically linker peptide with the amino acid sequence in one of SEQ ID NOS 55-60, which are 100% identical to instant SEQ ID NOS 181-186 (Wilson et al., page 8, paragraph 65 and Table of Linker sequences). Wilson et al. also teaches where the expression vector is a non-viral vector such as a plasmid, or viral vector, and more specifically a recombinant viral vector such adenovirus, lentivirus, retrovirus, herpesvirus, or adeno-associated virus (AAV) (Wilson et al., paragraph 89, and 92-93). Wilson et al. also teaches a pharmaceutical composition comprising the expression vector in a physiologically compatible liquid which may contain a buffer (Wilson et al., paragraph 134). Wilson et al. demonstrates that the vIGF2-hGAA fusion protein increases the uptake of GAA into target cells expressing CI-MPR (Wilson et al., Figure 9C). Wilson et al. also shows that administration of vector to a mouse model of Pompe disease corrected glycogen storage in quadriceps muscle, heart, and spinal cord (Wilson et al., Examples 2 and 4). Finally, Wilson et al. teaches a method of treating a patient having Pompe disease- a lysosomal storage disorder, or a patient having a deficiency in alpha-glucosidase (GAA) by administering the expression vector encoding the vIGF2-hGAA fusion protein to the subject by intravenous, intrathecal, intranasal, or intramuscular delivery (Wilson et al., page 2).
While Wilson et al. teaches a number of nucleotide sequences encoding a vIGF2 peptide useful as part of the vIGF2-hGAA fusion protein, Wilson et al. does not specifically teach a vIGF2 peptide which is at least 98% identical to an IGF2 variant peptide selected from a group which includes SEQ ID NO:106.
Do et al. supplements Wilson et al. by teaching additional vIGF2 peptide sequences which can be functionally liked to a lysosomal enzyme for the treatment of a lysosomal storage disease, including the enzyme GAA for treatment of Pompe disease (Do et al., paragraphs 6-8, and 31-32). Do et al. teaches variant insulin-like growth factor 2 (vIGF2), preferably a variant of human insulin-like growth factor 2, which include amino acid deletions and substitutions that permit vIGF2 peptide to maintain high affinity for the IGF-2/CI-MPR while reducing peptide binding affinity to IGF-1 and Insulin receptors (Do et al., paragraph 31). In particular, Do et al. teaches the a vIGF2 peptide with sequence identified as SEQ ID NO:2 which is 98.5% identical to instant SEQ ID NO:106 (Do et al., paragraph 32 and Table II).
Query is SEQ ID NO:106 and Db is Do et al. SEQ ID NO:2.
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Do et al. teaches that functional coupling of the vIGF2 peptide to a lysosomal enzyme in order to improve binding and uptake of the vIGF2-enzyme by IGF2/CI-MPR on the cell surface (Do et al., paragraphs 7-8 and 62).
Therefore, in view of the motivation by both Wilson et al. and Do et al. to use vIGF2 peptides functional linked to lysosomal enzymes in order to improve uptake of the enzyme in target cells, and the teachings and motivation provided by Do et al. for a particular vIGF2 which is greater than 98% identical to instant SEQ ID NO:106, it would have been prima facie obvious to the skilled artisan at the time of filing to utilize SEQ ID NO:2 as disclosed by Do et al. as the vIGF2 in the nucleic acid constructs, vectors, pharmaceutical compositions, and methods taught by Wilson et al. with a reasonable expectation of success.
Claims 11-12, 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0193261 (6/23/22), hereafter referred to as Wilson et al., with an effective filing date of 4/30/19, in view of US 2016/0129126 (2016), hereafter referred to as Do et al., as applied to claims 1-2, 4, 7-11, 13-14, and 18-29 above, and further in view of Gabig-Ciminska et al. (2015) Curr. Mol. Med., Vol. 15, 746-771.
As set forth above, Wilson et al. in view of Do et al. provides the teachings and motivation to make a nucleic acid construct encoding a fusion protein comprising a vIGF2 peptide which is at least 95% identical to SEQ ID NO:2 or at least 98% identical to SEQ ID NO:106 and a lysosomal enzyme for use in the treatment of a lysosomal storage disease. While Wilson et al. is focuses primarily on the GAA as the enzyme for the treatment of Pompe disease, Do et al. teaches that vIGF2 peptides can be functionally linked to other lysosomal enzymes useful for enzyme replacement therapy of lysosomal storage diseases (Do et al., paragraphs 3, 4, and 34).
