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 .
Claim status
Claims 1-44 are pending.
Claims 1-44 are under examination.
Claim Rejections - 35 USC § 112a
Written Description
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 1-44 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.
The purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the 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. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997).
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include a disclosure of a representative number of species to describe the complete structure of the claimed genus and/or disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof.
Scope of the invention
Instant application recite the genera, functional equivalents, sequences with 80% or 90% sequence identity to ITRs, LTRs or leader or trailer sequences, as well as ‘various modifications’ to base sequences in claims 1, 31, 33, 36, and 39, as well as ‘variants’ of adenovirus and Sendai virus respectively in claims 29 and 37 as described below.
Regarding claim 1, embodiments 1-6 recite functional equivalents of; ITRs (embodiments 1 and 2), LTRs (embodiment 3 and 4), leader sequences (embodiments 5 and 6). Specification defines functional equivalents as ‘equivalents that can be used in place of ITRs, LTRs or leader sequences from a functional viewpoint’. However, the specification fails to identify the specific sequences or the segments of the sequences that are essential to perform the function of the various functional equivalents in any of the embodiments. Therefore the specification does not enable a person of ordinary skill in the art to use the invention.
Regarding claim 31, this claim recites first ITR with 80% or 90% identity to SEQ ID NO:4 (embodiments 1 and 2) and second ITR with 80% or 90% identity to SEQ ID NO:5 (embodiments 4 and 5). The broadest reasonable interpretation of the scope of this genus is all possible sequences of any length that comprise a sequence at least 80% or 90% identical to SEQ ID NOs: 4 and 5 . For example, in the instant application, sequences set forth by the SEQ ID NOs: 4 and 5 have 145 nucleotides each, and 80% sequence identity encompasses at least any 29 mismatches in the sequences, and 90% sequence identity encompasses at least any 15 mismatches which may cause the claimed genus to encompass an exponential number of species. Also, the specification fails to disclose a representative numbers/sequences of species within the claimed genera or to identify parts of the sequences that are essential to perform the function of the ITRs. Therefore, applicant was not in possession of the claimed genera in embodiments 1-2, and 4-5.
Also, various modifications to SEQ ID NOs: 4 and 5 recited in embodiments 3 and 6 of claim 31 may also result in an exponential number of species under those genera, thus failing to explicitly disclose the species in possession of the claimed invention.
Regarding claim 33, this claim recites functional equivalents of first ITR with 80% or 90% identity to SEQ ID NO:6 (embodiments 1 and 2) and functional equivalents of second ITR with 80% or 90% identity to SEQ ID NO:7 (embodiments 4 and 5). The broadest reasonable interpretation of the scope of this genus is all possible sequences of any length that comprise a sequence at least 80% or 90% identical to SEQ ID NOs: 6 and 7 respectively. For example, in the instant application, nucleotide sequence set forth by the SEQ ID NO: 6 have 145 nucleotides. Hence, 80% sequence identity encompasses at least any 29 mismatches in the sequences, and 90% sequence identity encompasses at least any 15 mismatches which may cause the claimed genus to encompass an exponential number of species. Similarly functional equivalent of second ITR set forth by the SEQ ID NO: 7 have 141 nucleotides, 80% and 90% sequence identity encompasses at least any 29 and 15 mismatches respectively which may also cause the claimed genus to encompass an exponential number of species. Therefore, applicant was not in possession of the claimed genera in embodiments 1-2, and 4-5.
Also, various modifications to SEQ ID NOs: 6 and 7 recited in embodiments 3 and 6 of claim 33 may also result in an exponential number of species under those genera, thus failing to explicitly disclose the species in possession of the claimed invention.
Regarding claim 36, this claim recites first LTR with 80% or 90% identity to SEQ ID NO:43 (embodiments 1 and 2) and a second LTR with 80% or 90% identity to SEQ ID NO:44 (embodiments 4 and 5). The broadest reasonable interpretation of the scope of this genus is all possible sequences of any length that comprise a sequence at least 80% or 90% identical to SEQ ID NOs: 6 and 7 respectively. For example, in the instant application, the first LTR sequence set1 forth by the SEQ ID NO: 43 have 589 nucleotides. Hence, 80% sequence identity encompasses at least any 117 mismatches in the sequences, and 90% sequence identity encompasses at least any 58 mismatches which may cause the claimed genus to encompass an exponential number of species. Similarly the second LTR sequence set forth by the SEQ ID NO: 44 have 594 nucleotides, 80% and 90% sequence identity encompasses at least any 118 and 59 mismatches respectively which may also cause the claimed genus to encompass an exponential number of species. Therefore, applicant was not in possession of the claimed genera in embodiments 1-2, and 4-5.
Also, various modifications to SEQ ID NOs: 43 and 44 recited in embodiments 3 and 6 of claim 36 may also result in an exponential number of species under those genera, thus failing to explicitly disclose the species in possession of the claimed invention.
