DETAILED ACTION
Applicant’s amendment and response received on 12/11/25 has been entered. Claims 1-3, 6-13, 15-16, and 23-28 remain pending and under examination in this application based on the elected species of VH1-2 or VH1-69 as the single human VH segment. 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 Interpretation
The claims currently recite a rat or mouse having a restricted immunoglobulin heavy chain locus which has “a Vh gene segment repertoire consisting of multiple copies of a single human Vh gene segment”. The applicant previously cited several paragraphs within the instant specification as providing support for this limitation-see the response filed on 9/12/25. In particular, applicant has pointed to paragraph 9 which is quoted as disclosing:
Loci are provided that are capable of rearranging and forming a gene encoding a heavy chain variable domain... Modified loci that comprise multiple copies of a single VH gene segment, including wherein one or more of the copies comprises a polymorphic
variant, are provided. Modified loci that comprise multiple copies of a single VH
segment, operably linked with one or more D segments and one or more J segments,
operably linked to a non-human immunoglobulin constant sequence, e.g., a mouse or rat
sequence, are provided. Non-human animals comprising such humanized loci are also
provided. (emphasis added by examiner)
From this paragraph of the specification, it can be seen that a “multiple copies” of a single VH gene segment encompasses “copies” which are polymorphic variants of the single VH gene segment. The applicant agrees with this interpretation of “multiple copies” as including polymorphic variants as evidenced by page 8 of 23 of applicant’s response or 9/12/25 which states, “[a]ccordingly, a skilled artisan would understand that “a Vh gene segment repertoire consisting of multiple copies of a single human Vh gene segment” encompasses a Vh gene segment repertoire that consists of multiple copies of an identical human Vh gene segment, multiple polymorphs of the single human Vh gene segment, and any combination thereof”. Thus, in accordance with applicant’s statements on record as to the broadest reasonable interpretation of the claims, the phrase “a Vh gene segment repertoire consisting of multiple copies of a single human Vh gene segment” has been interpreted to encompass a Vh gene segment repertoire that consists of multiple polymorphs of a single human Vh gene segment”.
Claim Rejections - 35 USC § 103
The rejection of 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 maintained. Applicant’s amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
The applicant reiterates their previous arguments that the claims recite a rat or mouse having a restricted immunoglobulin heavy chain locus which has “a Vh gene segment repertoire consisting of multiple copies of a single human Vh gene segment”, and that none of the references individually or in combination teach this limitation. The applicant also argues that both independent claims 1 and 26 recite, “wherein the only immunoglobulin heavy chain variable region expressed by the art or mouse comprises the single human Vh gene segment”. The applicant further argues that 1) Kucherlapati did not reduce to practice a transgenic mouse or rat comprising a heavy chain locus comprising a SPEI fragment comprising a single VH 6-1 gene segment or show that such a transgenic mouse or rat would exhibit a diversified antibody repertoire, 2) that Kucherlapati only reduced to practice the xenomice described in detail in WO 94/02602, and that WO 94/02602 describes xenomice as having 5 different VH gene segments, and 3) that WO 94/02602 while disclosing the SPEI fragment, also did not reduce to practice a transgenic mouse or rat comprising a heavy chain locus comprising a SPEI fragment comprising a single VH 6-1 gene segment. The applicant further argues that Friedrich et al. doesn’t teach a heavy chain locus, but rather the insertion of a VH1-69 segment, and polymorphic variants thereof, in a light chain locus, and does not teach or reduce to practice a transgenic mouse or rat with a heavy chain locus comprising a single a VH1-69 segment, and polymorphic variants thereof. The applicant also argues that Friedrich et al. exemplifies a heavy chain locus that while comprising several polymorphic variant gene segments of VH1-69 also includes endogenous heavy chain variable region gene segments. Thus, the applicant concludes that none of Kucherlapati et al., Murphy et al., and Friedrich et al., alone or in combination teaches or enables the generation of transgenic mice or rats with the claimed structure and capacity for generation of a diversified antibody repertoire.
In response, it is first noted that in accordance with applicant’s statements as to the broadest reasonable interpretation of the claims, the phrase “a Vh gene segment repertoire consisting of multiple copies of a single human Vh gene segment” has been interpreted to encompass a Vh gene segment repertoire that consists of multiple polymorphs of a single human Vh gene segment”. See also the claim interpretation section above. It is also noted that the claims under examination do not recite any functional limitations for the claimed transgenic mouse or rat products other than that the only heavy chain variable region expressed in the mouse or rat comprises the single human VH gene segment. The claimed products do contain any limitations the level of antibody diversity in an antibody repertoire present in the mouse or rat. Further, the methods of immunizing the mouse or rat also do not include any functional limitation regarding the diversity of antibodies present in an immunized mouse.