However, neither Wilson et al. nor Do et al. specifically teach to link vIGF2 to the enzyme palmitoyl-protein thioesterase 1 (PPT-1) or tripeptidyl peptidase 1 (TPP-1) for the treatment of either CLN-1 or CLN-2 respectively.
Gabig-Ciminska et al. supplements Wilson et al. and Do et al. by providing a review of the current state of treatment of lysosomal storage diseases including the use of monotherapies like enzyme replacement therapy and combination therapy, and further provides a list therapies approved for use in humans on under investigation (Gabig-Ciminska et al., pages 746-751, and Tables I-III). Gabig-Ciminska et al. teaches that in regards to treatment of Neuronal ceroid lipofuscinosis Types I (CLN1) and II (CLN2), which are associated with PPT1 and TPP1 deficiencies respectively, high-dose enzyme replacement therapy with either recombinant PPT in CLN1 mice or TPP1 in the CLN2 mouse resulted in a decreased amount of storage and an increase in life span (Gabig-Ciminska et al., page 763).
Therefore, based on the teachings of Gabig-Ciminska et al. for enzyme replacement therapy of the lysosomal storage diseases CLN1 or CLN2 with the enzymes PPT or TPP1 respectively, the teachings of Do et al. that enzyme replacement with lysosomal enzymes benefits from functional linking of lysosomal enzyme to a variant IGF-2 peptide, and the teachings of Do et al. and Wilson et al. for specific vIGF2 peptides useful for enhancing uptake of functionally linked lysosomal enzymes, it would have been prima facie obvious to the skilled artisan at the time of filing to modify the nucleic acid constructs, vectors, pharmaceutical compositions, and methods taught by Wilson et al. to express either a PPT-IGF2 fusion protein or a TPP1-IGF2 fusion protein, where the IGF2 peptide is a vIGF2 peptide disclosed by Wilson et al. or Do et al., for the treatment of CLN1 or CLN2 with a reasonable expectation of success.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0193261 (6/23/22), hereafter referred to as Wilson et al., with an effective filing date of 4/30/19, in view of US 2016/0129126 (2016), hereafter referred to as Do et al., as applied to claims 1-2, 4, 7-11, 13-14, and 18-29 above, and further in view of Kan et al. (2014) Biochem. J., Vol. 458, 281-289.
As set forth above, Wilson et al. in view of Do et al. provides the teachings and motivation to make a nucleic acid construct encoding a fusion protein comprising a vIGF2 peptide which is at least 95% identical to SEQ ID NO:2, or at least 98% identical to SEQ ID NO:106, and a lysosomal enzyme for use in the treatment of a lysosomal storage disease. While Wilson et al. is focuses primarily on the GAA as the enzyme for the treatment of Pompe disease, Do et al. teaches that vIGF2 peptides can be functionally linked to other lysosomal enzymes useful for enzyme replacement therapy of lysosomal storage diseases (Do et al., paragraphs 3, 4, and 34).
However, neither Wilson et al. nor Do et al. specifically teach to link vIGF2 to alpha-N-acetylglucosaminidase (NAGLU) for the treatment of mucopolysaccharidosis type IIIB (MPS IIIB)
Kan et al. supplements Wilson et al. and Do et al. by teaching enzyme replacement therapy for mucopolysaccharidosis type IIIB (MPS IIIB) using rhNAGLU (recombinant human alpha-N-acetylglucosaminidase) (Kan et al., page 281). Kan et al. teaches to generate a fusion protein comprising NAGLU and the receptor-binding motif of IGF2 in order to increase intracellular uptake of the fusion enzyme into target cells, and demonstrates substantial reduction of glycosaminoglycan storage in cell expressed to rhNAGLU-IGF2 (Kan et al., pages 281-282, and Figures 3 and 6). Kan et al. explains that cells transfected with NAGLU cDNA secrete a poorly phosphorylated enzyme which hampers its uptake in target cells via the cation-independent M6P receptor (Kan et al., page 281). Kan et al. teaches that fusing the enzyme with IGF2 allows for uptake of the fusion enzyme by the M6P/IGF2R receptor (Kan et al., pages 281-282). Kan et al. further teaches an expression vector encoding the hNAGLU-IGF2 fusion protein (Kan et al., page 282).
