DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 6/17/26 has been entered.
Claims 1-15, and 17-28 are now canceled, and new claims 29-34 have been added. Claims 16 and 29-34 are now pending and under examination in this application.
The previously pending claims had been examined based on the elected species of VH1-2 or VH1-69 as the single human VH segment. Amended claim 16 and new claims 29-34 do not include any generic claims and are all now limited to a restricted locus which has “only a single human VH gene segment, wherein the single human VH gene segment is a VH3 gene segment family member”. Although the applicant has amended the claims to recite a previously non-elected species, the claim amendment has been entered as no generic claims remain.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
Those sections of Title 35, US code, not included in this action can be found in a previous office action.
Claim Rejections - 35 USC § 103
The rejection of previously pending claims 1-3, 6-13, 15-16, and 23-28 under 35 U.S.C. 103 as being unpatentable over U.S. Patent 6,657,103 (2003), hereafter referred to as Kucherlapati et al., in view of U.S. Patent No. 6,596,541 (2003), hereafter referred to as Murphy et al., and U.S. Patent Application Publication 2014/0212416 (2014), hereafter referred to as Friedrich et al., with an effective filing date of 9/19/2011, is withdrawn in view of applicant’s cancellation of claims 1-3, 6-13, 15, and 23-28, and the amendments to the claims, which now recite that the restricted locus has “only a single human VH gene segment, wherein the single human VH gene segment is a VH3 gene segment family member”, and arguments.
Double Patenting
The rejection of previously pending claims 1-3, 6-13, 15-16, and 23-28 on the ground of nonstatutory double patenting as being unpatentable over 1) claims 1-16 of U.S. Patent No. 10,694,725, hereafter referred to as the ‘725 patent OR 2) claims 1-16 of U.S. Patent No. 10,577,430, hereafter referred to as the ‘430 patent, OR 3) claims 1-12 of U.S. Patent No. 10,905,108, hereafter referred to as the ‘108 patent, OR 4) claims 1-14 of U.S. Patent No. 11,950,578, hereafter referred to as the ‘578 patent, each individually, in view of U.S. Patent Application Publication 2014/0212416 (2014), hereafter referred to as Friedrich et al., with an effective filing date of 9/19/2011, and Zibellini et al. (2008) Blood, Vol. 112 (11):1175, pages 1-3, is maintained in modified form as set forth below over amended claim 16 and new claims 29-34, claims 1-3, 6-13, 15-16, and 23-28 having been canceled.
Claims 16 and 29-34 are now rejected on the ground of nonstatutory double patenting as being unpatentable over 1) claims 1-16 of U.S. Patent No. 10,694,725, hereafter referred to as the ‘725 patent OR 2) claims 1-16 of U.S. Patent No. 10,577,430, hereafter referred to as the ‘430 patent, OR 3) claims 1-12 of U.S. Patent No. 10,905,108, hereafter referred to as the ‘108 patent, OR 4) claims 1-14 of U.S. Patent No. 11,950,578, hereafter referred to as the ‘578 patent, each individually, either alone, or for claims 29 and 33-34 in view of U.S. Patent No. 6,596,541 (2003), hereafter referred to as Murphy et al.
As noted above, the applicant has substantially amended independent claim 16 to recite that the restricted heavy chain locus has “only a single human VH gene segment, wherein the single human VH gene segment is a VH3 gene segment family member”. New independent claim 33 recites the same limitation regarding the human VH gene segment. Both independent claims 16 and 33 recite the same method steps as previously recited. It is further noted that new claims 29 and 33-34 further recite that restricted heavy chain locus comprises a deletion of all or substantially all endogenous VH, DH, and JH gene segments (claim 29), or where all or substantially all endogenous VH, DH, and JH gene segments are replaced by the single human VH3 family member gene segment, the one or more human DH gene segments and the one or more human JH gene segments (claims 33-34).