Applicant’s arguments concerning Kucherlapati et al. are not persuasive. The majority of applicant’s argument concern the teachings of Kucherlapati et al., and to a lesser extent those of Friedrich et al. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). The Kucherlapati Patent cited in this rejection clearly includes a description of the SPEI fragment which comprises a single VH6-1 gene segment, see in particular Figure 20. Applicant’s argument as to the lack of enablement in Kucherlapati appears to be based solely on a lack of reduction to practice of a mouse containing the aforementioned SPEI fragment. However, a reference may enable one of skill in the art to make and use a compound even if the author or inventor did not actually make or reduce to practice that subject matter. Bristol-Myers, 246 F.3d at 1379; see also In re Donohue, 766 F.2d at 533. Kucherlapati et al., as noted by applicant, did indeed successfully generate transgenic mice whose genome comprises human VH, JH, and DH gene segments. The teachings of Kucherlapati et al. provide enablement for generating alternative humanized heavy chain loci, as the techniques utilized to introduce the exogenous human genetic material into the mouse genome in the working examples are the same techniques which would be used to modify the genome to incorporate the SPEI fragment disclosed by Kucherlapati et al. Thus, it is maintained that Kucherlapati et al. teaches and enables a transgenic mouse whose endogenous heavy and light chain loci have been inactivated and whose genome further comprises a transgene comprising a human genomic unrearranged heavy chain locus SPEI fragment comprising a single VH6-1 gene segment, all of the DH gene segments, all of the JH gene segments, and a human constant region gene, and a transgene comprising an unrearranged human kappa light chain locus comprising multiple VK and JK gene segments, and methods of using the transgenic mice to produce human antibodies wherein the methods include steps of immunizing the mouse, obtaining B cells/splenocytes, making a hybridoma, and recovering antibody from the cells or recovering variable region sequences, both heavy and light chain, from the cells (Kucherlapati et al., Figure 20, claims 1-4).
The applicant further argues in regards to Kucherlapati et al. that Kucherlapati et al. does not teach or exemplify to targeted replacement of the endogenous heavy chain variable region gene segments in the mouse with the transgene comprising a human genomic unrearranged heavy chain locus SPEI fragment comprising a single VH6-1 gene segment, all of the DH gene segments, all of the JH gene segments. Applicant’s argues that Kucherlapati only taught random integration. In response, Kucherlapati et al. is not read in a vacuum. The rejection relies on the combination of teachings of Kucherlapati et al., Murphy et al., and Friedrich et al. Murphy et al. was cited for providing the teachings for targeted integration and replacement of endogenous heavy and light chain variable region sequences with human heavy and light chain sequences respectively. Applicant’s arguments do not specifically address the teachings of Murphy et al. Murphy et al. was specifically cited to supplement Kucherlapati et al. by teaching “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). 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 is maintained that 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 Kucherlapati et al. wherein the human Vk and Jk sequences replaces all the endogenous mouse light chain VK and JK sequences and wherein and unrearranged single human heavy chain VH gene segment sequence, D gene segment sequences, and 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 with a reasonable expectation of success.
The rejection of record further acknowledged that Kucherlapati et al. and Murphy et al. differ from the instant claims but not teaching that the human unrearranged heavy chain locus comprises multiple “copies” of a single VH gene segment, all of the DH gene segments, and all of the JH gene segments which replace the mouse endogenous heavy chain V, D, and J gene sequences in the genome of the mouse. Again, “copies” encompasses multiple polymorphic variants of the single VH1-69 gene segment. Friedrich et al. was cited to supplement Kucherlapati et al. and Murphy et al. by teaching similar transgenic mice whose genome comprises a single human heavy chain V gene segment, one or more D gene segments, and one or more J gene segments, and in particular a genetically modified locus in a mouse which, “comprises or consists of one human VH gene segment; optionally germline VH and one or more polymorphic variants thereof, eg, where each polymorphic variant differs from the germline VH nucleotide sequence by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 positions” (Friedrich et al., paragraphs 11, 18, and 22, see also Figure 1). Friedrich et al. further provides motivation for expressing more than one polymorphic variant of a single human VH gene segment which is VH1-69 by teaching, “[a]n example of constructing an immunoglobulin locus comprising VH1-69 and polymorphic variants is given below. By using a particular gene segment (e.g. one commonly found in human antibodies raised in humans against an infection or other condition) and one or more polymorphic variants thereof, it is possible to provide a repertoire of genes and yet still bias the antibody gene repertoire to a gene segment that is relevant to the disease (eg, an infectious disease, such as a bacterial or viral disease, eg, influenza). This provides a useful pool of genes from which to ultimately generate and isolate a lead antibody for a therapeutic/prophylactic against the disease in question” (Friedrich et al. paragraph 18). Applicant’s arguments that Friedrich et al. either 1) teaches the inclusion of the single VH1-69 gene segment or one or more polymorphic variants thereof in a light chain locus rather than a heavy chain locus, or 2) does not teach a heavy chain locus comprising a single VH1-69 gene segment or more than one polymorphic