Therefore, based on the teachings and motivation provided by Kan et al. for generating an expression vector encoding a NAGLU-IGF2 fusion protein for enzyme replacement therapy of the lysosomal storage disease MPS IIIB, and the teachings of Do et al. and Wilson et al. for specific vIGF2 peptides useful for enhancing uptake of functionally linked lysosomal enzymes, it would have been prima facie obvious to the skilled artisan at the time of filing to modify the nucleic acid constructs, vectors, pharmaceutical compositions, and methods taught by Wilson et al. to express a NAGLU-vIGF2 fusion protein where the vIGF2 is a vIGF2 peptide as taught by Wilson et al. or Do et al. for the treatment of MPS IIIB with a reasonable expectation of success.
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 1-2, 4, 7-11, 13-15, and 18-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10,874,750, hereafter referred to as the ‘750 patent. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
The ‘750 patent claims are drawn to a species of the instant broader claims. The ‘750 patent claims recite products which include a gene therapy vector comprising a nucleic acid that encodes a polypeptide comprising a therapeutic protein, a vIGF2 peptide comprising the sequence of SEQ ID NO:31 that binds to CI-MPR, linker between the therapeutic protein and the vIGF2, and a signal peptide from BiP or a Gaussia signal peptide (see ‘750 claim 1). Note that SEQ ID NO:31 is greater than 98% identical to SEQ ID NO:109. See below where query is SEQ ID NO:109 from the instant application, and Db is ‘750 patent SEQ ID NO:31
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The ‘750 patent claims further recite that the therapeutic protein comprises a lysosomal enzyme which include lysosomal enzymes GAA and PPT1 as recited in instant claims 13-15 for the treatment of Pompe Disease and CLN1 respectively as recited in instant claims 9-10 (‘750 patent claims 4-10, and 19). The ‘750 patent claims also recite linker sequences which correspond to the linker sequences set forth in instant claim 4 (‘750 patent claim 17). In addition, the ‘750 patent claims recite the order of functional linkage and the species of gene therapy vector recited in instant claims 20-21 and 24 (‘750 patent claims 15-16 and 18). It is well established that a species of a claimed invention renders the genus obvious. In re Schaumann , 572 F.2d 312, 197 USPQ 5 (CCPA 1978). Thus, by teaching a species of the instant claimed products, the ‘750 patent claims render obvious instant claims 1-2, 4, 7-11, 13-15, and 18-27.
Claims 16-17 and 28-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10,874,750, hereafter referred to as the ‘750 patent, in view of US 2022/0193261 (6/23/22), hereafter referred to as Wilson et al., with an effective filing date of 4/30/19, in view of Gabig-Ciminska et al. (2015) Curr. Mol. Med., Vol. 15, 746-771, and Kan et al. (2014) Biochem. J., Vol. 458, 281-289.
In regards to instant claims 28-29, as noted above, the ‘750 patent claims are drawn to a species of the instant broader claimed products where the ‘750 patent claims recite products which include a gene therapy vector comprising a nucleic acid that encodes a polypeptide comprising a therapeutic protein, a vIGF2 peptide comprising the sequence of SEQ ID NO:31 that binds to CI-MPR, linker between the therapeutic protein and the vIGF2, and a signal peptide from BiP or a Gaussia signal peptide (see ‘750 claim 1). Note that SEQ ID NO:31 is greater than 98% identical to SEQ ID NO:109. The ‘750 patent claims further recite that the therapeutic protein comprises a lysosomal enzyme. Instant claims 28-29 are method claims for treating a lysosomal storage disorder by administering the nucleic acid construct. However, it is noted that the ‘750 patent claims, while product claims, further recite the intended use for the gene therapy vector for replacing a defective or deficient protein associated with a lysosomal storage disorder, where the disease include those recited in the instant claims (‘750 patent claims 2-6). Treating a lysosomal storage disorder by replacing a defective or deficient protein with a functional protein was well known in the prior art as enzyme replacement therapy (ERT). Wilson et al. supplements the ‘750 patent claims by specifically teaching that enzyme replacement therapy for lysosomal storage disease can be effected by administering a vector/gene therapy vector encoding a fusion protein of the lysosomal enzyme and a vIGF2 peptide (Wilson et al., page 2). Thus, based on intended use recited in the ‘750 patent claims and the well known techniques of ERT and the specific method of administering a vector/gene therapy vector encoding a fusion protein of the lysosomal enzyme and a vIGF2 peptide to a patient to treat a lysosomal storage disease taught by Wilson et al., it would have been obvious to administer the ‘750 gene therapy vectors to treat a lysosomal storage disease with a reasonable expectation of success. Thus, the ‘750 patent claims in view of Wilson et al. render obvious instant claims 28-29.