Claims 1-16 of the ‘725 patent, claims 1-16 of the ‘430 patent, claims 1-12 of the ‘108 patent, OR claims 1-14 of the ‘578 patent, each individually recite methods which include the same method steps of immunizing transgenic mouse with a genetically modified heavy chain locus and isolating a nucleic acid encoding a human heavy chain variable region sequence which are both broader and narrower than the instant claimed methods. The ‘725 patent claims, the ‘430 patent claims, the ‘108 patent claims , and the ‘578 patent claims are narrower than the instant claimed methods in that they are limited to transgenic mice, and they are broader in that they recite that the endogenous heavy chain locus comprises “one or more” human VH gene segments instead of “only a single” human VH gene segment, one or more human DH gene segments, and one or more human JH gene segments operatively linked to a mouse heavy chain constant region gene segment. It is also noted that the claims further recite that the mouse genome comprises one or more human VL gene segments, and one or more human JL gene segments operatively linked to a light chain constant region gene segment. However, note that “one or more” clearly encompasses “one” human VH gene segment. Further, the ‘725 patent claims, the ‘430 patent claims, the‘108 patent claims, and the ‘578 patent claims all include dependent claims which recite that the human VH gene segment is selected from a group which includes VH3 gene segment family members VH3-9, VH3-11, VH3-13, VH3-15, VH3-16, VH3-20, VH3-21, VH3-23, VH3-30, VH3-31, VH3-33, VH3-34, VH3-35, and more. Thus, the ‘725 patent claims, the ‘430 patent claims, the‘108 patent claims, and the ‘578 patent claims encompass and specifically recite that the one or more VH gene segment is a VH3 family member and thus render obvious a restricted heavy chain locus where the “one” VH is a VH3 family member gene segment.
In regards to claims 29 and 33-34, it is noted that the broader ‘725 patent claims, ‘430 patent claims,‘108 patent claims, and ‘578 patent claims encompass but do not specifically recite that all or substantially all endogenous VH, DH, and JH gene segments are replaced by the single human VH3 family member gene segment, the one or more human DH gene segments and the one or more human JH gene segments, or where all or substantially all endogenous VL, and JL gene segments are replaced by the one or more human VL gene segments, and the one or more human JL gene segments. However, at the time of filing, Murphy et al. teaches “knock-in” transgenic mice in which all or part of the endogenous genomic immunoglobulin light chain variable region and/or heavy chain variable region are substituted by homologous recombination for human light chain and/or heavy chain genes respectively (Murphy et al., paragraphs 35-36, 38-44, 46-48, 83, 85, 99, and claims 1-4, and 7-10). Murphy et al. further teaches that direct substitution of the mouse light and heavy chain VJ/VDJ regions with human VJ/VDJ regions using homologous recombination such that all the sequences necessary for proper transcription, recombination, and/or class switching in the mouse genome remain intact (Murphy et al., paragraph 85). For homologous recombination, Murphy teaches that the human VDJ sequences are flanked by homology arms comprising mouse genomic DNA from the mouse heavy chain locus (Murphy et al., Figure 4d). In addition, Murphy et al. teaches that immunization of these transgenic mice generates antibodies comprising human variable regions and mouse constant regions (Murphy et al., paragraphs 46 and 49). Further, Murphy et al. teaches that human heavy chain and light chain variable region knockin mice can be used to make a human antibody by exposing the mouse to antigenic stimulation, such that the mouse produces an antibody against the antigen, and isolating the DNA encoding the variable regions of the heavy and light chains of the antibody (Murphy et al., paragraph 49 of the detailed description). In regards to the light chain, Murphy et al. teaches “knock-in” of the human kappa light chain and/or lambda light chain into the endogenous mouse kappa or lambda light chain variable region respectively (Murphy et al., paragraph 99). Murphy et al. further provides motivation to replace the endogenous V, D, J, genes with the human genes and retain the mouse constant region genes by teaching that antibodies comprising human constant regions in mice have reduced affinity and that the mouse constant region and associated regulatory elements are important for development and optimization of B cell antibody production (Murphy et al., paragraph 80).
