DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/18/2025 has been entered.
Applicant’s response filed on December 18, 2025 have been received and entered. Upon further consideration, the objection to claim 2 is hereby withdrawn. Applicants’ arguments with respect to the withdrawn objection is thereby rendered moot. Claims 1-30 are under consideration.
Priority
This application is a Divisional application of 14/818162 filed on August 4, 2015, which is a Divisional of US application 13/310431 filed on December 2, 2011, which is a CIP of PCT/GB2011/050019 01/07/2011, which is a CIP of PCT/GB2010/051122, dated 07/07/2010, and claims benefit of 61/355,666, dated 06/17/2010, which claims benefit of 61/223,960 07/08/2009 and foreign application filed in UK 0911846.4 on 07/08/2009 and UK 0913102.0 filed on 07/28/2009. Upon review of the disclosure of the prior-filed application, ‘122, ‘666, ‘960, 846.4 and ‘102.0 fails to provide descriptive support for instant claims 1-3, 21, 26-29. Claims 1-3, 21, 26-29 are not enabled in applications ‘122, ‘666, ‘960, 846.4 and ‘102.0 from which applicant is claiming benefit of priority. It is noted that applications ‘122, ‘666, ‘960, 846.4 and ‘102.0 do not support the claimed phenotype of moue exhibiting the IgH-VDJCg transcripts comprise transcripts encoding a human variable region comprising a CDR-H3 length of 17 amino acids and transcripts encoding human variable region comprising a CDR-H3 length of 18 amino acids, wherein the mean frequency of the group consisting of said transcripts encoding CDR-H3 lengths of 17 and 18 amino acids present in said IgH-VDJCg transcripts of said mouse is between 5% and 10% (claims 1-3). There is not adequate support or enablement for claims 1-3, 21, 26-29 in the manner provided by the first paragraph of 35 U.S.C. 112 in any of these applications ‘122, ‘666, ‘960, 846.4 and ‘102.0. In case, if applicants have evidence to support otherwise, applicants are invited to indicate page and line number for the written support as recited in claims 1-3, 21, 26-29 of the instant application. Therefore, the effective filing date for instant claims 1-30 is 01/07/2011.
Claims 1-30 are under consideration.
Allowable Subject Matter
The following claims 1-3 are drafted by the examiner and considered to distinguish patentably over the art of record in this application, claim is presented to applicant for consideration:
A method of providing an immunized transgenic mouse expressing an antigen-specific polypeptide comprising a human IgH variable region (VH), antibody comprising said polypeptide, a cell producing said polypeptide, a nucleic acid encoding said polypeptide and/or a biological sample comprising one or more of said polypeptide, said cell and said nucleic acid, the method comprising:
(a) immunizing a naïve transgenic mouse with an antigen under condition sufficient such that said mouse expresses said polypeptide, said antibody comprising said polypeptide, said cell producing said polypeptide, said nucleic acid encoding said polypeptide and/or said biological sample comprising said polypeptide, thereby providing said immunized transgenic mouse;
wherein said transgenic mouse comprises a germline with a homozygous chimeric immunoglobulin heavy chain ([gH) locus comprising unrearranged human IgH variable region gene segments positioned within the JC intron of the endogenous IgH locus, upstream of a constant (C) region;
wherein said homozygous IgH locus comprises in 5' to 3' transcriptional orientation:
unrearranged human immunoglobulin heavy chain (IgH) variable region (VH) DNA comprising a plurality all of a plurality of human JH gene segments comprising a human 3' JH6 gene segment,
a chimeric JC intron comprising human IgH JC intronic DNA and mouse IgH JC intronic DNA, wherein said human IgH JC intronic DNA is downstream of and naturally contiguous with a said human JH gene segment, and wherein said mouse IgH JC intronic DNA is truncated at its 5'end and comprises an enhancer, wherein said chimeric JC intron comprises mouse 129 strain DNA upstream of said enhancer, wherein the 3’ end of said one or more human JH gene segments is less than 1 kb upstream from said chimeric junction, and
said C region,
wherein said homozygous chimeric IgH locus is functional to undergo human IgH gene segment rearrangement, wherein said transgenic mouse is functional to form rearranged human VH, D and JH gene segments and to express mRNA transcripts encoding chimeric immunoglobulin heavy chain polypeptide comprising a human VH region and a mouse Cu region, and wherein said immunized mouse forms rearranged human VH, D and JH gene segments, and expresses mRNA transcripts encoding said antigen-specific polypeptide, and
wherein prior to immunization said transgenic mouse comprises IgH mRNA transcripts comprising IgH-VDJCm transcripts comprising rearranged human heavy chain V, D, and J gene segments and mouse Cu and encoding chimeric IgH polypeptides, wherein each IZH-VDJCm transcript encodes a human variable region comprising a CDR-H3, wherein said IgH-VDJCm transcripts comprise transcripts encoding a human variable region comprising a CDR-H3 length of 17 amino acids and transcripts encoding human variable region comprising a CDR-H3 length of 18 amino acids, wherein the mean frequency of the group consisting of said transcripts encoding CDR- H3 lengths of 17 and 18 amino acids present in said IgH-VDJCm transcripts of said mouse is between 5% and 10%, and
(b) isolating from said transgenic immunized mouse one or more of said polypeptide, said antibody comprising said polypeptide, said cell producing said polypeptide, said nucleic acid encoding said polypeptide and/or said biological sample comprising said polypeptide
Examiner’s note: A telephone call was made to applicant’s representative on February 12, 2026 to discuss the minor amendments to the claims to put the application in condition of allowance. Applicant’s representative indicated that inventor may not pursue instant application and would consider responding at a later date.