variant of VH1-69 because the transgenic mice exemplified in Friedrich include additional heavy chain gene segments is not persuasive as Friedrich et al. was also not cited in a vacuum, and was not relied upon for the structure of the heavy chain locus. Kucherlapati et al. and Murphy et al., as discussed in detail above, provided the teachings, motivation, and a reasonable expectation of success in making a transgenic mouse according to Kucherlapati et al. wherein the human Vk and Jk sequences replaces all the endogenous mouse light chain VK and JK sequences and wherein and unrearranged single human heavy chain VH gene segment sequence, D gene segment sequences, and 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. Friedrich et al. was cited for providing motivation to select the VH1-69 gene segment as the single VH gene segment, and also to provide motivation to further include more than one polymorphic VH gene segment of VH1-69. Friedrich et al. provides this motivation for expressing more than one polymorphic variant of a single human VH gene segment which is VH1-69 by teaching, “[a]n example of constructing an immunoglobulin locus comprising VH1-69 and polymorphic variants is given below. By using a particular gene segment (e.g. one commonly found in human antibodies raised in humans against an infection or other condition) and one or more polymorphic variants thereof, it is possible to provide a repertoire of genes and yet still bias the antibody gene repertoire to a gene segment that is relevant to the disease (eg, an infectious disease, such as a bacterial or viral disease, eg, influenza). This provides a useful pool of genes from which to ultimately generate and isolate a lead antibody for a therapeutic/prophylactic against the disease in question” (Friedrich et al. paragraph 18). That Friedrich et al. disclosed modified light chain loci, or alternative heavy chain loci comprising the VH1-69 gene segment does not negate the motivation to utilize the VH1-69 gene segment, or more than one polymorphic variant of VH1-69 as the single VH gene segment in transgenic mice taught by Kucherlapati et al. in view of Murphy et al.
Therefore, it is maintained that in view of the motivation provided by Friedrich et al. to introduce a single human VH gene segment such as a single VH1-69 gene segment, or the VH1-69 gene segment and several polymorphic variants of VH1-69 into the mouse immunoglobulin locus in order to bias the antibody gene repertoire to a gene segment commonly found in humans and/or relevant to disease, it is maintained that would have been prima facie obvious to the skilled artisan at the time of filing to modify the heavy chain locus present in the mouse as taught by Kucherlapati et al. in view of Murphy et al. to contain either a single VH1-69 gene segment, or several polymorphic variants of the VH 1-69 gene segment, with a reasonable expectation of success.
Double Patenting
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 1-16 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. Applicant’s arguments have been fully considered but have not been found persuasive for reasons discussed in detail below.
The applicant argues that their arguments made in regards to the teachings of Kucherlapati, or Friedrich et al., as part of their response to the 103 rejection above, overcome this double patenting rejection. Kucherlapati et al. is not a part of this rejection. Applicant’s arguments regarding Friedrich et al. were not found persuasive, see above for a detailed discussion of the teachings of this reference. Further, the primary basis of the double patenting rejection is the claims allowed in each of these patents. Applicant does not address these claims, or the teachings of Zibellini et al.
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. Applicant’s arguments have been fully considered but have not been found persuasive for reasons discussed in detail below.
The applicant argues that their arguments made in regards to the teachings of Kucherlapati, or Friedrich et al., as part of their response to the 103 rejection above, overcome this double patenting rejection. Kucherlapati et al. is not a part of this rejection. Applicant’s arguments regarding Friedrich et al. were not found persuasive, see above for a detailed discussion of the teachings of this reference. Further, the primary basis of the double patenting rejection is the claims allowed in each of these patents. Applicant does not address these claims, or the teachings of Zibellini et al.
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. Applicant’s arguments have been fully considered but have not been found persuasive for reasons discussed in detail below.
The applicant argues that their arguments made in regards to the teachings of Kucherlapati, or Friedrich et al., as part of their response to the 103 rejection above, overcome this double patenting rejection. However, applicant’s arguments regarding Kucherlapati et al., or Friedrich et al. were not found persuasive, see above for a detailed discussion of the teachings of these references. Further, the basis of the double patenting rejection is the claims allowed in each of these patents. Applicant does not address these claims, or the teachings of Zibellini et al.
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 maintained. Applicant’s arguments have been fully considered but have not been found persuasive for reasons discussed in detail below.
The applicant argues that their arguments made in regards to the teachings of Kucherlapati, or Friedrich et al., as part of their response to the 103 rejection above, overcome this double patenting rejection. However, applicant’s arguments regarding Kucherlapati et al., or Friedrich et al. were not found persuasive, see above for a detailed discussion of the teachings of these references. Further, the basis of the double patenting rejection is the claims allowed in each of these patents. Applicant does not address these claims, or the teachings of Zibellini et al. or Matsuda et al.
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634