Regarding claim 39, this claim recites leader sequence with 80% or 90% identity to SEQ ID NO:45 (embodiments 1 and 2) and a trailer sequence with 80% or 90% identity to SEQ ID NO:46 (embodiments 4 and 5). The broadest reasonable interpretation of the scope of this genus is all possible sequences of any length that comprise a sequence at least 80% or 90% identical to SEQ ID NOs: 45 and 46 respectively. For example, in the instant application, the leader sequence set forth by the SEQ ID NO: 45 have 52 nucleotides. Hence, 80% sequence identity encompasses at least any 10 mismatches in the sequences, and 90% sequence identity encompasses at least any 5 mismatches which may cause the claimed genus to encompass an exponential number of species. Similarly trailer sequence set forth by the SEQ ID NO: 46 have 54 nucleotides, 80% and 90% sequence identity encompasses at least any 11 and 5 mismatches respectively which may also cause the claimed genus to encompass an exponential number of species. Therefore, applicant was not in possession of the claimed genera in embodiments 1-2, and 4-5.
Also, various modifications to SEQ ID NOs: 45 and 46 recited in embodiments 3 and 6 of claim 39 may also result in an exponential number of species under those genera, thus failing to explicitly disclose the species in possession of the claimed invention.
Regarding claims 29 and 37, these claims recite adeno and Sendai viral variants. Viral variants are constantly formed. For example there are at least 13 natural AAV serotypes and more than 100 different variants have been isolated as evidenced by Lopez-Gordo et al., 2024 (page 47, paragraph 1). Similarly Sendai virus also have multiple other viral variants with various mutations that cause the virus to have various inherent characteristics such as enhanced cleavability, and plaque forming ability as evidenced by (introduction, page 130) Hou et al., 2005. Therefore the genera ‘viral variants’ recited in claims 29 and 37 encompasses a significant number of species and the applicant was not in possession of the claimed genera.
Structure/function Relationship
The recited functional equivalents of LTRs, leader and trailer sequences or the sequences with 80% or 90% sequence identity to ITRs, LTRs or leader or trailer sequences do not have specific sequences set forth in the specification. Though the specification defines functional equivalents as ‘equivalents that can be used in place of ITRs, LTRs, leader or trailer sequences from a functional viewpoint’, their functional efficiency can vary depending on the specific sequences and may interfere with the protein yield produced by the vector containing them. For example, Chen et al., 2024 conducted a comprehensive analysis of the correlation between the sequence truncation within AAV ITRs and the function of AAV vectors. Their work revealed specific roles of various regions with in ITRs and certain mutations pertaining to specific regions resulted in significant negative effects related to the function of the vectors (abstract, page 1). Similarly the viral variants with various mutations may cause the virus to have various structure related characteristics such as enhanced cleavability, and plaque forming ability as evidenced by Hou et al., 2005.
Conclusion
Therefore, the examiner concludes there’s insufficient written description for the instantly claimed genera of functional equivalents, sequences with 80% or 90% sequence identity to ITRs, and ‘various modifications’ to base sequences, and variants of adeno and Sendai viruses in claims 29 31, 33, 36, 37 and 39. Specifically such varying sequence identities, base modifications, and viral variants may result in large number of species under those genera. However, specification fails to disclose a representative numbers/sequences or viral variants of species within the claimed genera or to identify parts of the sequences that are essential to perform the function of each of the genera.
Therefore, there’s insufficient written description support for instant claims.
Claims 2-28, 30, 32, 34, 35, 38, 40-44 are also included in this rejection as they directly or indirectly dependent on the rejected claim.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-13, 16, 17, 19-25, 27-29, 43, 44 are rejected under 35 U.S.C. 103 as being unpatentable over Koshimura et al., WO2018038243A1, and Blumenkranz et al., US2019/0100582 A1.
Regarding claim 1, Blumenkranz teaches a plasmid used for production of recombinant adeno associated virus (rAAV) vector containing a nucleic acid sequence with first ITR, a sequence encoding transgene encoding anti-VEGF or a transgene encoding anti-VEGF fusion protein followed by a second ITR sequence equivalent which teaches the embodiment 1 of claim 1(0079).
Blumenkranz also teaches a plasmid used for production of recombinant adeno associated virus (rAAV) vector containing a nucleic acid sequence with first ITR, a promoter sequence, a sequence encoding transgene encoding anti-VEGF (0079) or a transgene encoding a fusion protein (0030), followed by a second ITR sequence equivalent which teaches the embodiment 2 of claim 1 (0079).
Blumenkranz does not teach a nucleotide sequence encoding a fusion protein of a ligand and a protein having physiological activity.
However, before the effective filling date of the instant application a nucleotide sequence encoding a fusion protein of a ligand and a protein having physiological activity was known.
Koshimura teaches a method of producing a fusion protein of an anti-TfR antibody (interpreted as the ligand in instant claim 1) and a lysosomal enzyme which is a physiologically active protein (abstract, claims 1-12). The fusion protein was produced by expressing a vector incorporating a gene or a nucleotide molecule encoding the recombinant fusion protein, (description, page 3, lines 1-3 on the machine translation version).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of Blumenkranz that teaches various embodiments of a nucleic acid molecule consisting two ITR sequences, and a gene that encodes a fusion protein in between the ITRs with Koshimura that teaches a method of producing fusion protein of an anti-TfR antibody (interpreted as the ligand in instant claim 1) and a lysosomal enzyme which is a physiologically active protein( abstract, claims 1-12), by expressing a vector that may produce a recombinant protein with medicinal use (description, page 2, paragraph 1). One of ordinary skill in the art would have been motivated to combine the teachings of Blumenkranz and Koshimura to generate a nucleic acid molecule comprising two ITRs, a promoter sequence and a nucleic acid sequence encoding a fusion protein consisting a ligand and a physiologically active protein, to produce a nucleic acid molecule with therapeutic use. There would have been a reasonable expectation of success to combine the teachings of Blumenkranz and Koshimura, because Blumenkranz teaches a nucleotide molecule that can be adopted to generate a fusion protein and Koshimura teaches a successful method of producing a fusion protein consisting of a ligand and the physiologically active protein.