Maintained-Claim Rejections - 35 USC § 112
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 1-30 remain 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 claims are directed to a method of using a mouse comprises a germline with a homozygous chimeric immunoglobulin heavy chain (IgH) locus comprising unrearranged human IgH variable region gene segments positioned within the JC intron of the endogenous IgH locus, upstream of a constant (C) region comprising an endogenous IgH C gene segment, wherein said human variable region gene segments in said chimeric IgH locus are operably linked to said C region at a human/mouse chimeric junction;
wherein said homozygous chimeric IgH locus comprises in 5' to 3' transcriptional orientation (i) unrearranged human immunoglobulin heavy chain (IgH) variable region (VH) DNA comprising one or more human IgH V gene segments, one or more human D gene segments and one or more human JH gene segments comprising a human JH6 gene segment, (ii) a chimeric JC intron comprising human DNA downstream of and naturally contiguous with a said human JH gene segment, mouse DNA and an enhancer, wherein said chimeric JC intron comprises mouse 129 strain DNA upstream of said enhancer, wherein the 3' end of said one or more human JH gene segments is less than 2 kb upstream from said chimeric junction; (iii) said C region; wherein said homozygous chimeric IgH locus is functional to undergo human IgH gene segment rearrangement, wherein said transgenic mouse is functional to form rearranged human VH, D and JH gene segments and to express mRNA transcripts encoding chimeric immunoglobulin heavy chain polypeptide comprising a human VH region and a mouse Cp region, and wherein said immunized mouse forms rearranged human VH, D and JH gene segments, and expresses mRNA transcripts encoding said antigen-specific polypeptide,
wherein prior to immunization said transgenic mouse comprises IgH mRNA transcripts comprising IgH-VDJCm transcripts comprising rearranged human heavy chain V, D, and J gene segments and mouse Cm and encoding chimeric IgH polypeptides, wherein each IgH-VDJ Cm transcript encodes a human variable region comprising a CDR-H3, wherein said IgH-VDJCp transcripts comprise transcripts encoding a human variable region comprising a CDR-H3 length of 17 amino acids and transcripts encoding human variable region comprising a CDR-H3 length of 18 amino acids, wherein the mean frequency of the group consisting of said transcripts encoding CDR-H3 lengths of 17 and 18 amino acids present in said IgH-VDJCm transcripts of said mouse is between 5% and 10%.
Claims 1-3 recite functional phenotype of mouse wherein said mouse comprises IgH- VDJCmu transcripts encoding chimeric IgH polypeptides comprising CDR-H3 lengths of 17, 18 and 19 amino acids, wherein the mean frequency of the group consisting of said transcripts encoding CDR-H3 lengths of 17, 18 and 19 amino acids is between 5% and 105 and, wherein said mouse further comprises IgH-VDJCmu transcripts encoding chimeric IgH polypeptide comprising CDR-H3 lengths selected from the group consisting of: 20, 21, and 22 amino acids.
The claims embrace a chimeric IgH locus comprises in 5' to 3' transcriptional orientation; (i) said unrearranged human immunoglobulin heavy chain (IgH) variable region (VH) DNA comprising one or more human IgH V (at least one VH ) gene segments, one or more of human D gene segments (at least one DH) and one or more of human JH gene segments (at least oneJH) comprising a human JH6 gene segment comprising a 3' end, (ii) human IgH JC intronic DNA and mouse IgH JC intronic DNA that provide the different mean frequency of transcripts having the different CDR-H3 amino acid lengths.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that ''applicant must 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. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.'' Vas-cath Inc. v. Mahurkar, 19USPQ2d at 1 117. The specification does not ''clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.'' Vas-cath Inc. v. Mahurkar, 19USPQ2d at 1116.
In analyzing whether the written description requirement is met for the genus claim, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics, specific features and functional attributes that would distinguish different members of the claimed genus. The principle is well established that the disclosure of a species in a cited reference is sufficient to prevent a later applicant from obtaining a "generic claim." In re Gosteli, 872 F.2d 1008, 10 USPQ2d 1614 (Fed. Cir. 1989); In re Slayter, 276 F.2d 408, 125 USPQ 345 (CCPA 1960). The test is whether the species completed by applicant prior to the reference date or the activity’s date provided an adequate basis for inferring that the invention has generic applicability. In re Plumb, 470 F.2d 1403, 176 USPQ 323 (CCPA 1973); In re Rainer, 390 F.2d 771, 156 USPQ 334 (CCPA 1968); In re Clarke, 356 F.2d 987, 148 USPQ 665 (CCPA 1966); In re Shokal, 242 F.2d 771, 113 USPQ 283 (CCPA 1957).
The guidance provided in the specification is limited to creating the BACs having the inserts of human lg gene segments (plurality of human V, all D and all J gene segments). The landing pads were used in a method to construct chimeric lg loci in mouse embryonic stem cells (ES cells), such that chimeric IgH and IgK loci are made in which human gene segments are functionally inserted upstream of endogenous constant regions. The sequencing results indicate that JH, DH, and JK usages (FIG. 35 and FIG. 36) are similar to human results. In addition, the results from the IGH-VDJC.mu transcripts show that the range and mean of CDR-H3 length (FIG. 37) are similar to that observed in human. The junctional diversity generated from exonuclease and nucleotide addition activities (FIG. 38) was also observed. Example 11-13 disclose transgenic mice carrying all human JH, all human DH and human Vh2-5, Vh7-41, Vh-4-4, Vhl-3, Vhl-2 and Vh6-1 under control of a mouse Sp switch region were immunized and fused. The results demonstrate that mice comprising multiple human VDJ gene segments under the control of a rat C.mu switch are able to undergo productive recombination and produce high affinity antigen-specific antibodies whose CDR3 regions have sequences encoded by human gene segments (see table 4-5, fig. 37).
The specification fails to disclose a structural variant of the human/mouse chimeric immunoglobulin heavy chain locus unrearranged human immunoglobulin heavy chain (IgH) variable region (VH) DNA comprising one or more of human IgH V (at least one VH ) gene segments, one or more of human D gene segments (at least one DH) and one or more of human JH gene segments (at least one JH) that produces CDR-H3 amino acid lengths of 17 to 18 amino acids at a mean frequency of 5% to 10% other than chimeric IgH locus comprising all human JH, all human DH and human Vh2-5, Vh7-41, Vh-4-4, Vhl-3, Vhl-2 and Vh6-1, encompassed within the genus of chimeric IgH locus showing contemplated phenotype have not been disclosed. The specification fails to actually disclose the structure of the unrearranged IgH chimeric IgH locus comprising the human IgH V, D, and J gene segment(s) that produce [function] the transcript/CDR-H3 amino acid length profile of Figure 37 of the instant specification. Rather, it appears that the transcript/CDR-H3 amino acid length profile of Figure 37 requires a multitude of human IgH V gene segments (at least 12, as illustrated in Figure 13), a multitude of human D gene segments (at least 25 human DH gene segments, as illustrated in Figures 10 and 13), and all of the human JH gene segments (1 to 6, as shown in Figures 10 and 13 of the instant specification). The instant application fails to disclose the structure/function nexus between the number of unrearranged human IgH V, D, and J gene segments to necessarily and sufficiently achieve the functional properties of producing transcripts encoding CDR-H3 amino acid lengths and their corresponding transcript frequencies.