Thus, in view of the teachings and motivation provided by Murphy et al. to replace all or part of the endogenous mouse light chain V/J region with human VJ sequences and to replace all or part of the endogenous mouse heavy chain V/D/J region with human V, D, and J sequences, it would have been prima facie obvious to the skilled artisan at the time of filing to make and use a transgenic mouse according to the ‘725 patent claims, the ‘430 patent claims, the‘108 patent claims, OR the ‘578 patent claims where the human Vk and Jk sequences replaces all the endogenous mouse light chain VK and JK sequences and wherein the unrearranged “one” human heavy chain VH gene segment sequence, one or more D gene segment sequences, and one or more J gene segment sequences replace all the endogenous mouse heavy chain V, D, and J gene sequences, such that the resulting mouse produces chimeric antibodies with human variable regions and mouse constant regions as set forth in instant claims 29 and 33-34 with a reasonable expectation of success.
In so far as applicant’s arguments apply to the modified grounds of rejection necessitated by applicant’s amendments to the claims, it is noted that the applicant argues that the instant claims are method claims for using the composition claimed in U.S. Patent 11,261,248, hereafter referred to as the ‘248 patent, and are non-obvious over the cited patents for the reasons as acknowledged for the issued claims of ‘248 patent which are reiterated in the rebuttal to the 103 obviousness rejection presented in applicant’s response.
In response, the instant rejection is a non-statutory double patenting rejection and is not 103 rejection. The instant rejection is based on the ‘725 patent claims, the ‘430 patent claims, the ‘108 patent claims, OR the ‘578 patent claims. The applicant has not presented any arguments regarding the ‘725 patent claims, the ‘430 patent claims, the‘108 patent claims, OR the ‘578 patent claims. Further, the instant rejection does not recite Kucherlapati et al. and applicant’s arguments made in regards to the 103 rejection are irrelevant to the grounds of the instant rejection. As such, applicant’s arguments are not found persuasive.
The rejection of claims 1-3, 6-13, 15-16, and 23-28 on the ground of nonstatutory double patenting as being unpatentable over 1) claims 1-13 of U.S. Patent No. 10,905,109, hereafter referred to as the ‘109 patent, OR 2) claims 1-25 of 11,357,217, hereafter referred to as ‘217, OR 3) claims 1-19 of U.S. Patent No. 9,932,408, hereafter referred to as the ‘408 patent, in view of U.S. Patent Application Publication 2014/0212416 (2014), hereafter referred to as Friedrich et al., with an effective filing date of 9/19/2011, and Zibellini et al. (2008) Blood, Vol. 112 (11):1175, pages 1-3, is maintained in modified form as set forth below over amended claim 16 and new claims 29-34, claims 1-3, 6-13, 15-16, and 23-28 having been canceled.
Claims 16 and 29-34 are now rejected on the ground of nonstatutory double patenting as being unpatentable over 1) claims 1-13 of U.S. Patent No. 10,905,109, hereafter referred to as the ‘109 patent, OR 2) claims 1-25 of 11,357,217, hereafter referred to as ‘217, either alone, or for claims 29 and 33-34 in view of U.S. Patent No. 6,596,541 (2003), hereafter referred to as Murphy et al.
As noted above, the applicant has substantially amended independent claim 16 to recite that the restricted heavy chain locus has “only a single human VH gene segment, wherein the single human VH gene segment is a VH3 gene segment family member”. New independent claim 33 recites the same limitation regarding the human VH gene segment. Both independent claims 16 and 33 recite the same method steps as previously recited. It is further noted that new claims 29 and 33-34 further recite that restricted heavy chain locus comprises a deletion of all or substantially all endogenous VH, DH, and JH gene segments (claim 29), or where all or substantially all endogenous VH, DH, and JH gene segments are replaced by the single human VH3 family member gene segment, the one or more human DH gene segments and the one or more human JH gene segments (claims 33-34).