Regarding claim 2, Koshimura teaches a method of producing a fusion protein of an anti- TfR antibody (interpreted as the ligand in instant claim 1) and a lysosomal enzyme which is a physiologically active protein (abstract, claims 1-12).
Regarding claim 3, Koshimura teaches a conjugate of a fusion protein comprised of TfR antibody consisting of light and heavy chains and a lysosomal enzyme ( a physiologically active protein) derived from a nucleotide sequence, wherein the lysosomal enzyme is bound to the C-terminal side or the N-terminal side of the heavy chain directly by a peptide bond which teaches the embodiments 1 and 2 of the claim 3 (claim 14, page 1).
Koshimura also teaches another embodiment of the fusion protein in which the human lysosomal enzyme is bound to the C-terminal side or N-terminal side of the light chain of the TfR antibody directly by a peptide bond which teaches the embodiments 3 and 4 of the claim 3 (claim 14, page 1).
Regarding claim 4, Koshimura teaches a fusion protein comprised of TfR antibody consisting of light and heavy chains, and a lysosomal enzyme ( a physiologically active protein) derived from a nucleotide sequence, wherein the lysosomal enzyme is bound to the C-terminal side or the N-terminal side of the heavy chain of the antibody via a linker which teaches the embodiment 1 and 2 of the claim 4 (claim 14, page 1).
Koshimura also teaches another embodiment, wherein the human lysosomal enzyme is bound to the C-terminal side or N-terminal side of the light chain of the antibody via a linker which teaches the embodiment 3 and 4 of the claim 4 (claim 14, page 1).
Regarding claim 5, Koshimura teaches a linker sequence connecting the lysosomal enzyme to the TfR antibody consisting 1 to 50 amino acids (claim 15, page 1).
Regarding claim 6, Koshimura teaches a linker sequence connecting the lysosomal enzyme to the TfR antibody, wherein the linker sequence is one glycine, one serine, an amino acid sequence (Gly-Ser) or an amino acid sequence (Gly-Gly-Ser) (claim 18, page 2).
Regarding claim 7, Koshimura teaches a TfR-antibody which consists of one immunoglobulin light chain and a one immunoglobulin heavy chain, where the c-terminal side of the light chain is bound to the c-terminal side of the heavy chain via a linker (line 8-11, paragraph 2, page 6). The lysosomal enzyme (physiologically active protein) may be bound to the C- or the N- terminus of the light chain or the heavy chain (claim 14, page, 2). Thus, Koshimura teaches the embodiments 1 and 2 of the claim 7.
Regarding claim 8, Koshimura teaches a second linker sequence arranged between the light chain and the heavy chain of the TfR-antibody which is a peptide chain composed of 12 to 18 or 15 to 25 amino acid residues (line 29, paragraph 4, page 6) which are in the range of 1-50 amino acids.
Regarding claim 9, Koshimura teaches a second linker sequence arranged between the light chain and the heavy chain of the TfR-antibody, wherein the linker sequence is one glycine, one serine, an amino acid sequence (Gly-Ser) or an amino acid sequence (Gly-Gly-Ser) (line 31, paragraph 4, page 6).
Regarding claim 10, Koshimura teaches a second linker sequences arranged between the light chain and the heavy chain of the TfR-antibody is a peptide chain composed of 12 to 18 or 15 to 25 amino acid residues (line 29, paragraph 4, page 6) which are in the range of 8-50 amino acids.
Regarding claim 11, Koshimura teaches a second linker sequence arranged between the light chain and the heavy chain of the TfR-antibody, wherein the linker sequence is an amino acid sequence Gly-Ser, amino acid sequence Gly-Gly-Ser or an amino acid sequence Gly-Gly-Gly (line 30-31, paragraph 4, page 6).
Regarding claim 12, Koshimura teaches the use of an expression vector where an internal ribosomal binding site (IRES) is located downstream of a gene encoding a desired protein (description, paragraph 1, page 10). In one embodiment, the nucleotide sequence encoding the fusion protein consisting of the anti-TfR-antibody with heavy and light chains and lysosomal enzyme also consist of a base sequence encoding a conjugate in which the lysosomal enzyme (i.e. the physiologically active protein) binds to C-or N- terminus of the heavy chain (claim 14, page 1) which teaches the embodiments 1 and 2 of claim 12.
Koshimura also teaches the use of an expression vector where an internal ribosomal binding site (IRES) is located downstream of a gene encoding a desired protein in their invention (description, paragraph 1, page 10). In one embodiment, the nucleotide sequence encoding the fusion protein consisting of TfR-antibody (consist of heavy and light chains) and lysosomal enzyme (the gene of interest) also consist of a base sequence encoding a conjugate in which the lysosomal enzyme (i.e. the physiologically active protein) binds to C-or N- terminus of the light chain (claim 14, page 1) which teaches the embodiments 3 and 4 of claim 12.