Based upon the prior art there is expected to be sequence variation among the use of an IgH locus comprising IgH variable region (VH) DNA comprising one or more of human IgH V gene segments (at least one VH), one or more of human D gene segments (at least one DH) and one or more of human JH (at least one JH) gene segments.
Rosner et al (Immunology 103:179-187, 2001, IDS) reported that the length of" [t]he third complementarity-determining region (CDR3) of immunoglobulin variable genes for the heavy chain (VH)" (abstract). Rosner specifies at least some of "the individual components that comprise CDR3" sequences in at least some examples (Abstract). More specifically, Rosner teaches that, in some instances, "[t]he heavy chain CDR3 is formed by amino acid residues encoded by a variable (VH) gene segment, diversity (D) gene segment, and joining (JH) gene segment... [with] further diversity.., generated during joining by (a) addition of short palindromic (P) nucleotides to the ends of the coding sequences, (b) deletion of a variable number of nucleotides from the ends of the coding segments by exonuclease activity, and (c) subsequent insertion of a variable number of non-templated (N) nucleotides at the VH-D and DH-J junctions by terminal deoxynucleotidyl transferase" (page 179, col. 1, line 8, to col. 2, line 8). Rosner states that "D gene segments make the largest contribution to CDR3 length" (page 183, D gene segment, col. 1, lines 1-2). Furthermore, it is reported that there is a significant "[c]orrelation of D segment length with CDR3 length” (page 183, D gene segment, col. 2, lines 17-19). Accordingly, the D gene segments present in an organism can constitute a significant correlation to the length of CDR-H3 sequences in the organism. Rosner estimates the contribution of other components of CDR-H3 sequences. Rosner finds that "JH gene segments make a substantial contribution to CDR3 of around 12 nt (page 183, JH gene segment, col. 2, lines 1-2); "P nucleotides...make a minor contribution of 0-4 nt" (page 185, P nucleotides, col. 1, line 1); "N nucleotides...contribute a substantial 12 nt toCDR3" (page 185, N nucleotides, col. 1, lines 1-3); and, in the particularly studied sample of sequences having VH6 gene segments, "VH6 gene segment makes a minor contribution to CDR3of 0-2 nt" (page 181, VH6 gene segment, col. 2, lines 1-2). Regarding the total length of CDR-H3 sequences, Rosner reports CDR3 lengths ranging from 15 nucleotides (corresponding to 5 amino acids) to 72 nucleotides (corresponding to 24 amino acids) (see page 180, Total CDR3 length, col.2, lines 1-4). In view of foregoing, it is apparent that the length of the resulting CDR-H3 length would in part depend on number of human V, D and J gene segment. Claims as presented embrace a mouse whose genome comprises one human V, one human D and one human J gene segment either replace endogenous VDJ or inserted downstream of endogenous VDJ such that they are operably linked to endogenous IgC region.
The instant specification fails to disclose the structural features that objectively distinguishes the human/mouse chimeric immunoglobulin heavy chain locus of base claim. The instant specification fails to disclose the structural features that functionally modify the alternative use of DH and JH reading frames, variation in the site of gene recombination due to the inclusion of P-nucleotides or the exonucleolytic loss of terminal nucleotides, the terminal deoxynucleotidyl transferase catalyzed addition of random (N) nucleotides, somatic hypermutation, receptor editing, and gene conversion of the human/mouse chimeric immunoglobulin heavy chain locus to necessarily arrive at the different functional properties of the differently recited CDR-H3 amino acid lengths and corresponding transcript frequencies recited in Claims 1-3 21, 26 and 29.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements or motifs which are not adequately described in the specification and which is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics. Inc., 48 USPQ2d 1641, 1646 (1998).
In the instant case, the specification fails to disclose adequate written description, and thus possession, for the structural changes to the human/mouse chimeric immunoglobulin heavy chain locus to necessarily and predictably achieve the corresponding functional properties of CDR-H3 amino acid lengths, and their corresponding transcript frequencies within the genus of lack a written description. The specification fails to describe what chimeric immunoglobulin heavy chain locus fall into this genus. The skilled artisan cannot envision the detailed chemical structure of the encompassed chimeric immunoglobulin heavy chain locus showing contemplated CDRH3 amino acid lengths, and their corresponding transcript frequencies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 UsPQ2d 1481, 1483. In Fiddes, claims directed to mammalian FGF'S were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
In view of the above considerations one of skill in the art would not recognize that applicant was in possession of the necessary common features or attributes possessed by member of the genus of chimeric immunoglobulin heavy chain locus resulting in CDRH3 amino acid lengths, and their corresponding transcript frequencies, other than the IgH locus comprising all human JH, all human DH and human Vh2-5, Vh7-41, Vh-4-4, Vhl-3, Vhl-2 and Vh6-1 showing CDRH3 amino acid lengths, and their corresponding transcript frequencies recited in the claim. Dependent Claims 4-30are included in the basis of the rejection because although they recite and encompass the human/mouse chimeric immunoglobulin heavy chain locus of Claims 1-3, they do not correct the deficiencies of independent Claims establishing a nexus between the human/mouse chimeric immunoglobulin heavy chain locus structural requirements and the instantly recited functional properties of the CDR-H3 amino acid lengths and corresponding mean transcript frequencies in said mouse.
Therefore, Applicant was not in possession of the genus of chimeric immunoglobulin heavy chain locus showing contemplated CDRH3amino acid lengths, and their corresponding transcript frequencies as encompassed by the claims. University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that to fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that ''the inventor invented the claimed invention.''
Response to arguments
Applicant re-iterates prior arguments filed on March 31, 2025 that are substantially the same as discussed in previous office action mailed on July 1, 2025 and incorporated herein.