In regards to claim 16-17, while the ‘750 patent claims generically recite that the protein in the fusion protein is a lysosomal enzyme (‘750 patent claim 7), and further recites a list of enzyme for inclusion in the gene therapy vectors (‘750 patent claim 8), the ‘750 patent claims do not specifically recite that that the lysosomal enzyme is TPP1 or NAGLU for the treatment of CLN2 or MPS IIIB respectively. Gabig-Ciminska et al. and Kan et al. provide teachings and motivation to select TPP1 or NAGLU as the lysosomal enzyme in the gene therapy vector of the ‘750 patent claims. Gabig-Ciminska et al. provides a review of the current state of treatment of lysosomal storage diseases including the use of monotherapies like enzyme replacement therapy and combination therapy, and further provides a list therapies approved for use in humans on under investigation (Gabig-Ciminska et al., pages 746-751, and Tables I-III). Gabig-Ciminska et al. teaches that in regards to treatment of Neuronal ceroid lipofuscinosis Type II (CLN2), which is associated with TPP1 deficiency, high-dose enzyme replacement therapy with either recombinant TPP1 in the CLN2 mouse resulted in a decreased amount of storage and an increase in life span (Gabig-Ciminska et al., page 763). Kan et al. teaches enzyme replacement therapy for mucopolysaccharidosis type IIIB (MPS IIIB) using rhNAGLU (recombinant human alpha-N-acetylglucosaminidase) (Kan et al., page 281). Kan et al. also teaches to generate a fusion protein comprising NAGLU and the receptor-binding motif of IGF2 in order to increase intracellular uptake of the fusion enzyme into target cells, and demonstrates substantial reduction of glycosaminoglycan storage in cell expressed to rhNAGLU-IGF2 (Kan et al., pages 281-282, and Figures 3 and 6). Kan et al. explains that cells transfected with NAGLU cDNA secrete a poorly phosphorylated enzyme which hampers its uptake in target cells via the cation-independent M6P receptor (Kan et al., page 281). Kan et al. teaches that fusing the enzyme with IGF2 allows for uptake of the fusion enzyme by the M6P/IGF2R receptor (Kan et al., pages 281-282). Kan et al. further teaches an expression vector encoding the hNAGLU-IGF2 fusion protein (Kan et al., page 282).
Thus, in view of the teachings and motivation provided by both Gabig-Ciminska et al. and Kan et al. to utilize the lysosomal enzymes TPP1 or NAGLU for ERT, it would have been obvious to select either TPP1 or NAGLU as the lysosomal enzyme in the gene therapy vectors of the ‘750 patent with a reasonable expectation of success. As such, the ‘750 patent claims in view of Gabig-Ciminska et al. and Kan et al. render obvious instant claims 16-17.
Claims 1-2, 4, 7-11, 13-15, and 18-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,491,243, hereafter referred to as the ‘243 patent. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
The ‘243 patent claims are drawn to a species of the instant broader claims 28-29. The ‘243 patent claims methods of genetic disorder which is a lysosomal storage disorder comprising administering to a subject in need thereof a gene therapy vector comprising a nucleic acid that encodes a polypeptide comprising a therapeutic protein, a vIGF2 peptide comprising the sequence of SEQ ID NO:31 that binds to CI-MPR, linker between the therapeutic protein and the vIGF2, and a signal peptide from BiP or a Gaussia signal peptide (see ‘243 claims 1-2). Note that SEQ ID NO:31 is greater than 98% identical to SEQ ID NO:109. See below where query is SEQ ID NO:109 from the instant application, and Db is ‘243 patent SEQ ID NO:31
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It is well established that a species of a claimed invention renders the genus obvious. In re Schaumann , 572 F.2d 312, 197 USPQ 5 (CCPA 1978). Thus, by teaching a species of the instant method, the ‘243 patent claims render obvious instant claims 28-29.
