DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
The instant application is a CON of 17/000,140, now US Pat. No. 11,778,995, which is a CON of 15/804,989, now US Pat. No. 10,785,968, which is a DIV of 14/072,626, now US Pat. No. 9,901,082.
Claims 25-42 are examined in the instant application.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 25-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,778,995 in view of Hansen et al. (2004, European J. Cancer, Vol. 40, pgs. 858-880) since the instant invention generates an identical mouse to be used by the method of screening in ‘995. Further, Hansen et al. teach that at the time of filing it was obvious to use transgenic mouse models for screening candidate drugs for the treatment of cancer.
Further regarding the instant dependent claims they would be obvious over the dependent claims of ‘995 since the ES cells and embryo would be used in the creation of the transgenic mouse that would be used in the method of screening of ‘995.
The instant application was filed as a CON and the court has found that safe harbor does not apply when the continuing application is filed as CON. The court found that safe harbor from an ODP rejection only applies when a continuing application is filed as a DIV. See AMGEN INC., v. F. HOFFMANN-LA ROCHE LTD. 580 F.3d l340; 2009 U.S. App, LEXIS 20409; 92 U.S.P.Q.2D (BNA) 1289.
Claims 25-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 10,785,968 in view of Hansen et al. (2004, European J. Cancer, Vol. 40, pgs. 858-880) since the instant invention generates an identical mouse to be used by the method of screening in ‘968. Further, Hansen et al. teach that at the time of filing it was obvious to use transgenic mouse models for modeling human B cell development and function (see Table 1).
Further regarding the instant dependent claims they would be obvious over the dependent claims of ‘968 since the ES cells and embryo would be used in the creation of the transgenic mouse that would be used in the method of generating a mouse model of human B cell development of ‘968.
The instant application was filed as a CON and the court has found that safe harbor does not apply when the continuing application is filed as CON. The court found that safe harbor from an ODP rejection only applies when a continuing application is filed as a DIV. See AMGEN INC., v. F. HOFFMANN-LA ROCHE LTD. 580 F.3d l340; 2009 U.S. App, LEXIS 20409; 92 U.S.P.Q.2D (BNA) 1289.
Claims 25-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 9,901,082 in view of Hansen et al. (2004, European J. Cancer, Vol. 40, pgs. 858-880) since the instant invention generates an identical mouse that will comprise engrafted hematopoietic cells in ‘082. Further, Hansen et al. teach that at the time of filing it was obvious to use engrafted cells in transgenic mouse models for modeling human B cell development and function (see Table 1).
Further regarding the instant dependent claims they would be obvious over the dependent claims of ‘082 since the ES cells and embryo would be used in the creation of the transgenic mouse claimed in ‘082.
The instant application was filed as a CON and the court has found that safe harbor does not apply when the continuing application is filed as CON. The court found that safe harbor from an ODP rejection only applies when a continuing application is filed as a DIV. See AMGEN INC., v. F. HOFFMANN-LA ROCHE LTD. 580 F.3d l340; 2009 U.S. App, LEXIS 20409; 92 U.S.P.Q.2D (BNA) 1289.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 25, 28, 31, 34, 37 and 40 are rejected under pre-AIA 35 U.S.C. 103(a) as being obvious over Strowig et al. (2011, PNAS, Vol. 108, pgs. 13218-13223) in view of Wang et al. (U.S. Patent No. 8,878,001 B2, filed 10/29/2012) and King et al. (2008, Clinical Immunology, Vol. 126, pgs. 303-314).
The applied reference has a common inventor with the instant application. Based upon the earlier effective U.S. filing date of the reference, it constitutes prior art under pre-AIA 35 U.S.C. 102(e). This rejection under pre-AIA 35 U.S.C. 103(a) might be overcome by: (1) a showing under 37 CFR 1.132 that any invention disclosed but not claimed in the reference was derived from the inventor of this application and is thus not an invention “by another”; (2) a showing of a date of invention for the claimed subject matter of the application which corresponds to subject matter disclosed but not claimed in the reference, prior to the effective U.S. filing date of the reference under 37 CFR 1.131(a); or (3) an oath or declaration under 37 CFR 1.131(c) stating that the application and reference are currently owned by the same party and that the inventor (i.e., the inventive entity) named in the application is the prior inventor under pre-AIA 35 U.S.C. 104 as in effect on March 15, 2013, together with a terminal disclaimer in accordance with 37 CFR 1.321(c). This rejection might also be overcome by showing that the reference is disqualified under pre-AIA 35 U.S.C. 103(c) as prior art in a rejection under pre-AIA 35 U.S.C. 103(a). See MPEP § 706.02(l)(1) and § 706.02(l)(2).