Claims 1-13 of the ‘109 patent, OR claims 1-25 of the ‘217 patent, each individually recite methods which include the same method steps of immunizing transgenic mouse with a genetically modified heavy chain locus and isolating a nucleic acid encoding a human heavy chain variable region sequence which are both broader and narrower than the instant claimed methods. The ‘109 patent claims, and the ‘217 patent claims are narrower than the instant claimed methods in that they are limited to transgenic mice, and they are broader in that they recite that the endogenous heavy chain locus comprises “one or more” human VH gene segments (the ‘109 patent claims) or “at least one” human VH gene segment (the ‘217 patent claims) instead of “only a single” human VH gene segment, one or more human DH gene segments, and one or more human JH gene segments operatively linked to a mouse heavy chain constant region gene segment. It is also noted that the claims further recite that the mouse genome comprises one or more human VL gene segments, and one or more human JL gene segments operatively linked to a light chain constant region gene segment. However, note that “one or more” or “at least one” clearly encompasses “one” human VH gene segment. Further, the ‘109 patent claims, and the ‘217 patent claims all include dependent claims which recite that the human VH gene segment is selected from a group which includes VH3 gene segment family members VH3-9, VH3-11, VH3-13, VH3-15, VH3-16, VH3-20, VH3-21, VH3-23, VH3-30, VH3-31, VH3-33, VH3-34, VH3-35, and more. Thus, the ‘109 patent claims and the ‘217 patent claims encompass and specifically recite that the one or more/at least one VH gene segment is a VH3 family member and thus render obvious a restricted heavy chain locus where the “one” VH is a VH3 family member gene segment.
In regards to claims 29 and 33-34, it is noted that the broader ‘109 patent claims and ‘217 patent claims encompass but do not specifically recite that all or substantially all endogenous VH, DH, and JH gene segments are replaced by the single human VH3 family member gene segment, the one or more human DH gene segments and the one or more human JH gene segments, or where all or substantially all endogenous VL, and JL gene segments are replaced by the one or more human VL gene segments, and the one or more human JL gene segments. However, at the time of filing, Murphy et al. teaches “knock-in” transgenic mice in which all or part of the endogenous genomic immunoglobulin light chain variable region and/or heavy chain variable region are substituted by homologous recombination for human light chain and/or heavy chain genes respectively (Murphy et al., paragraphs 35-36, 38-44, 46-48, 83, 85, 99, and claims 1-4, and 7-10). Murphy et al. further teaches that direct substitution of the mouse light and heavy chain VJ/VDJ regions with human VJ/VDJ regions using homologous recombination such that all the sequences necessary for proper transcription, recombination, and/or class switching in the mouse genome remain intact (Murphy et al., paragraph 85). For homologous recombination, Murphy teaches that the human VDJ sequences are flanked by homology arms comprising mouse genomic DNA from the mouse heavy chain locus (Murphy et al., Figure 4d). In addition, Murphy et al. teaches that immunization of these transgenic mice generates antibodies comprising human variable regions and mouse constant regions (Murphy et al., paragraphs 46 and 49 of the detailed description). Further, Murphy et al. teaches that human heavy chain and light chain variable region knockin mice can be used to make a human antibody by exposing the mouse to antigenic stimulation, such that the mouse produces an antibody against the antigen, and isolating the DNA encoding the variable regions of the heavy and light chains of the antibody (Murphy et al., paragraph 49 of the detailed description). In regards to the light chain, Murphy et al. teaches “knock-in” of the human kappa light chain and/or lambda light chain into the endogenous mouse kappa or lambda light chain variable region respectively (Murphy et al., paragraph 99). Murphy et al. further provides motivation to replace the endogenous V, D, J, genes with the human genes and retain the mouse constant region genes by teaching that antibodies comprising human constant regions in mice have reduced affinity and that the mouse constant region and associated regulatory elements are important for development and optimization of B cell antibody production (Murphy et al., paragraph 80).
Thus, in view of the teachings and motivation provided by Murphy et al. to replace all or part of the endogenous mouse light chain V/J region with human VJ sequences and to replace all or part of the endogenous mouse heavy chain V/D/J region with human V, D, and J sequences, it would have been prima facie obvious to the skilled artisan at the time of filing to make and use a transgenic mouse according to the ‘109 patent claims, OR the ‘217 patent claims where the human Vk and Jk sequences replaces all the endogenous mouse light chain VK and JK sequences and wherein the unrearranged “one” human heavy chain VH gene segment sequence, one or more D gene segment sequences, and one or more J gene segment sequences replace all the endogenous mouse heavy chain V, D, and J gene sequences, such that the resulting mouse produces chimeric antibodies with human variable regions and mouse constant regions as set forth in instant claims 29 and 33-34 with a reasonable expectation of success.