Regarding claim 13, Koshimura teaches the use of an expression vector where an internal ribosomal binding site (IRES) is located downstream of a gene encoding a desired protein in their invention (description, paragraph 1, page 10). In one embodiment, the nucleotide sequence encoding the fusion protein consisting of TfR-antibody (consisting of heavy and light chains) and lysosomal enzyme (the gene of interest) also consist of a base sequence encoding a conjugate in which the lysosomal enzyme (i.e. the physiologically active protein) binds to C-or N- terminus of the heavy chain via a linker (claim 14, page 1) which teaches the embodiments 1 and 2 of claim 13.
Koshimura also teaches the use of an expression vector where an internal ribosomal binding site (IRES) is located downstream of a gene encoding a desired protein in their invention (description, paragraph 1, page 10). In one embodiment, the nucleotide sequence encoding the fusion protein consisting of TfR-antibody (consisting of heavy and light chains) and lysosomal enzyme (the gene of interest) also consist of a base sequence encoding a conjugate in which the lysosomal enzyme (i.e. the physiologically active protein) binds to C-or N- terminus of the light chain via a linker (claim 14, page 1) which teaches the embodiments 3 and 4 of claim 13.
Regarding claim 16, Koshimura teaches that the TfR-antibody in their invention to have a fab region in one embodiment which is an antigen binding fragment (description, line 12, paragraph 2, page 6) which is encoded by a nucleic acid molecule.
Regarding claim 17, Koshimura teaches that the TfR-antibody in their invention to have a fab region in one embodiment (description, line 12, paragraph 2, page 6), which is encoded by a nucleic acid molecule.
Regarding claim 19 and 20, Koshimura teaches that the TfR-antibody claimed in their invention has specific affinity for surface antigen present on the surface of vascular endothelial cells or in particular cerebral vascular endothelial cells (claims 8 and 10, page 3, description, lines 37-43, page 6).
Regarding claim 21 and 25, Koshimura teaches that the surface antigen present on vascular endothelial cells is selected from the group consisting of transferrin receptor, insulin receptor, leptin receptor, IGF receptor, lipoprotein receptor, organic anion transport receptor, monocarboxylic acid transporter and are not limited to these (claim 11, page 3, description, lines 37-39, page 6).
Regarding claim 23 and 24, the ligand in instant claim 1 is interpreted as the anti TfR-antibody portion of the fusion protein taught by Koshimura. Koshimura teaches that the TfR-antibody claimed in their invention has specific affinity for surface antigen present on the surface of vascular endothelial cells or in particular cerebral vascular endothelial cells (claims 1-7, page 1, description, lines 37-43, page 6).
Regarding claim 27, Koshimura teaches a fusion protein with lysosomal enzyme that has physiological activity (claim 1, page 3)
Regarding claim 28, Koshimura teaches a fusion protein of anti-TfR antibody and iduronic acid-2 -sulfatase, wherein iduronic acid-2 -sulfatase is a protein with physiological activity (preamble claim1, page 3).
Regarding claim 29, Blumenkranz teaches that the nucleic acid molecule used in the production of the fusion protein is recombinant AAV and comprising of first and second ITR sequences (0079, page 14).
Regarding claim 43, Blumenkranz teaches a plasmid containing a recombinant AAV molecule with two ITRs , a transgene, and a promoter sequence in between the ITRs (0079, page 14).
Regarding claim 44, Blumenkranz teaches a recombinant AAV virion with either parental or mutated capsid proteins (0112-0115, page 18).
Hence, the claimed invention as a whole was prima facie obvious.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Koshimura et al., WO2018038243A1, and Blumenkranz et al., US2019/0100582 A1. as applied to claims 1-13, 16, 17, 19-25, 27-29, 43, 44 above, and further in view of Colby et al., US 2005/0226863 A1
Teachings of Koshimura and Blumenkranz are as relied above.
Koshimura and Blumenkranz do not teach a single domain antibody.
However, before the effective filling date of the instant application a nucleotide molecule encoding a single domain antibody.
Regarding claim 18, Colby teaches a method of making single domain antibodies for diagnostic and therapeutic applications (field of the invention, 0002).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the nucleic acid molecule teachings of by Blumenkranz and Koshimura to include the teaching of Colby to include a single domain antibody in the fusion protein of the instant application. One of ordinary skill in the art would have been motivated to combine the teachings of Blumenkranz and, Koshimura and Colby to generate a fusion protein containing a single domain antibody which has diagnostic and therapeutic applications, as suggested by Colby. There would have been a reasonable expectation of success to combine the teachings of Blumenkranz, Koshimura and Colby. Taken together, these references teach a nucleotide molecule that can be adopted to generate the fusion protein with a single-domain antibody, and Colby teaches multiple single domain antibodies to treat Huntington disease (examples, 1,3 and 5, page 27-29).
Claim 14, 15, 22 are rejected under 35 U.S.C. 103 as being unpatentable over Koshimura et al., WO2018038243A1, and Blumenkranz et al., US2019/0100582 A1. as applied to claims 1-13, 16, 17, 19-25, 27-29, 43, 44 above, and further in view of Takashi et al., WO2012063799.
Teachings of Koshimura and Blumenkranz are as relied above.
Koshimura and Blumenkranz do not teach an internal ribosome entry site (IRES) is derived from the 5’ untranslated region of a virus, and a gene control site.