Regarding claims 25, 28, 37 and 40, Strowig et al. teach a method of generating a Rag2 -/- γc -/- knockout mouse, via an ES cell, whose genome comprises a nucleic acid encoding human SIRPa operably linked to the human SIRPa promoter, wherein the said nucleic acid is randomly integrated (see Abstract and pg. 13218 col. 2 last parag. bridge pg. 13219 col. 1 parag. 1).
Regarding claims GM-CSF, IL-3 and TPO, Strowig teaches that “Recently, several approaches have been used to improve human cell engraftment and the unbalanced lineage differentiation in CD34+ cell engrafted mice. These include transient approaches such as hydrodynamic injection of plasmid DNA (34), injections of cytokines, and infections of mice or CD34+ cells with lentiviruses (35–37). Alternatively, transgenic expression of human MHC molecules has been demonstrated to improve the development of antigen-specific immune responses in vivo (38–40). Nonetheless, overexpression of cytokines might also have detrimental side effects due to the unphysiological expression such as in mice transgenic for SCF, GM-CSF, and IL-3 (41). An alternative approach to provide human growth factors in vivo is to genetically engineer mice and replace the mouse genes with their human counterparts resulting in their expression in the appropriate niche at physiological levels. Indeed, faithful replacement of mouse GM-CSF and IL-3 as well as thrombopoietin (TPO) by our group has resulted in improved development of human macrophages in the lung and HSC and HPC maintenance in the bone marrow, respectively (23, 24). Notably, in human TPO knockin mice, despite a highly increased engraftment level of stem and progenitor cells in the bone marrow, no changes were observed in the periphery, demonstrating the existence of limiting factors in the periphery such as destruction by phagocytes. With the hSIRPa-DKO mice, we have generated a strain that combines superior engraftment level and the possibility of long-term genetic manipulations to further enhance the murine host” (pg. 13222 col. 1 parag. 2 bridge col. 2 parag. 1).
Strowig et al. does not teach:
an immunodeficient human SIRPa expressing mouse that also expresses human IL-6;
a Rag2 -/- IL-2rg -/- knockout mouse
(i) Wang et al. teach:
“Genetically modified mice are provided that express a human IL-6 and/or a humanized IL-6 receptor from endogenous mouse loci, wherein the endogenous mouse IL-6 gene and/or the endogenous mouse IL-6 receptor gene have been replaced with a human IL-6 gene and/or a human sequence comprising a sequence that encodes an ectodomain of a human IL-6 receptor. The genetically modified mice express the human IL-6 and/ or humanized IL-6 receptor from humanized endogenous loci that are under control of mouse promoters and/or mouse regulatory elements. The replacement(s) at the endogenous mouse loci provide non-human animals that
express human IL-6 and a humanized IL-6 receptor in a manner that does not result in the panoply of substantial pathologies observed in IL-6 transgenic mice known in the art." (col. 10, lines 58-67 bridge col. 11 lines 1-5).
Wang continues to teach that “the inventors demonstrate that a replacement with human sequence at an endogenous locus under control of endogenous regulatory elements provides a physiologically appropriate expression pattern and level that results in a useful humanized animal whose physiology with respect to the replaced gene are meaningful and appropriate and context of the humanized animal's physiology.” (col. 11 lines 37-43).
Wang continues to teach that “IL-6 in humans mediates the acute phase response, hematopoiesis, B cell differentiation, T cell activation, growth and/ or differentiation and/ or activation of a variety of cell types (e.g., hepatocytes, fibroblasts, endothelial cells, neurons, pituitary cells, lymphomas, myelomas, breast carcinomas, NK cells, macrophages, osteoclasts, etc.)” (col. 9 lines 8-13).
Regarding an embryo in claims 31 and 34, Wang teaches that they can generate a mouse embryo which comprises the human IL-6 gene (col. 6 lines 1-19).