In so far as applicant’s arguments apply to the modified grounds of rejection necessitated by applicant’s amendments to the claims, it is noted that the applicant argues that the instant claims are method claims for using the composition claimed in U.S. Patent 11,261,248, hereafter referred to as the ‘248 patent, and are non-obvious over the cited patents for the reasons as acknowledged for the issued claims of ‘248 patent which are reiterated in the rebuttal to the 103 obviousness rejection presented in applicant’s response.
In response, the instant rejection is a non-statutory double patenting rejection and is not 103 rejection. The instant rejection is based on the ‘109 patent claims OR the ‘217 patent claims. The applicant has not presented any arguments regarding the ‘109 patent claims OR the ‘217 patent claims. Further, the instant rejection does not recite Kucherlapati et al. and applicant’s arguments made in regards to the 103 rejection are irrelevant to the grounds of the instant rejection. As such, applicant’s arguments are not found persuasive.
Claims 16 and 29-34 are now rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 9,932,408, hereafter referred to as the ‘408 patent, in view of U.S. Patent No. 6,596,541 (2003), hereafter referred to as Murphy et al.
As noted above, the applicant has substantially amended independent claim 16 to recite that the restricted heavy chain locus has “only a single human VH gene segment, wherein the single human VH gene segment is a VH3 gene segment family member”. New independent claim 33 recites the same limitation regarding the human VH gene segment. Both independent claims 16 and 33 recite the same method steps as previously recited. It is further noted that new claims 29 and 33-34 further recite that restricted heavy chain locus comprises a deletion of all or substantially all endogenous VH, DH, and JH gene segments (claim 29), or where all or substantially all endogenous VH, DH, and JH gene segments are replaced by the single human VH3 family member gene segment, the one or more human DH gene segments and the one or more human JH gene segments (claims 33-34).
Claims 1-19 of the ‘408 patent are drawn to a genetically modified mouse with a modified endogenous heavy chain locus that comprises “one or more” human VH gene segment, at least one human DH gene segments, and at least one human JH gene segments operatively linked to a mouse heavy chain constant region gene segment (’408 patent claims 9-11). However, note that “one or more” clearly encompasses “one” human VH gene segment. Further, the ‘408 patent claims include dependent claims which recite that the human VH gene segment is selected from a group which includes VH3 gene segment family members VH3-9, VH3-11, VH3-13, VH3-15, VH3-20, VH3-23, VH3-30, VH3-33, VH3-43, and VH3-48. Thus, the ‘408 patent claims encompass and specifically recite that the at least one VH gene segment is a VH3 family member and thus render obvious a restricted heavy chain locus where the “one” VH is a VH3 family member gene segment.
While the ‘408 patent claims are drawn to a mouse, and not a method of using the mouse to obtain heavy chain variable region encoding nucleotide sequences as claimed in the instant methods, Note that MPEP 804(II)(2)(a) sets forth instances where it is acceptable to utilize the disclosure of a U.S. patent document in conjunction with its claims for obvious-type double patenting rejections. In particular, the MPEP notes that the portion of the specification that supports the patent claims may be considered. The court in AbbVie Inc. v. Kennedy Institute of Rheumatology Trust pointed out that “this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined.” In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014). The court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003). In the instant case, the ‘408 patent specification clearly discloses the same use for the genetically modified mouse as currently claimed. Furthermore, such methods of obtaining nucleotide sequences encoding human variable regions from a transgenic mouse with a modified endogenous heavy chain locus where known in the prior art. At the time of filing, Murphy et al. teaches “knock-in” transgenic mice in which all or part of the endogenous genomic immunoglobulin light chain variable region and/or heavy chain variable region are substituted by homologous recombination for human light chain and/or heavy chain genes respectively (Murphy et al., paragraphs 35-36, 38-44, 46-48, 83, 85, 99, and claims 1-4, and 7-10). Murphy et al. further teaches that direct substitution of the mouse light and heavy chain VJ/VDJ regions with human VJ/VDJ regions using homologous recombination such that all the sequences necessary for proper transcription, recombination, and/or class switching in the mouse genome remain intact (Murphy et al., paragraph 85). For homologous recombination, Murphy teaches that the human VDJ sequences are flanked by homology arms comprising mouse genomic DNA from the mouse heavy chain locus (Murphy et al., Figure 4d). In regards to the light chain, Murphy et al. teaches “knock-in” of the human kappa light chain and/or lambda light chain into the endogenous mouse kappa or lambda light chain variable region respectively (Murphy et al., paragraph 99). Murphy et al. further provides motivation to replace the endogenous V, D, J, genes with the human genes and retain the mouse constant region genes by teaching that antibodies comprising human constant regions in mice have reduced affinity and that the mouse constant region and associated regulatory elements are important for development and optimization of B cell antibody production (Murphy et al., paragraph 80). Most importantly, Murphy et al. teaches that immunization of these transgenic mice generates antibodies comprising human variable regions and mouse constant regions (Murphy et al., paragraphs 46 and 49 of the detailed description). Murphy et al. teaches that human heavy chain and light chain variable region knockin mice can be used to make a human antibody by exposing the mouse to antigenic stimulation, such that the mouse produces an antibody against the antigen, and isolating the DNA encoding the variable regions of the heavy and light chains of the antibody (Murphy et al., paragraph 49 of the detailed description).