Applicant continue to argue that Applicant has described and claimed a transgenic mouse having the recited structural characteristics and has not set forth or claimed a structure/function relationship. Applicant assert that the structural limitations of the transgenic mouse include those pertaining to the homozygous chimeric IGH locus and those pertaining to the recited IgH- VDJCu transcripts encoding said chimeric IgM heavy chain polypeptide, including the recited structure(s) of the CDRH3 length(s) and mean frequencies. That is, Applicant has described and claimed a transgenic mouse having the recited structural characteristics and has not set forth or claimed a structure/function relationship. Applicant’s specification describes multiple embodiments of the instantly recited chimeric IgH locus. Specifically, Applicant’s specification describes a range of coordinates between mouse J4 and Cu in which unrearranged human V region gene segments are positioned at any one of multiple selected positions upstream of Eu, see for example the following excerpts from Applicant’s specification published as US20170081423 (see para. 55, 66, 70, 292, 293 and Fig. 21). Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it is noted that the instant methods require that the transcripts produced by the transgenic IgH locus produce (functional property) structurally different CDR-H3 lengths, each at respective percentages recited in the claims. The instant claims fail to recite what structure(s) is/are responsible for the corresponding functional properties to yield the recited CDR-H3 lengths, each at respective percentages recited in the claims.
In other words, the recited human-mouse chimeric heavy chain locus comprising (i) unrearranged human immunoglobulin heavy chain (IgH) variable region (VH) DNA comprising one or more human IgH V gene segments, one or more human D gene segments and one or more human JH gene segments comprising a human JH6 gene segment; [structure] must recombine in some way in order to achieve [function] the production of instantly claimed CHR-H3 transcript distributions, required by the claimed method prior to immunization . Given that independent Claims 1-3 recite CDRH3 transcript distributions [functional properties] produced from the recited human-mouse chimeric heavy chain locus comprising one or more human IgH V gene segments, one or more human D gene segments and one or more human JH gene segments [structure]. It is emphasized that instant Claims 1-3 merely require just one human VH, just one human DH, and just one human JH gene segment to be present in the germline human/mouse chimeric immunoglobulin heavy chain locus (emphasis added), which, would indicate that a single human VH, single human DH, and single human JH gene segments of Claims 1-3 cannot naturally produce (functional property) the required structurally different CDR-H3 lengths, at respective percentages recited in the claims. The guidance provided in the specification is limited to all human JH, all human DH and human Vh2-5, Vh7-41, Vh-4-4, Vhl-3, Vhl-2 and Vh6-1 the germline human/mouse chimeric immunoglobulin heavy chain locus.
On pages 17-20 of the applicant’s arguments,
Applicant notes that the transcript/CDR-H3 amino acid length profile of Figure 37 requires a multitude of human IgH V gene segments, a multitude of human D gene segments, and a multitude of the human JH gene segments. Applicant continue to argue that the mice of each of the pending claims under examination is supported by the data represented in Figure 37. As such, the instantly recited mean frequencies are not exclusive to each other. Applicant continue to argue that he recited frequency of 5-10% of IgM transcripts encoding CDR-H3 lengths comprising 17 and 18 amino acids is described regardless of the number of the human unrearranged VH, D and JH gene segments present in the chimeric IgH recited in the instant claims, and is higher than the frequency found in a wild type mouse and more similar to the frequency found in a human, as illustrated by figure of paragraph 23 of the declaration of Dr. Lee attached, dated February 12, 2018 (filed on 03/31/20255), in which various ratios of VH gene segments were comprised by the chimeric IgH locus of three individual mice. one of ordinary skill in the art would, upon studying Fig. 37, immediately appreciate that Fig. 37 provides clear and unambiguous information as to both the mean frequency of CDR-H3 lengths, and the distribution of lengths, in the chimeric IgM transcript population present in the mice comprising the recited chimeric IgH locus. At the same time, one of ordinary skill in the art would immediately appreciate that Fig. 37 provides information not only as to mean frequencies of individual CDR-H3 lengths but also with respect to combined mean frequencies of selected CDR-H3 lengths and a mean frequency or mean frequency in a range of frequencies of selected CDR-H3 lengths. Discussed herein and in paragraph 4 of the expert declaration, dated April 22, 2020 by Dr. E-Chiang Lee, dated April 22, 2020, Attached. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, Figure 37 illustrates that the same human/mouse chimeric immunoglobulin heavy chain locus [structure] produces [function] the combination of CDR-H3 amino acid lengths from 5 to 22 amino acids, and, whereby the mean frequency of said transcripts encoding CDR-H3 lengths of 10 to 19 amino acids are present in said IgH-VDJCμ transcripts of said mouse is between 5% and 10%.
However, the instant claims are not so limited because independent claims 1-3 in part only requires one human VH, just one human DH, and just one human JH gene segment to be present in the germline human/mouse chimeric immunoglobulin heavy chain locus, which, would indicate that the single human VH, single human DH, and single human JH gene segments that cannot naturally produce (functional property) the required structurally different CDR-H3 lengths, at respective percentages recited in the claims (emphasis added). In other words, instant independent claims only recite CDR-H3 lengths of 17 to 18 amino acids with a transcript frequency between5% and 10%. The absence of reciting the other CDR-H3 lengths and their corresponding transcript frequencies clearly denotes that Applicant is seeking to claim possession of different human/mouse chimeric immunoglobulin heavy chain locus [structure] having different functional properties [CDR-H3 lengths and their corresponding transcript frequencies].
The specification fails to disclose adequate written description for the structural changes to the human/mouse chimeric immunoglobulin heavy chain locus (at least one VH, one DH and one JH) [structure] to necessarily and predictably arrive at the different scopes of the corresponding functional properties [CDR-H3 amino acid lengths, and their corresponding transcript frequencies]. The instant application fails to disclose the structure/function nexus between the minimal number of unrearranged human IgH V, D, and J gene segments to necessarily and sufficiently achieve the functional properties of producing transcripts encoding CDR-H3 amino acid lengths and their corresponding transcript frequencies.