In regards to the product of instant claims 1-2, 4, 7-11, 13-15, and 18-27, while the ‘243 patent claims are method claims, they involve the use of a product which is a species of the products recited in the instant product claims, which is a gene therapy vector as described in the above paragraph. The ‘243 patent claims further recite that the therapeutic protein comprises a lysosomal enzyme which include lysosomal enzymes GAA and PPT1 as recited in instant claims 13-15 for the treatment of Pompe Disease and CLN1 respectively as recited in instant claims 9-10 (‘243 patent claims 8-10, and 2-5). The ‘243 patent claims also recite linker sequences which correspond to the linker sequences set forth in instant claim 4 (‘243 patent claim 17). In addition, the ‘243 patent claims recite the order of functional linkage and the species of gene therapy vector recited in instant claims 20-21 and 24 (‘243 patent claims 15-16 and 18).
Thus, by specifically reciting a gene therapy vector which is species of the instant claims products, the ‘243 patent claims render obvious instant claims 1-2, 4, 7-11, 13-15, and 18-27.
Claims 16-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,491,243, hereafter referred to as the ‘243 patent, in view of Gabig-Ciminska et al. (2015) Curr. Mol. Med., Vol. 15, 746-771, and Kan et al. (2014) Biochem. J., Vol. 458, 281-289.
In regards to claim 16-17, while the ‘243 patent claims generically recite that the protein in the fusion protein is for treatment of a lysosomal storage disorder, and further recites a list of enzymes for inclusion in the gene therapy vectors (‘243 patent claim 8), the ‘243 patent claims do not specifically recite that that the lysosomal enzyme is TPP1 or NAGLU for the treatment of CLN2 or MPS IIIB respectively. Gabig-Ciminska et al. and Kan et al. provide teachings and motivation to select TPP1 or NAGLU as the lysosomal enzyme in the gene therapy vector of the ‘243 patent claims. Gabig-Ciminska et al. provides a review of the current state of treatment of lysosomal storage diseases including the use of monotherapies like enzyme replacement therapy and combination therapy, and further provides a list therapies approved for use in humans on under investigation (Gabig-Ciminska et al., pages 746-751, and Tables I-III). Gabig-Ciminska et al. teaches that in regards to treatment of Neuronal ceroid lipofuscinosis Type II (CLN2), which is associated with TPP1 deficiency, high-dose enzyme replacement therapy with either recombinant TPP1 in the CLN2 mouse resulted in a decreased amount of storage and an increase in life span (Gabig-Ciminska et al., page 763). Kan et al. teaches enzyme replacement therapy for mucopolysaccharidosis type IIIB (MPS IIIB) using rhNAGLU (recombinant human alpha-N-acetylglucosaminidase) (Kan et al., page 281). Kan et al. also teaches to generate a fusion protein comprising NAGLU and the receptor-binding motif of IGF2 in order to increase intracellular uptake of the fusion enzyme into target cells, and demonstrates substantial reduction of glycosaminoglycan storage in cell expressed to rhNAGLU-IGF2 (Kan et al., pages 281-282, and Figures 3 and 6). Kan et al. explains that cells transfected with NAGLU cDNA secrete a poorly phosphorylated enzyme which hampers its uptake in target cells via the cation-independent M6P receptor (Kan et al., page 281). Kan et al. teaches that fusing the enzyme with IGF2 allows for uptake of the fusion enzyme by the M6P/IGF2R receptor (Kan et al., pages 281-282). Kan et al. further teaches an expression vector encoding the hNAGLU-IGF2 fusion protein (Kan et al., page 282).
Thus, in view of the teachings and motivation provided by both Gabig-Ciminska et al. and Kan et al. to utilize the lysosomal enzymes TPP1 or NAGLU for ERT, it would have been obvious to select either TPP1 or NAGLU as the lysosomal enzyme in the gene therapy vectors of the ‘243 patent with a reasonable expectation of success. As such, the ‘243 patent claims in view of Gabig-Ciminska et al. and Kan et al. render obvious instant claims 16-17.
It is noted that neither the claims of U.S. Patent No. 10,874,750 nor U.S. Patent No. 11,491,243 have been applied under non-statutory double patenting over instant claims 5-6 because both sets of patent claims recite a functional limitation that the vIGF2 peptide has specific enhanced functional activities compare to a vIGF2 peptide with the sequence of SEQ ID NO:80 and the vIGF2 peptide of SEQ ID NO:31 in both patents is 100% identical to instant SEQ ID NO:80.
No claims are allowed.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634