Thus, in view of the teachings and motivation provided by Murphy et al. to replace all or part of the endogenous mouse light chain V/J region with human VJ sequences and to replace all or part of the endogenous mouse heavy chain V/D/J region with human V, D, and J sequences, and the further motivation provided by Murphy et al. to utilize such knockin mice to generate nucleotide sequences encoding human heavy chain variable regions comprising immunizing the knockin mouse with an antigen, and isolating a nucleotide sequence encoding a human heavy chain variable domain, it would have been prima facie obvious to the skilled artisan at the time of filing to make a transgenic mouse according to the ‘408 patent claims where the human Vk and Jk sequences replaces all the endogenous mouse light chain VK and JK sequences and wherein the unrearranged “one” human heavy chain VH3 family member gene segment sequence, one or more D gene segment sequences, and one or more J gene segment sequences replace all the endogenous mouse heavy chain V, D, and J gene sequences, and to further immunize such a mouse with antigen to obtain human heavy chain variable domain nucleotide sequences as set forth in instant claims 16 and 29-30 with a reasonable expectation of success.
In so far as applicant’s arguments apply to the modified grounds of rejection necessitated by applicant’s amendments to the claims, it is noted that the applicant argues that the instant claims are method claims for using the composition claimed in U.S. Patent 11,261,248, hereafter referred to as the ‘248 patent, and are non-obvious over the cited patents for the reasons as acknowledged for the issued claims of ‘248 patent which are reiterated in the rebuttal to the 103 obviousness rejection presented in applicant’s response.
In response, the instant rejection is a non-statutory double patenting rejection and is not a 103 rejection. The instant rejection is based on the ‘408 patent claims. The applicant has not presented any arguments regarding the ‘408 patent claims. Further, the instant rejection does not recite Kucherlapati et al. and applicant’s arguments made in regards to the 103 rejection are irrelevant to the grounds of the instant rejection. As such, applicant’s arguments are not found persuasive.
The rejection of claims 1-3, 6-13, 15-16, and 23-28 on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10,130,081, hereafter referred to as the ‘081 patent, in view of U.S. Patent Application Publication 2014/0212416 (2014), hereafter referred to as Friedrich et al., with an effective filing date of 9/19/2011, Zibellini et al. (2008) Blood, Vol. 112 (11):1175, pages 1-3, and U.S. Patent 6,657,103 (2003), hereafter referred to as Kucherlapati et al., is maintained in modified form as set forth below over amended claim 16 and new claims 29-30, claims 1-3, 6-13, 15-16, and 23-28 having been canceled.
Claims 16 and 29-30 are now rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10,130,081, hereafter referred to as the ‘081 patent, in view of U.S. Patent No. 6,596,541 (2003), hereafter referred to as Murphy et al.
As noted above, the applicant has substantially amended independent claim 16 to recite that the restricted heavy chain locus has “only a single human VH gene segment, wherein the single human VH gene segment is a VH3 gene segment family member”. Independent claim 16 recites the same method steps as previously recited. It is further noted that new claim 29 recites that restricted heavy chain locus comprises a deletion of all or substantially all endogenous VH, DH, and JH gene segments.