In response to applicant’s submission of the Lee Declarations under 37 CFR 1.132 dated February 12, 2018 (the dec is made of record on 03/31/2025) illustrates CDR-H3 lengths and transcript frequencies of HKv1, v2, and v2.1 mice individually (para. 23 of the declaration), clearly evidencing that different structural transgenic configuration yield [functional property] different CDR-H3 lengths and transcript frequencies. Dr. Lee declaration is silent to disclosing how many human IgH V, D, and J gene segments are present in each of HKv1, v2, and v2.1. Thus, instant claims are broader in scope to Applicant’s data. It is noted that while Figure 37 illustrates a CDR-H3 length of 19 amino acids with a transcript frequency of about 5%, as also achieved via HKv1, v2, and v2.1, instant specification fails to disclose the structural configuration of the transgenic mouse from which this number was obtained.
The specification fails to actually disclose the structure of the unrearranged IgH chimeric IgH locus comprising the human IgH V, D, and J gene segment(s) that produce [function] the transcript profile of Figure 37. Rather, it appears that the transcript profile of Figure 37 requires a multitude of human IgH V gene segments (at least 12, as illustrated in Figure 13), a multitude of human D gene segments (at least 25 human DH gene segments, as illustrated in Figures 10 and 13), and all of the human JH gene segments (1 to 6, as illustrated in Figures 10 and 13). Claims 1 -3 are broader in scope than these structural requirements.
On pages 23-24 of the applicant’s argument, Applicant notes that there are several differences between the cells and the IgH genomes thereof, taught by Rosner et al. versus those of the instant claims. For example, in Rosner, both the Variable and Constant Region gene segments of the IgH locus are human (vs the instantly recited chimeric IgH locus comprising unrearranged human Variable but mouse Constant Region gene segments of the IgH locus). Additionally, in Rosner, the B cells in which the Variable gene segments of the IgH locus rearrange are human B cells, (vs the instantly recited mouse B cells). The Office Action has provided no evidentiary basis that the rearrangement properties of unrearranged human variable gene segments of a fully human IgH locus situated in human B cells taught by Rosner are equivalent to the rearrangement properties of the instantly recited unrearranged human variable gene segments of a chimeric IgH locus situated in mouse B cells. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it is emphasized that the Rosner reference was cited to provide context as to what was known in the art to be required for the production of the resulting CDR-H3 amino acid lengths and transcript frequencies (Figure 2), which is the product of both combinatorial and junctional diversification, biological mechanisms not being restricted to this interval, such as somatic hypermutation, receptor editing, and gene conversion, also contribute to CDR-H3 diversity. The reference teaches that there is a significant "[c]orrelation of D segment length with CDR3 length” (page 183, D gene segment, col. 2, lines 17-19). Accordingly, the D gene segments present in an organism can constitute a significant correlation to the length of CDR-H3 sequences in the organism. Rosner estimates the contribution of other components of CDR-H3 sequences. Rosner finds that "JH gene segments make a substantial contribution to CDR3 of around 12 nt (page 183, JH gene segment, col. 2, lines 1-2); "P nucleotides...make a minor contribution of 0-4 nt" (page 185, P nucleotides, col. 1, line 1); "N nucleotides...contribute a substantial 12 nt toCDR3" (page 185, N nucleotides, col. 1, lines 1-3); and, in the particularly studied sample of sequences having VH6 gene segments, "VH6 gene segment makes a minor contribution to CDR3of 0-2 nt" (page 181, VH6 gene segment, col. 2, lines 1-2). Regarding the total length of CDR-H3 sequences, Rosner reports CDR3 lengths ranging from 15 nucleotides (corresponding to 5 amino acids) to 72 nucleotides (corresponding to 24 amino acids) (see page 180, Total CDR3 length, col.2, lines 1-4). In the instant case, the claims fail to disclose the structural configuration of the transgenic mouse from which the CDR-H3 length and their corresponding transcript frequencies are obtained. Thus, the ordinary artisan would not know a priori what must be changed to the positively recited structural elements of the human/mouse chimeric immunoglobulin heavy chain locus in order to predictably produce (functional property) the required structurally different CDR-H3 lengths, at respective percentages recited in independent claim.
On page 25 of the applicant’s argument, applicant states the scope of Applicant's claims is not limited to exemplified embodiments which comprises all human JH and all human DHs. Applicant notes that exemplified data is of course routinely more narrow than disclosed data. Applicant makes reference to paragraph 9 of the expert declaration by Dr. Lee of record which states : "In my opinion, one of skill reading the instant specification would readily understand that a mouse such as that claimed above may contain a homozygous chimeric IgH locus which comprises all or fewer than all the human D gene segments, and such a mouse should produce IgM heavy chain transcripts encoding CDR-H3 lengths of 17 and 18 amino acids having a mean frequency between 5% and 10%".Applicant assert on light of such a statement by an expert in the field, Applicant requests official notice that the examiner is an expert in this filed if this aspect of the rejection is maintained. Applicants’ arguments have been fully considered, but are not found persuasive.
In response as stated above, the Lee’s declaration is silent to disclosing how many human IgH V, D, and J gene segments are present in each of HKvl, v2, and v2.1. The data from the instant specification clearly evidences that the CDR-H3 lengths of 11 to 22 amino acids varies substantially and unpredictably in transcript frequencies. No official notice is required as statement by Dr. Lee homozygous chimeric IgH locus which comprises all or fewer than all the human D gene segments, and such a mouse should produce IgM heavy chain transcripts encoding CDR-H3 lengths of 17 and 18 amino acids having a mean frequency between 5% and 10% does not provide basis for possession of IgH locus comprising one of human IgH V gene segments, one of human D gene segments and one of human JH gene segments and such a mouse would produce IgM heavy chain transcripts recited in the instant application. In the instant case, neither the instant specification, nor the Lee Declaration, nor the prior art makes up for the deficiencies in the nexus of trans gene structures that yield the functional properties of transcript frequencies encoding the respective CDR-H3 amino acid lengths. The specification fails to disclose what are the structural features of the human/mouse chimeric immunoglobulin heavy chain locus that is/are responsible for the CDRH3 transcript frequencies observed in Figure 37. The declaration fails to comment on how many fewer than all the human D segment or J gene segment that expresses IgM heavy chain transcripts encoding CDR-H3 lengths of 17 and 18 amino acids at a mean frequency of between 5% and 10%. It is relevant to note that figure 37 of the specification teaches transcripts encoding CDR-H3 lengths of 18 amino acids present in said IgH-VDJCμ transcripts of said mouse, before immunization is at 10%, however, none of the three mouse HKvl, v2, and v2.1 disclosed this feature of transcripts encoding CDR-H3 lengths of 18 amino acids present in said IgH-VDJCμ transcripts frequency of 10%, suggesting different structural transgenic configurations yielding different CDR-H3 (emphasis added). The art teaches D gene segments make the largest contribution to CDR3 length of about 15 nt, JH gene segments make a substantial contribution to CDR3 of around 12 n (see page 183, col. 1, para. 1 and col. 2, para. 3, Rosner et al Immunology 2001 103 179±187). It is further disclosed that the VH6 gene segment makes a minor contribution to CDR3 of 0±2 nt (see page 181). In view of foregoing, it is apparent that instant claims fail to recite what structures are responsible for the corresponding functional properties to yield the recited CDR-H3 lengths, each at respective percentages recited in the claims.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the broad genus of structurally different human/mouse chimeric immunoglobulin heavy chain loci having the different CDR-H3 amino acid lengths and corresponding mean transcript frequencies in said mouse at the time the application was filed.