Regarding knocking out IL-2rg -/-, King et al. teach that “Recent breakthroughs in the generation of improved recipients for human hematopoietic cell engraftment have been based on immunodeficient mice bearing a targeted mutation in the IL-2 receptor common gamma chain (Il2rγ) locus” (pg. 304, col. 1 parag. 3 lines 1-4).
King continues to teach a NOD-scid Il2rγnull mouse and that “Immunodeficient NOD-scid
mice bearing a targeted mutation in the IL2 receptor common gamma chain (Il2rγnull) readily engraft with human stem cells” (Abstract lines 1-2).
Thus the ordinary artisan would have it prima facie obvious at the time of filing to modify the teachings of Strowig regarding a Rag2 -/- γc -/- knockout mouse expressing human SIRPa with the teachings of Wang regarding replacing the endogenous mouse IL-6 gene with a human IL-6 gene and with the teachings of King regarding the benefits of knocking out the IL-2rg gene in a mouse to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to make such a combination since Strowig teaches that to improve human cell engraftment and the unbalanced lineage differentiation in CD34+ cell engrafted mice, human growth factors can be provided in vivo in genetically engineered mice by replacing the mouse genes with their human counterparts which improves development of human macrophages in the lung and HSC and HPC maintenance in the bone marrow. Thus incorporating human genes such as, IL-3, IL-6 and TPO, for example, would have been an obvious and advantageous modification of the mouse of Strowig. Further motivation is provided by King to substitute a knockout of the IL-2rg gene for γc since King teaches that knocking out IL-2rg results is an improvement in immunodeficient mice for engrafting human cells.
One of skill in the art would have had a reasonable expectation of making the claimed genetically-modified mouse as the technology for homologous recombination to make genetically-modified mice was well known at the time of filing.
Thus the cited art provides the requisite teaching and motivations to make and use the inventions as claimed.
Claims 26, 27, 29, 30, 32, 33, 35, 36, 38, 39, 41 and 42 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Strowig et al. (2011, PNAS, Vol. 108, pgs. 13218-13223) in view of Wang et al. (U.S. Patent No. 8,878,001 B2, filed 10/29/2012) and King et al. (2008, Clinical Immunology, Vol. 126, pgs. 303-314) as applied to claims 25, 28, 31, 34, 37 and 40 above, and further in view of Bernier et al. (2001, Exp. Toxic Pathol., Vol. 53, pgs. 165-173) and NCBI nucleotide sequence encoding human M-CSF, 2005).
Strowig, Wang and King are relied upon above in teaching a method of a making a genetically modified mouse.
Strowig, Wang and King do not teach:
Expressing M-CSF.
Regarding expressing M-CSF, Bernier et al. teach a transgenic mouse
overexpressing mouse M-CSF (pg. 166 col. 2 parag. 2 and Fig. 1) and teaches (citations omitted) “Macrophage colony stimulating factor (M-CSF) stimulates the proliferation, activation and differentiation of macrophage precursor cells and promotes the activation and proliferation of mature mouse macrophages. M-CSF has been reported to influence various functions of mature mononuclear phagocytes, and is also a potent chemoattractant” (pg. 165 col. 1 last two lines bridge col. 2 lines 1-7).
While Bernier used the murine M-CSF sequence to generate their transgenic mouse, at the time of filing the human nucleotide sequence encoding M-CSF was known as set forth in the attached sequence report from NCBI.
Thus the ordinary artisan would have it prima facie obvious at the time of filing to modify the teachings of Strowig, Wang and King regarding a Rag2 -/- γc -/- knockout mouse expressing human SIRPa with the teachings of Bernier regarding overexpressing M-CSF in a mouse to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to make such a combination since Bernier teaches that M-CSF expression is involved in the immune system through macrophage development.
One of skill in the art would have had a reasonable expectation that human M-CSF could be expressed in the transgenic mouse of Strowig, Wang and King since Bernier teaches successful expression of M-CSF in a mouse and that the human nucleotide sequence encoding M-CSF was known at the time of filing.
Thus the cited art provides the requisite teaching and motivations to make and use the inventions as claimed.
Conclusion
No claims are allowed.
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/DAVID A MONTANARI/Examiner, Art Unit 1632