However, before the effective filling date of the instant application a nucleotide molecule containing IRES derived from the 5’ untranslated region of a virus, and a gene control site was known in the art.
Regarding claims 14 and 15 Takashi teaches a novel expression vector for efficient expression of recombinant proteins with IRES (abstract, page 1) is derived from the 5’ untranslated region of a virus of the Picornaviridae family (claim 4, page 3), or gene selected from virus belonging to the family Picornaviridae, foot-and-mouth disease virus, hepatitis A virus, hepatitis C virus, coronavirus, bovine enterovirus, Cyler's murine encephalomyelitis virus, Coxsackievirus group B, the human immunoglobulin heavy chain binding protein gene, the Drosophila Antennapedia gene.
Regarding claim 22, Takashi teaches an expression vector which encodes gene expression control site or a regulatory element of gene expression consisting of a cytomegalovirus-derived promoter, SV40 early promoter and elongation factor-1α (claim 2, page 3) that may enhance translation efficiency of the vector.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the nucleic acid molecule teachings of Blumenkranz and Koshimura to include a picornavirus IRES at the 5’ UTR , and viral gene control site taught by Takashi. One of ordinary skill in the art would have been motivated to combine the teachings of Blumenkranz and Koshimura to include the teachings of Takashi to produce a nucleic acid molecule with IRES at the 5’ UTR, and viral gene control site for increased translational efficiency, as suggested by Takashi. There would have been a reasonable expectation of success to combine the teachings of Blumenkranz, Koshimura and Takashi. Taken together, these references teach a nucleotide molecule that can be adopted to generate the fusion protein of the claimed invention, and Takashi teaches that the presence of the regulatory elements (i.e., IRES at the 5’ UTR , and viral gene control site) may produce the protein of interest at high levels ( Takashi, 0065). .
Hence, the claimed invention as a whole was prima facie obvious.
Claims 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over Koshimura et al., WO2018038243A1, and Blumenkranz et al., US2019/0100582 A1. as applied to claims 1-13, 16, 17, 19-25, 27-29, 43, 44 above, and further in view of Logan et al., WO2016179644 A1, as evidenced by Chen et al., 2024. .
Teachings of Koshimura and Blumenkranz are as relied above.
Koshimura and Blumenkranz do not teach ITR sequences set forth as SEQ ID NOs :4 and 5 for the first and second ITRs respectively.
However, before the effective filling date of the instant application a nucleotide molecule containing ITR sequences set forth as SEQ ID NOs :4 and 5 for the first and second ITRs were known in the art.
Regarding claim 30, Logan teaches AAV, ITR sequences set forth as SEQ ID NOs :4 and 5 (first and second ITRs respectively), in the instant application with 100% match as shown below. Logans disclosure relates to vectors and recombinant viruses comprising promoters for enhanced expression of heterologous coding sequences (filed of invention, page 2). The sequences of instant application and Logan SEQ ID NOs: 24 and 25 were aligned using the NCBI Blast align tool to determine the sequence similarities.
Alignment of SEQ ID NO:4 of the instant application and SEQ ID NO: 24 of Logan with 100% match.
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Alignment of SEQ ID NO:5 of the instant application and SEQ ID NO: 25 of Logan with
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100% match.
Regarding claim 31, Logan teaches ITRs that are 100% identical to the sequences set forth by SEQ ID NOs: 4 and 5 of the instant application (see claim 30 rejection). Therefore Logan teaches sequences that are not lower than 80% and 90% identical to the sequences set forth in SEQ ID NOs: 4 and 5. Thus Logan teaches the 1, 2, 4 and 5 embodiments of the claim 31. The presence of ITRs sequences may ensure vector genome replication and transgene expression, as evidenced by Chen et al., 2024.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the nucleic acid molecule teachings of Blumenkranz and Koshimura to include the first and second ITRs sequences of Logan. One of ordinary skill in the art would have been motivated to combine the teachings of Blumenkranz, Koshimura and Logan to produce a nucleic acid molecule with Logans’ ITR sequences that may increase vector replication, and transgene expression, as suggested by Chen. There would have been a reasonable expectation of success to combine the teachings of Blumenkranz, Koshimura and ITRs of Logan, because Blumenkranz and Koshimura teaches a nucleotide molecule that can be adopted to generate the fusion protein of the claimed invention, and the ITR sequences of Logan would result in increased vector genome replication and transgene expression. In addition ITRs are known in the art to increase the potency of AAV vectors as suggested by Chen. Logan teaches ITR sequences that are a 100% match to the instantly claimed sequences and Logan has demonstrated the use of the aforementioned ITRS in a recombinant viruses resulted in enhanced expression of proteins (filed of invention, page2).
Hence, the claimed invention as a whole was prima facie obvious.
Claims 26, 32 -33 are rejected under 35 U.S.C. 103 as being unpatentable over Koshimura et al., WO2018038243A1, and Blumenkranz et al., US2019/0100582 A1. as applied to claims 1-13, 16, 17, 19-25, 27-29, 43, 44 above, and further in view of Tang et al., WO2005037226-A2, as evidenced by Chen et al., 2024.
Teachings of Koshimura and Blumenkranz are as relied above.
Koshimura and Blumenkranz do not teach the ITR sequences set forth as SEQ ID NOs :6 and 7 for the first and second ITRs respectively and a vector carrying a ligand selected from a group of proteins that include insulin.