Withdrawn-Claim Rejections - 35 USC § 103
Claims 1, 7, 9, 10, 20-23, 27, and 29 were rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Murphy et al (WO 02/066630; IDS or USP 8,791,323, filed on 11/09/2006) in view of Tanamachi et al (WO 07/117410; IDS), Wagner et al (Eur. J. Imunol. 24: 2672-2681,1994, IDS)/ Morrison et al ((US Patent no 5807715, dated 09/15/1998, IDS), as evidenced by Zemlin et al (J. Mol. Biol. 334:733-749, 2003), Aguilera et al (EMBO 4(l3B): 3689-3693, 1985; IDS). Applicant argument that predictable results for the instantly recited transgenic mouse cannot be extrapolated on the basis of the teachings by Zemlin. Figure 1 of Zemlin that illustrates the distinct shift to increased CDRH3 lengths generated by a fully human IgH locus in a human vs. those generated by a fully mouse IgH locus in mice is found persuasive. Further, Applicant’s argument that Zemlin does not address CDRH3 length of human V regions in a mouse comprising a chimeric IgH locus. Therefore, the CDRH3 lengths generated by the multifactorial process in the recited mouse could not be predicted based on Zemlin et al.'s teaching is also found persuasive, therefore, previous rejection of claims are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Claims 1, 7, 9-10, 15, 20-23, 27, and 29 were rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Murphy et al (WO 02/066630; IDS or USP 8,791,323, filed on 11/09/2006) in view of Tanamachi et al (WO 07/117410; IDS), Wagner et al (Eur. J. Imunol. 24: 2672-2681,1994)/ Morrison et al ((US Patent no 5807715, dated 09/15/1998, IDS), as evidenced by Zemlin et al (J. Mol. Biol. 334:733-749, 2003; IDS), Aguilera et al (EMBO 4(l3B): 3689-3693, 1985; IDS) as applied above and further in view of Adams (Genomics. 2005 December; 86 (6):753-8). The rejection is withdrawn for the reasons discussed above.
Claims 2-4, 8, 26, 28 and 30 were rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Murphy et al (WO 02/066630; IDS or USP 8,791,323, filed on 11/09/2006) in view of Tanamachi et al (WO 07/117410; IDS), Wagner et al (Eur. J. Imunol. 24: 2672-2681,1994)/ Morrison et al ((US Patent no 5807715, dated 09/15/1998, IDS), as evidenced by Zemlin et al (J. Mol. Biol. 334:733-749, 2003; IDS), Aguilera et al (EMBO 4(l3B): 3689-3693, 1985; IDS), Adams (Genomics. 2005 December; 86 (6):753-8) and further in view of Casrouge (The Journal of Immunology, 2000, 164: 5782–5787, IDS)/Bruggemann et al (Eur. J. Immunol. 1991.21: 1323-1326, IDS). The rejection is withdrawn for the reasons discussed above.
Claims 1, 18 and 19 were rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Murphy et al (WO 02/066630; IDS or USP 8,791,323, filed on 11/09/2006) in view of Tanamachi et al (WO 07/117410; IDS), Wagner et al (Eur. J. Imunol. 24: 2672-2681,1994)/ Morrison et al ((US Patent no 5807715, dated 09/15/1998, IDS), as evidenced by Zemlin et al (J. Mol. Biol. 334:733-749, 2003; IDS), Aguilera et al (EMBO 4(l3B): 3689-3693, 1985; IDS) , Adams (Genomics. 2005 December; 86 (6):753-8) and further in view of Zheng et al (Mol. Cell Biol. 2000, 20, 648-655, IDS), Oberdoerffer et al (Nucleic Acids Res. 2003, 31: e140, IDS) as evidenced by Torres and Kuhn, (Laboratory Protocols for Conditional Gene Targeting, 1997, p37-40, IDS). The rejection is withdrawn for the reasons discussed above.
Claims 1, 5-6, 24-25 were rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Murphy et al (WO 02/066630; IDS or USP 8,791,323, filed on 11/09/2006) in view of Tanamachi et al (WO 07/117410; IDS), Wagner et al (Eur. J. Imunol. 24: 2672-2681,1994)/ Morrison et al ((US Patent no 5807715, dated 09/15/1998, IDS), as evidenced by Zemlin et al (J. Mol. Biol. 334:733-749, 2003; IDS), Aguilera et al (EMBO 4(l3B): 3689-3693, 1985; IDS), Adams (Genomics. 2005 December; 86 (6):753-8), Casrouge et al (The Journal of Immunology, 2000, 164: 5782–5787) as applied above and further in view of Houtzager et al (USPGPUB 20100069614, dated 03/18/2010, filed on 06/29/2009) . The rejection is withdrawn for the reasons discussed above.
Maintained-Double Patenting
Claims 1-30 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-6 of US patent no. 9447177 (13416684) in view of Zemlin et al (J. Mol. Biol. 334:733-749, 2003. Although the claims at issue are not identical, they are not patentably distinct from each other. In the instant case, the '177 claims are drawn to a transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3' JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as used in the in the instantly recited Claims 1-30 directed to a method of providing an antigen-specific polypeptide comprising a human IgH variable region, antibody comprising said polypeptide, a cell producing said polypeptide, a nucleic acid encoding said polypeptide and/or a biological sample comprising said polypeptide, the method comprising the step of exposing or immunizing said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of' ‘177 appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of '177 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus.