The ‘081 patent claims are drawn to a genetically modified mouse with a modified endogenous heavy chain locus that comprises “at least one” human VH gene segment, at least one human DH gene segments, and at least one human JH gene segments operatively linked to a mouse heavy chain constant region gene segment. However, note that “at least one” clearly encompasses “one” human VH gene segment. Further, the ‘081 patent claims include dependent claims which recite that the human VH gene segment is selected from a group which includes VH3 gene segment family members VH3-9, VH3-11, VH3-13, VH3-15, VH3-20, VH3-23, VH3-30, VH3-33, VH3-43, and VH3-48. Thus, the ‘081 patent claims encompass and specifically recite that the at least one VH gene segment is a VH3 family member and thus render obvious a restricted heavy chain locus where the “one” VH is a VH3 family member gene segment.
While the ‘081 patent claims are drawn to a mouse, and not a method of using the mouse to obtain heavy chain variable region encoding nucleotide sequences as claimed in the instant methods, Note that MPEP 804(II)(2)(a) sets forth instances where it is acceptable to utilize the disclosure of a U.S. patent document in conjunction with its claims for obvious-type double patenting rejections. In particular, the MPEP notes that the portion of the specification that supports the patent claims may be considered. The court in AbbVie Inc. v. Kennedy Institute of Rheumatology Trust pointed out that “this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined.” In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014). The court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003). In the instant case, the ‘081 patent specification clearly discloses the same use for the genetically modified mouse as currently claimed. Furthermore, such methods of obtaining nucleotide sequences encoding human variable regions from a transgenic mouse with a modified endogenous heavy chain locus where known in the prior art. At the time of filing, Murphy et al. teaches “knock-in” transgenic mice in which all or part of the endogenous genomic immunoglobulin light chain variable region and/or heavy chain variable region are substituted by homologous recombination for human light chain and/or heavy chain genes respectively (Murphy et al., paragraphs 35-36, 38-44, 46-48, 83, 85, 99, and claims 1-4, and 7-10). Murphy et al. further teaches that direct substitution of the mouse light and heavy chain VJ/VDJ regions with human VJ/VDJ regions using homologous recombination such that all the sequences necessary for proper transcription, recombination, and/or class switching in the mouse genome remain intact (Murphy et al., paragraph 85). For homologous recombination, Murphy teaches that the human VDJ sequences are flanked by homology arms comprising mouse genomic DNA from the mouse heavy chain locus (Murphy et al., Figure 4d). In regards to the light chain, Murphy et al. teaches “knock-in” of the human kappa light chain and/or lambda light chain into the endogenous mouse kappa or lambda light chain variable region respectively (Murphy et al., paragraph 99). Murphy et al. further provides motivation to replace the endogenous V, D, J, genes with the human genes and retain the mouse constant region genes by teaching that antibodies comprising human constant regions in mice have reduced affinity and that the mouse constant region and associated regulatory elements are important for development and optimization of B cell antibody production (Murphy et al., paragraph 80). Most importantly, Murphy et al. teaches that immunization of these transgenic mice generates antibodies comprising human variable regions and mouse constant regions (Murphy et al., paragraphs 46 and 49 of the detailed description). Murphy et al. teaches that human heavy chain and light chain variable region knockin mice can be used to make a human antibody by exposing the mouse to antigenic stimulation, such that the mouse produces an antibody against the antigen, and isolating the DNA encoding the variable regions of the heavy and light chains of the antibody (Murphy et al., paragraph 49 of the detailed description).
Thus, in view of the teachings and motivation provided by Murphy et al. to replace all or part of the endogenous mouse light chain V/J region with human VJ sequences and to replace all or part of the endogenous mouse heavy chain V/D/J region with human V, D, and J sequences, and the further motivation provided by Murphy et al. to utilize such knockin mice to generate nucleotide sequences encoding human heavy chain variable regions comprising immunizing the knockin mouse with an antigen, and isolating a nucleotide sequence encoding a human heavy chain variable domain, it would have been prima facie obvious to the skilled artisan at the time of filing to make a transgenic mouse according to the ‘081 patent claims where the human Vk and Jk sequences replaces all the endogenous mouse light chain VK and JK sequences and wherein the unrearranged “one” human heavy chain VH3 family member gene segment sequence, one or more D gene segment sequences, and one or more J gene segment sequences replace all the endogenous mouse heavy chain V, D, and J gene sequences, and to further immunize such a mouse with antigen to obtain human heavy chain variable domain nucleotide sequences as set forth in instant claims 16 and 29-30 with a reasonable expectation of success.