However, before the effective filling date of the instant application a nucleotide molecule containing ITR sequences set forth as SEQ ID NOs : 6 and 7 for the first and second ITRs, and vector carrying a ligand selected from a group of proteins including insulin were known in the art.
Regarding claim 26, Tang teaches a AAV vector carrying a transgene for pre-insulin or insulin to treat glucose-related metabolic disorders (abstract, title, page 1).
Regarding claim 32, Tang teaches ITR sequence set forth as SEQ ID NO:2 is a 100% sequence match with the SEQ ID NO: 6 set forth by the instant application (shown below). The alignment of the two nucleotide sequences were given on ABSS search results.
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Tang ITR sequence set forth as SEQ ID NO:11 is a 100% sequence match with the SEQ ID NO: 7 set forth by the instant application (shown below). The alignment of the two nucleotide sequences were given on ABSS search results.
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Regarding claim 33, Tang teaches ITRs that are 100% identical to the sequences set forth by SEQ ID NOs: 6 and 7 of the instant application (see claim 30 rejection). Therefore Tang teaches sequences that are not lower than 80% and 90% identical to the sequences set forth by SEQ ID NOs: 6 and 7, thus Tang teaches the embodiments 1, 2, 4 and 5 of the claim 33.
The presence of ITRs sequences may ensure vector genome replication and transgene expression, as evidenced by Chen et al., 2024.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the nucleic acid molecule teachings of Blumenkranz and Koshimura to include the teachings of Tang that teaches the functional equivalents of first and second ITRs sequences. One of ordinary skill in the art would have been motivated to combine the teachings of Blumenkranz, Koshimura and Tang to result in a nucleic acid molecule encoding the fusion protein consisting insulin as the ligand and the ITR sequences taught by Tang. One of ordinary skill in the art would have been motivated to combine the teachings of Blumenkranz, Koshimura and Tang to produce a nucleic acid molecule with ITR sequences that may increase vector replication, and transgene expression. There would have been a reasonable expectation of success to combine the teachings of Blumenkranz, Koshimura, ITRs and the fusion protein containing insulin of Tang, because Blumenkranz and Koshimura teaches a nucleotide molecule that can be adopted to generate the fusion protein of the claimed invention, and Tang teaches the ITR sequences that would result in increased vector genome replication and transgene expression. In addition, ITRs are known in the art to increase the potency of AAV vectors as suggested by Chen. Tang teaches ITR sequences that are 100% match to the instantly claimed sequences and has demonstrated the use of the aforementioned ITRS in AAV vectors that successfully express insulin (abstract, title, page 1).
Hence, the claimed invention as a whole was prima facie obvious.
Claims 34 -36 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Koshimura et al., WO2018038243A1, and Blumenkranz et al., US2019/0100582 A1. as applied to claims 1-13, 16, 17, 19-25, 27-29, 43, 44 above, and further in view of Bleck et al., WO0202783-A2, as evidenced by Marzio et al., 2002.
Teachings of Koshimura and Blumenkranz are as relied above.
Koshimura and Blumenkranz do not teach first and second LTRs, derived from lentivirus or retrovirus.
However, before the effective filling date of the instant application a nucleotide molecule containing first and second LTRs, derived from lentivirus or retrovirus were known in the art.
Regarding claim 34, Bleck teaches novel regulatory elements and vectors for the expression of proteins, and teaches a first 5’LTR derived from MoMuSV and second 3’ LTR derived from MoMuLV which are retroviruses (page 97-98, fig. 12a-b).
Regarding claim 35, Bleck teaches 5’ LTR sequence (1-589 base sequence), set forth in fig. 12a is a 100% sequence match with the SEQ ID NO: 43 set forth by the instant application is shown below (page 97-98, fig. 12a-b). The alignment of the two nucleotide sequences were given on ABSS search results.
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Bleck also teaches 3’ LTR sequence (4537-5130 base sequence), set forth in fig. 12b is a 100% sequence match with the SEQ ID NO: 44 set forth by the instant application (shown below). The alignment of the two nucleotide sequences were given on ABSS search results (page 97-98, fig. 12a-b).
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Regarding claim 36, Bleck teaches LTRs that are 100% identical to the sequences set forth by SEQ ID NOs: 43 and 44 of the instant application (see claim 35 rejection). Therefore, Bleck teaches sequences that are not lower than 80% and 90% identical to the sequences set forth in SEQ ID NOs: 43 and 44, thus Bleck teaches the 1, 2, 4 and 5 embodiments of the claim 36. LTRs sequences may ensure vector genome persistence and transgene expression, as evidenced by Marzio et al, 2002.
Regarding claim 40, Bleck teaches expressing plasmids and vectors containing genes (i.e. nucleic acid molecules) in host cells, including mammalian cells to produce the proteins (abstract, background of inventio, page 1).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the nucleic acid molecule teachings of Blumenkranz and Koshimura to include the first and second LTRs sequences of Bleck. One of ordinary skill in the art would have been motivated to combine the teachings of Blumenkranz, Koshimura and Bleck to produce a nucleic acid molecule with increased vector genome persistence and transgene expression, as suggested by Marzio. There would have been a reasonable expectation of success to combine the teachings of Blumenkranz, Koshimura and LTRs of Bleck, because Blumenkranz and Koshimura teaches a nucleotide molecule that can be adopted to generate the fusion protein of the claimed invention, and Bleck teaches LTR sequences that would result in increased vector genome persistence and transgene expression, that may facilitate efficient production of the fusion protein in the claimed invention.