Claims 1-30 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-19 of USP 9788534 (13846672) for the reasons of record. Although the claims at issue are not identical, they are not patentably distinct from each other. In the instant case, the '534 claims are drawn to a transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3' JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as used in the in the instantly recited Claims 1-30 directed to a method of providing an antigen-specific polypeptide comprising a human IgH variable region, antibody comprising said polypeptide, a cell producing said polypeptide, a nucleic acid encoding said polypeptide and/or a biological sample comprising said polypeptide, the method comprising the step of exposing or immunizing said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of' ‘534 appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of '534 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus.
Claims 1-30 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claim 1-10 of US Patent no 9505827 (Application No. 13740727). Although the claims at issue are not identical, they are not patentably distinct from each other. In the instant case, the '827 claims are drawn to a transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3' JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as used in the in the instantly recited Claims 1-30 directed to a method of providing an antigen-specific polypeptide comprising a human IgH variable region, antibody comprising said polypeptide, a cell producing said polypeptide, a nucleic acid encoding said polypeptide and/or a biological sample comprising said polypeptide, the method comprising the step of exposing or immunizing said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of' ‘827 appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of '827 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus.
Claims 1-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of US Patent no 9434782 (Application No. 14137902).
Although the claims at issue are not identical, they are not patentably distinct from each other. In the instant case, the '782 claims are drawn to a transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3' JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as used in the in the instantly recited Claims 1-30 directed to a method of providing an antigen-specific polypeptide comprising a human IgH variable region, antibody comprising said polypeptide, a cell producing said polypeptide, a nucleic acid encoding said polypeptide and/or a biological sample comprising said polypeptide, the method comprising the step of exposing or immunizing said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of' ‘782 appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of '782 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus.
Claims 1-30 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-16 of USP 10165763 (14080630).
Although the claims at issue are not identical, they are not patentably distinct from each other. In the instant case, the '763 claims are drawn to a transgenic mouse and method of using said transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3' JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as used in the in the instantly recited Claims 1-30 directed to a method of providing an antigen-specific polypeptide comprising a human IgH variable region, antibody comprising said polypeptide, a cell producing said polypeptide, a nucleic acid encoding said polypeptide and/or a biological sample comprising said polypeptide, the method comprising the step of exposing or immunizing said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of' ‘763and method of using said transgenic mouse appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of '763 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus.
Claims 1-30 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-13 of USP 11812731.
Although the claims at issue are not identical, they are not patentably distinct from each other. In the instant case, the '731 claims are drawn to a transgenic mouse and method of using said transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3' JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as used in the in the instantly recited Claims 1-30 directed to a method of providing an antigen-specific polypeptide comprising a human IgH variable region, antibody comprising said polypeptide, a cell producing said polypeptide, a nucleic acid encoding said polypeptide and/or a biological sample comprising said polypeptide, the method comprising the step of exposing or immunizing said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of' ‘731 and method of using said transgenic mouse appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of '731 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus.
Claims 1-30 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-25 of USP 10064398 (14516461).
Although the claims at issue are not identical, they are not patentably distinct from each other. In the instant case, the '398 claims are drawn to a transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3' JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as used in the in the instantly recited Claims 1-30 directed to a method of providing an antigen-specific polypeptide comprising a human IgH variable region, antibody comprising said polypeptide, a cell producing said polypeptide, a nucleic acid encoding said polypeptide and/or a biological sample comprising said polypeptide, the method comprising the step of exposing or immunizing said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of' 398 appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of '398 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus.
Claims 1-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 9504236.
Although the claims at issue are not identical, they are not patentably distinct from each other. In the instant case, the '236 claims disclose a transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3' JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as claimed in the instant application (Claims 1-30) directed to providing an antigen-specific polypeptide comprising a human IgH variable region, antibody comprising said polypeptide, a cell producing said polypeptide, a nucleic acid encoding said polypeptide and/or a biological sample comprising said polypeptide, the method comprising the step of exposing or immunizing said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of' ‘236 appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of '236 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus.
Claims 1-30 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-41 of US patent no 11564380. Although the claims at issue are not identical, they are not patentably distinct from each other. In the instant case, the '380 claims uses a transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3' JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as claimed in the instant application (Claims 1-30) directed to providing an antigen-specific polypeptide comprising a human IgH variable region, antibody comprising said polypeptide, a cell producing said polypeptide, a nucleic acid encoding said polypeptide and/or a biological sample comprising said polypeptide, the method comprising the step of exposing or immunizing said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of' ‘380 appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of '380 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus.
Claims 1-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-16 of copending Application No. 17943533 n view of Tanamachi et al (WO 07/117410; IDS). Although the claims at issue are not identical, they are not patentably distinct from each other. In the instant case, the '533 claims uses a transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3' JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as claimed in the instant application (Claims 1-30) directed to providing an antigen-specific polypeptide comprising a human IgH variable region, antibody comprising said polypeptide, a cell producing said polypeptide, a nucleic acid encoding said polypeptide and/or a biological sample comprising said polypeptide, the method comprising the step of exposing or immunizing said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of' ‘533 appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of '533 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of copending Application No. 17703750 and Tanamachi et al (WO 07/117410; IDS). Although the claims at issue are not identical, they are not patentably distinct from each other. ‘750 claims use a transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3’ JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as claimed in the instant application (Claim 1), and a method of obtaining an antigen specific antibody or antigen binding fragment thereof comprising a human immunoglobulin heavy chain comprising human IgH chain variable region (VH), the method comprising the step of contacting said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of ‘750 appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of ‘750 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-10, 15-21 of copending Application No. 17878628 and Tanamachi et al (WO 07/117410; IDS). Although the claims at issue are not identical, they are not patentably distinct from each other. ‘628 claims use a transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3’ JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as claimed in the instant application (Claim 1), and a method of obtaining an antigen specific antibody or antigen binding fragment thereof comprising a human immunoglobulin heavy chain comprising human IgH chain variable region (VH), the method comprising the step of contacting said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of ‘628 appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of ‘628 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of US11606941 and Tanamachi et al (WO 07/117410; IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other. ‘941 claims use a transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3’ JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as claimed in the instant application (Claim 1), and a method of obtaining an antigen specific antibody or antigen binding fragment thereof comprising a human immunoglobulin heavy chain comprising human IgH chain variable region (VH), the method comprising the step of contacting said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of ‘941 appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of ‘941 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus.