In so far as applicant’s arguments apply to the modified grounds of rejection necessitated by applicant’s amendments to the claims, it is noted that the applicant argues that the instant claims are method claims for using the composition claimed in U.S. Patent 11,261,248, hereafter referred to as the ‘248 patent, and are non-obvious over the cited patents for the reasons as acknowledged for the issued claims of ‘248 patent which are reiterated in the rebuttal to the 103 obviousness rejection presented in applicant’s response.
In response, the instant rejection is a non-statutory double patenting rejection and is not a 103 rejection. The instant rejection is based on the ‘081 patent claims. The applicant has not presented any arguments regarding the ‘081 patent claims. Further, the instant rejection does not recite Kucherlapati et al. and applicant’s arguments made in regards to the 103 rejection are irrelevant to the grounds of the instant rejection. As such, applicant’s arguments are not found persuasive.
The rejection of amended claims 1-3, 6-13, 15-16, and 23-28 on the ground of nonstatutory double patenting as being unpatentable over 1) claims 1-20 of U.S. Patent No. 9,622,459, hereafter referred to as the ‘459 patent, OR claims 2) claims 1-19 of U.S. Patent No. 10,561,124, hereafter referred to as the ‘124 patent, OR 3) claims 1-21 of U.S. Patent No. 8,697,940, hereafter referred to as the ‘940 patent, OR 4) claims 1-5 and 10-23 of U.S. Patent No. 8,642,835, hereafter referred to as the ‘835 patent, in view of U.S. Patent 6,657,103 (2003), hereafter referred to as Kucherlapati et al., U.S. Patent Application Publication 2014/0212416 (2014), hereafter referred to as Friedrich et al., with an effective filing date of 9/19/2011, Zibellini et al. (2008) Blood, Vol. 112 (11):1175, pages 1-3, and Matsuda et al. (1988) EMBO J., Vol. 7(4), 1047-1051, is withdrawn in view of applicant’s amendments to the claims. Neither the patent claims themselves, nor the specifications of these patents discloses a mouse or rat whose heavy chain locus has a single human VH3 family member gene segment.
Claims 16 and 29-34 are newly rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-46 of U.S. Patent No. 11,666,040, hereafter referred to as the ‘040 patent. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
The ‘040 patent claims recite methods of obtaining nucleotide sequence encoding a human variable domain from an immunized transgenic mouse where the endogenous heavy chain locus of the mouse comprises a single human VH gene segment, one or more DH gene segments, and one or more huma JH gene segments operably linked to the endogenous mouse heavy chain constant region gene using the same method steps recited in the instant claims -see in particular ‘040 patent claims 1, 16-25 and 36-46. The ‘040 patent claims are broader than the instant claims in that the single human VH is not limited to a VH3 family member. However, dependent claims of the ’040 patent limit the single human VH is a group which includes VH3 family members, including all the VH3 family members recited in the instant dependent claims-see ‘040 patent claims 2, 17, and 39. It is further noted that additional dependent limitations of the instant claims are recited in the dependent claims of the ‘040 patent. Thus, the ‘040 patent claims both encompass and specifically recite species of single human VH gene segments from the VH3 family and thus render the instant methods obvious.
Additional Comments
It is noted that obviousness type double patenting has not been applied based on the claims of the following US Patents: US Patent 11,261,248, US Patent 9,932,398, US Patent 10,246,509, US Patent 10,238,093, US Patent 11,559,050, and US Patent 10,432,735. US Patent 9,932,398, US Patent 10,246,509, US Patent 10,238,093, US Patent 11,559,050, and US Patent 10,432,735 are limited to a single human VH which is either VH1-69 or VH 1-2 and thus does not overlap with the instant claims which now limit the single human VH to a VH3 family member. Further, the instant application is a divisional application of US Patent 11,261,248 and thus obviousness type double patenting is prohibited under 35 U.S.C. 121.
No claims are allowed.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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