Hence, the claimed invention as a whole was prima facie obvious.
Claims 37 -39 are rejected under 35 U.S.C. 103 as being unpatentable over Koshimura et al., WO2018038243A1, and Blumenkranz et al., US2019/0100582 A1, as applied to claims 1-13, 16, 17, 19-25, 27-29, 43, 44 above, and further in view of Fujii, et al., Virus genes 22.1 (2001): 47-52, as evidenced by Warner et al., 2023.
Teachings of Koshimura and Blumenkranz are as relied above.
Koshimura and Blumenkranz do not teach leader or trailer sequences, derived from a Sendai virus, or a variant thereof.
However, before the effective filling date of the instant application a nucleotide molecule containing leader or trailer sequences, derived from a Sendai virus, or a variant thereof were known in the art.
Regarding claim 37, Fujii teaches the entire genome sequence of a virulent Sendai virus and the nucleic acid comparison between the Hamamatsu and Z strain are given in fig.2 which shows leader and trailer sequences.
Regarding claim 38, Fujii teaches the leader sequence, set forth in fig. 2 is a 100% sequence match with the SEQ ID NO: 45 set forth by the instant application (shown below) (page 51, fig. 2). The alignment of the two nucleotide sequences were given on ABSS search results.
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Fujii also teaches a trailer sequence, set forth in fig. 2 is a 100% sequence match with the SEQ ID NO: 46 set forth by the instant application (shown below). The alignment of the two nucleotide sequences were given on ABSS search results (page 97-98, fig. 12a-b).
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Regarding claim 39, Fujii teaches leader and trailer sequences that are 100% identical to the sequences set forth by SEQ ID NOs: 45 and 46 of the instant application (see claim 38 rejection). Therefore, Fujii teaches sequences that are not lower than 80% and 90% identical to the sequences set forth in SEQ ID NOs: 43 and 44, thus Fujii teaches the 1, 2, 4 and 5 embodiments of the claim 39. The leader and trailer sequences ensure efficient translation as evidenced by Warner et al., 2023.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the nucleic acid molecule teachings of Blumenkranz and Koshimura to include Fujii that teaches the leader and trailer sequences derived from Sendai virus. One of ordinary skill in the art would have been motivated to combine the teachings of Blumenkranz, Koshimura and Fujiito produce a nucleic acid molecule with increased translational efficiency, as suggested by Warner. There would have been a reasonable expectation of success to combine the teachings of Blumenkranz, Koshimura and Fuji because Blumenkranz and Koshimura teaches a nucleotide molecule that can be adopted to generate the fusion protein of the claimed invention, and Fujii teaches the leader and trailer sequences that would result in a vector that produces a high expression of the fusion protein as suggested by Warner. One of ordinary skill in the art could predict the success of the combined method, because the use of leader and trailer sequences are known in the art as suggested by Fuji and Warner, and they are conserved across strains of Sendai viruses (Fuji, abstract, second promoter sequence, page 52), indicating their functionality is preserved.
Hence, the claimed invention as a whole was prima facie obvious.
Claims 41-42 are rejected under 35 U.S.C. 103 as being unpatentable over Koshimura et al., WO2018038243A1, and Blumenkranz et al., US2019/0100582 A1, as applied to claims 1-13, 16, 17, 19-25, 27-29, 43, 44 above, and further in view of Lakshmipathy et al., Stem cells 22.4 (2004): 531-543.
Teachings of Koshimura and Blumenkranz are as relied above.
Koshimura and Blumenkranz do not teach stem cells or embryonic stem cells into which a nucleic acid molecule has been introduced.
However, before the effective filling date of the instant application, stem cells or embryonic stem cells into which a nucleic acid molecule has been introduced was known in the art.
Regarding claim 41 and 42, Lakshmipathy teaches a method to introduce plasmid DNA (i.e. nucleic acid molecule) into embryonic and adult stem cells with enhanced efficiency, to use in therapeutic applications (abstract, page 531).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the nucleic acid molecule teachings of Blumenkranz and Koshimura to include Lakshmipathy that teaches a method to introduce nucleic acid molecule into stem cells. One of ordinary skill in the art would have been motivated to combine the teachings of Blumenkranz, Koshimura and Lakshmipathy to generate a nucleic acid molecule that can be introduced into stem cells for therapeutic applications, as suggested by Lakshmipathy. There would have been a reasonable expectation of success to combine the teachings of Blumenkranz, Koshimura and Lakshmipathy, because Blumenkranz and Koshimura teach a nucleotide molecule that can be adopted to generate the fusion protein of the claimed invention, and Lakshmipathy teaches the delivery of nucleic acid molecules into stem cells with high efficiency.
Hence, the claimed invention as a whole was prima facie obvious.
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 Terminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-13, 16, 17, 19-21, 23-25, 27, 29-32, 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 16-18, 20-22, 24 , and 36 of copending application No. 18/724,856. Although the claims at issue are not identical, they are not patentably distinct from each other because of the reasons mentioned below.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding instant claim 1, the limitations of the nucleic acid molecule encoding a fusion protein of ligand and physiologically active protein recited in embodiments 1-6 of instant claim 1 are recited in the embodiments 1-6 of claim 1 of the U.S. application No. 18/724,856. However, the claim limitations in application No 18/724,856 recite a species and that of instant application recite the genus. The species anticipate the genus and therefore make the claim limitations of the genus obvious over the species. Therefore, claim 1 is rejected on the ground of nonstatutory double patenting.