Claims 1-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of copending Application No. 16870365 and Tanamachi et al (WO 07/117410; IDS). Although the claims at issue are not identical, they are not patentably distinct from each other. ‘365 claims a transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3’ JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as claimed in the instant application (Claim 1), and a method of obtaining an antigen specific antibody or antigen binding fragment thereof comprising a human immunoglobulin heavy chain comprising human IgH chain variable region (VH), the method comprising the step of contacting said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of ‘365 appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of ‘365 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of US 11297810 and Tanamachi et al (WO 07/117410; IDS). Although the claims at issue are not identical, they are not patentably distinct from each other. ‘810 claims a transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3’ JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as claimed in the instant application (Claims 1), and a method of obtaining an antigen specific antibody or antigen binding fragment thereof comprising a human immunoglobulin heavy chain comprising human IgH chain variable region (VH), the method comprising the step of contacting said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of ‘810 appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of ‘810 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus.
Claims 1-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 18-29 of copending Application No. 18059809 and Tanamachi et al (WO 07/117410; IDS). Although the claims at issue are not identical, they are not patentably distinct from each other. ‘809 claims use a transgenic mouse whose genome comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising: i) unrearranged human immunoglobulin heavy chain variable region (VH) gene segments, ii) one or more human D gene segments, iii) one or more human JH gene segments, iv) a chimeric J/C intron comprising human DNA downstream of and naturally contiguous with said human 3’ JH gene segment, which is contiguous at a chimeric junction with mouse DNA, said mouse DNA being upstream of and naturally contiguous with mouse Eμ and an endogenous murine constant CH gene segment (Figure 21), as claimed in the instant application (Claim 1), and a method of obtaining an antigen specific antibody or antigen binding fragment thereof comprising a human immunoglobulin heavy chain comprising human IgH chain variable region (VH), the method comprising the step of contacting said transgenic mouse with an antigen. The human/mouse chimeric immunoglobulin heavy chain locus of ‘809 appears to be structurally indistinguishable from the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus, and thus anticipates and/or renders obvious the instant claims. Figure 37 of ‘809 illustrates the transgenic mouse comprising the human/mouse chimeric immunoglobulin heavy chain locus yields an identical CDR-H3 range of amino acid lengths and mean frequencies as the instantly claimed human/mouse chimeric immunoglobulin heavy chain locus.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to arguments
While Applicant has requested that the rejection be held in abeyance until allowable subject matter can be identified, a request of abeyance does not overcome or address an issue of obvious double patenting between claims in the instant case and US Patent and US patent applications. Thus, the rejection is maintained.
Conclusion
No claims allowed.
Stevens et al (Pharma Focus Asia, 2008, 8, 72-74, IDS) teaches entire human Ig heavy and kappa light chain variable repertoire has been integrated into ES cells. The resulting genomic loci are stable throughout multiple generations of mice and have been shown to be used productively, generating antibodies of diverse fully-human variable sequences. High affinity therapeutic antibodies have been generated to many different antigens utilizing standard hybridoma and cloning techniques, further highlighting the speed and efficiency (see page 74). It is further disclosed that method employed to remove the ~3 megabase murine variable genomic sequences at the heavy and kappa light chain Ig loci in mouse ES cells, followed by the stepwise insertion of the unrearranged human heavy and kappa light chain variable genomic loci, or ~1 megabase of genomic DNA of the human heavy chain locus and 0.5 megabase of the human kappa light chain locus (Stevens page 74,), therefore, expression of IgH heavy chain comprising endogenous mouse variable region implicitly be reduced or prevented.
Goepfert et al (US8771988) teaches an expression construct that includes a heavy chain encoding sequence and a light chain encoding sequence, both of which include a human/mouse hybrid intron. See col. 17:57-60, col. 21:3-21).
Homo sapiens immunoglobulin heavy locus (IGH) on chromosome 14. NCBI
Reference Sequence: NG_001019.1; 2002 Jun 26 (“GenBank Human IgH, IDS”)’ GenBank Human IgH is the GenBank entry for the human immunoglobulin heavy chain germline sequence that contains the J-C intronic region and constant region sequence. The annotation of the sequence indicates that the distance between the 3’ most Ju gene segment and the intronic enhancer region (from bp 960082 to 960908) is less than 2 kb (ie 826 bp).
Mus musculus immunoglobulin heavy chain locus constant region and partial variable region, strain 129S1. GenBank: AJ851868.3; 2007 Jul. 26 (hereafter “GenBank Mouse IgH, IDS”)’ GenBank Mouse IgH is the GenBank entry for the mouse immunoglobulin heavy chain germline sequence that contains the J-C intronic region and constant region sequence. The annotation of the sequence indicates that the mouse JC intron spans bases 1416058 to 1417363 (1306 bp), and the mouse intronic enhancer in the JC intron is within bases 1416975 to 1417287 (entitled “Ig enhancer region”). Thus, GenBank Mouse IgH discloses that the distance between the 3’ most Ju gene segment and the mouse intronic enhancer region is less than 2 kb (i.e., about 900 bp) and, in fact, the entire mouse JC intron is less than 2 kb in length (1.e., about 1300 bp).
WO 2009/013620 discloses host heavy chain loci ... selectively engineered so that natural or engineered V gene segments of the species of choice replace host heavy chain V segments host D and J segments are similarly replaced" (page 18, 11. 8-11). In at least one embodiment, as hown in Figure 1 such modification results in a JC intron including both human JC intronic
PNG
media_image1.png
686
960
media_image1.png
Greyscale
DNA and mouse JC intronic DNA, so that the chimeric DNA junction is at a position downstream from last human heavy chain J segment (see figure 1 that supports the teaching of Tanamachi/Morrison).
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANOOP K. SINGH whose telephone number is (571)272-3306. The examiner can normally be reached Monday-Friday, 8AM-5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANOOP K SINGH/Primary Examiner, Art Unit 1632