Regarding instant claim 2, the limitation of the fusion protein wherein the ligand is an antibody is recited in the preamble of claim 1 of the U.S. application No. 18/724,856.
Regarding instant claim 3, the limitations of how the physiologically active protein is bound to the antibody including the 4 embodiments of the said limitation are recited in claim 2 of U.S. application No. 18/724,856.
Regarding instant claim 4, the limitations of how the physiologically active protein is bound to the antibody via a linker, including the 4 groups of varying embodiments of the said limitation are recited in claim 3 of U.S. application No. 18/724,856.
Regarding instant claim 5, the limitation of the number of amino acid residues in the linker peptide is recited in the claim 4 of U.S. application No. 18/724,856.
Regarding instant claim 6, the limitation of various embodiments of the liker peptide sequences are recited in claim 5 of U.S. application No. 18/724,856.
Regarding instant claim 7, the limitations of how the second linker is connected between the light chain and heavy chain, and the limitation of how a first linker or a linker is used to bind the antibody and the physiologically active protein recited in various embodiments in groups 1-4 are recited in claim 6 of U.S. application No. 18/724,856.
Regarding instant claim 8, the limitation of the number of amino acids in the linker peptide (recited in claim 6) sequence is recited in the claim 7 of U.S. application No. 18/724,856.
Regarding instant claim 9, the limitation of various embodiments of the liker peptide sequences are recited in claim 8 of U.S. application No. 18/724,856.
Regarding instant claim 10, the limitation of the number of amino acids in the second linker peptide sequence is recited in the claim 9 of U.S. application No. 18/724,856.
Regarding instant claim 11, the limitation of various embodiments of the linker peptide sequences are recited in claim 10 of U.S. application No. 18/724,856.
Regarding instant claim 12, limitations of the nucleotide sequence, where in the nucleotide contains a sequence that encode varying embodiments of the fusion protein with regard to how the physiologically active protein is bound to the antibody portion of the fusion protein (i.e., C-or N- terminus of the heavy or the light chain), followed by a sequence encoding an internal ribosome binding site, downstream there of nucleotide sequence encoding light or the heavy chain of the antibody are recited in claim 11 of U.S. application No. 18/724,856.
Regarding instant claim 13, limitations of the nucleotide sequence, where in the nucleotide contains a sequence that encode varying embodiments of the fusion protein with regard to how the physiologically active protein is bound via a linker to the antibody portion of the fusion protein (i.e., C-or N- terminus of the heavy or the light chain), followed by a sequence encoding an internal ribosome binding site, downstream there of nucleotide sequence encoding the light or the heavy chain of the antibody are recited in claim 12 of U.S. application No. 18/724,856.
Regarding instant claim 16, the limitation that the antibody is an antigen-binding fragment is recited in claim 16 of U.S. application No. 18/724,856.
Regarding instant claim 17, the limitation that the antibody is Fab is recited in claim 17 of U.S. application No. 18/724,856.
Regarding instant claims 19, 20, 21; claim 19, and 20 recite that the nucleic acid molecule according to claims 2, has specific affinity for a protein present on the surfaces of vascular endothelial cells wherein the said endothelial cells are cerebrovascular endothelial cells. Claim 21 further narrows the limitations of claims 19, and 20 to a protein encoded by the nucleic acid is selected from a group of proteins that include transferrin receptor which is recited in the preamble of the claim 1 of U.S. application No. 18/724,856.
Regarding instant claims 23- 25; claim 23, and 24 recite that the nucleic acid molecule according to claims 2, has specific affinity for a protein present on the surfaces of vascular endothelial cells wherein the said endothelial cells are cerebrovascular endothelial cells. Claim 25 further narrows the limitations of claims 23, and 24 to a protein encoded by the nucleic acid is selected from a group of proteins that include transferrin receptor which is recited in the preamble of the claim 1 of U.S. application No. 18/724,856.
Regarding instant claim 27, the limitations of the group of proteins from which the physiologically active protein is selected is recited in claim 18 of U.S. application No. 18/724,856.
Regarding instant claim 29, the limitations of how the first and second ITRs are derived (i.e. from adeno-associated virus, adenovirus or mutants) are recited in claim 20 of U.S. application No. 18/724,856.
Regarding instant claim 30, the limitations that disclose the first and second ITR sequences are recited in claim 21 of U.S. application No. 18/724,856.
Regarding instant claim 31, the limitations that disclose the allowable sequence identity percentages, and the base sequence modifications for first and second ITR sequences are recited in claim 22 of U.S. application No. 18/724,856.
Regarding instant claim 32, and 33; the limitations that disclose the allowable sequence identity percentages, and the base sequence modifications for functional equivalents of first and second ITR sequences are recited in claim 24 of U.S. application No. 18/724,856.
Regarding instant claim 44, the limitations that disclose the viral virion comprising the nucleic acid molecule in claim 1 is recited in claim 36 of U.S. application No. 18/724,856.
Conclusion
No claim is allowed.
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/HASHANTHI KOMITIGE ABEYRATNE-PERERA/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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