Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 September 29, 2025, has been entered.
Election/Restrictions
Applicant’s election without traverse of Group II (Claims 15, 19, and 32-33; drawn to a human G-CSF knock-in rodent further deficient in Fcer1g and Fcgr2b) in the reply filed on September 24, 2024, is acknowledged.
Claims 1, 5, 20-21, 24, 28, and 30-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups II and III), there being no allowable generic or linking claim.
DETAILED ACTION
The amended claims filed on September 29, 2025, have been acknowledged. Claims 2-4, 6-14, 16-18, 22-23, and 29 were cancelled. Claims 32-33 are new. In light of the Applicant’s elected invention, claims 1, 5, 20-21, 24-28, and 30-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 15, 19, and 32-33 are pending and examined on the merits.
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).The applicant claims foreign priority from JP2019-062919 filed on March 28, 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received September 27, 2021. Receipt is acknowledged of a certified English translation of said foreign patent application on February 3, 2025. Applicant has not complied with one or more conditions for receiving priority to an earlier filing date under 35 U.S.C. 119(a)-119(d) for the reasons as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original foreign application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. JP2019-062919 filed on March 28, 2019, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. This provisional application does not provide information related to an immunodeficient rodent with knock-in of human G-CSF at a G-CSF receptor locus and wherein the rodent is further deficient in Fcer1g and Fcgr2b. However, Application No. PCT/JP2020/013635, filed on March 26, 2020, did provide the above information. Therefore, claims 15, 19, and 32-33 receive domestic benefit from Application No. PCT/JP2020/013635, filed on March 26, 2020.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 19 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 19 recites the limitation "the humanized rodent according to claim 15" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 15 does not recite “a humanized rodent” anywhere within the claims nor does claim 15 recite that the rodent is a humanized rodent, only that it is an immunodeficient rodent. Relatedly, claims 32-33 recite “the immunodeficient rodent of claim 15”. As Claims 15 and 32-33 only refer to the rodent as an immunodeficient rodent and claim 19 is the only one to refer to it as a humanized rodent, it is unclear whether claim 19 is referring to the same rodent as claim 15 or a different one. It is recommended that Applicant use one term to refer to the rodent of claim 15, either an immunodeficient rodent or a humanized rodent for each of the claims.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 15 and 18-19 under 35 U.S.C. 103 as being unpatentable over Ito et al. (Poster PS2-1-2. October 2018; referenced in IDS), Inoue (J Immunol 179: 764–774 2007), Bruhns et al. (Immunological Reviews 268: 25–51. 2015), and Kruijf et al. (Human Immunology 68: 368–374. 2007) is withdrawn in favor of a new rejection based on the combined teachings of Ito 2018, Li, Ito 2012, Smith, Inoue, and Bruhns as discussed below.
The prior rejection of claims 15 and 18 under 35 U.S.C. 103 as being unpatentable over Liu et al. (Blood 95: 3025-3031.2000), Carstanjen et al. (Transfusion 45: 1192-1200. 2005), Zhang et al. (Biotechnology Letters 23: 1249-1255. 2001), Inoue (J Immunol 179: 764–774 2007), Bruhns et al. (Immunological Reviews 268: 25–51. 2015), and Kruijf et al. (Human Immunology 68: 368–374. 2007) is withdrawn in favor of a new rejection based on the combined teachings of Ito 2018, Li, Ito 2012, Smith, Inoue, and Bruhns as discussed below.
The prior rejection of claims 15 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (Blood 95: 3025-3031.2000), Carstanjen et al. (Transfusion 45: 1192-1200. 2005), Zhang et al. (Biotechnology Letters 23: 1249-1255. 2001), Inoue (J Immunol 179: 764–774 2007), Bruhns et al. (Immunological Reviews 268: 25–51. 2015), and Kruijf et al. (Human Immunology 68: 368–374. 2007), as applied to claims 15 and 18, and further in view of Ramakrishna et al. (PLoS Pathogens 14: 1-27. 2018) is withdrawn in favor of a new rejection based on the combined teachings of Ito 2018, Li, Ito 2012, Smith, Inoue, and Bruhns as discussed below.
New Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 15, 19, and 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over Ito et al. (Poster PS2-1-2. October 2018; referenced in IDS), Li et al. (Mol Cancer Ther; 18: 780-787. 2019, previous art of record), Ito et al. (Experimental Hematology 40: 953–963. 2012), Smith et al. (PNAS 109: 6181-6186. 2012), Inoue (J Immunol 179: 764–774 2007), and Bruhns et al. (Immunological Reviews 268: 25–51. 2015). This is a new rejection. Applicant’s traversal has been fully considered but is moot in response to the new rejection.
Regarding claim 15, Ito 2018 teaches that they generated humanized G-CSF knock-in mouse wherein the knock-in occurs at the G-CSFR locus and teaches that G-CSFR expression is abolished in granulocytes while human G-CSF is highly expressed (Section 3). Ito 2018 teaches that humanized mice, in which the human hematopoietic system is reconstituted in immunodeficient mice, are a useful animal model for studying human hematology and immunology. Furthermore, Ito teaches that although human T or B lymphocytes significantly differentiate in human HSC-transferred humanized mice, myeloid lineage cells, especially granulocytes, do not fully develop in them. In this study, they generated a novel NOG mouse strain, human G-CSF knock.in mouse, to induce mature human neutrophils in their circulation. During weeks 4-12 of transplantation, human neutrophils and monocytes were significantly differentiated and detected in the peripheral blood of hG-CSF Kl mice compared to conventional NOG mice (abstract and Sections 3-4). Ito teaches that they transplanted 104-105 human HSPCs into their G-CSF knock-in mouse after irradiating the mouse and generated circulating neutrophils (Section 4).
Ito does not teach wherein the G-CSF gene knock-in mouse is also deficient in Fcer1g and Fcgr2b.
However, Li teaches that NSG and NOG mice undergo rapid clearance of therapeutic antibodies. Li teaches that macrophages that express FcγRs may be responsible for the antibody clearance (abstract, page 784, column 2, paragraphs 4-5, and Figure 4). Li teaches that before entering clinical trials, the efficacy and toxicity of antibody drugs are studied in various in vitro and in vivo models. Most oncology drugs are tested using xenografts, which are implanted in immuno-deficient mouse strains such as NSG mice. Compared with wild-type mice, these mice lack one or more types of immune cells, allowing the engraftment of foreign tumor cells. Among them, NSG mice are considered the most immune-compromised, because they lack mature T cells, B cells, and natural killer (NK) cells. They also have defective macrophages and dendritic cells due to impaired IL2R signaling (page 780, column 1, paragraph 2).
Although Li did not examine NOG mice for FcγR expression, Ito 2012 teaches that NOG mice lack T, B, and natural killer cells but still comprise macrophages with reduced function, similar to NSG mice (page 953, column 1, paragraph 1-column 2, paragraph 1). Therefore, as NOG and NSG mice similarly lack mature T cells, B cells, and natural killer (NK) cells and NOG mice have similar antibody clearance as NSG mice, it is reasonable to conclude that NOG mice also have macrophages that express FcγRs.
Furthermore, Li and teaches that humanized mice derived from immunodeficient mice are adopted to study infectious disease, cancer, and graft versus host disease. Their study shows that the study of therapeutic antibodies may have been penalized due to macrophages that express FcγRs may be responsible for the antibody clearance. However, one can circumvent the caveat by using transgenic strains containing human FcRn or FcgR genes and serve as better animal models for preclinical evaluation of therapeutic antibodies (abstract and page 786, column 1, paragraph 2). Li cites to Smith for teaching one of the mouse transgenic strains containing human FcRn or FcgR genes.
Smith teaches that they developed a mouse model in which all murine FcγRs have been deleted and human FcγRs, encoded as transgenes, have been inserted into the mouse genome resulting in recapitulation of the unique profile of human FcγR expression. These human FcγRs are shown to function to mediate the immunomodulatory, inflammatory, and cytotoxic activities of human IgG antibodies and Fc engineered variants and provide a platform for the detailed mechanistic analysis of therapeutic and pathogenic IgG antibodies (abstract). Attempts to model huIgG interactions with human FcγR-expressing cells in vitro fail to mirror the diversity of cellular populations that may be required for an in vivo response. Therefore, new systems to study the in vivo function of the huFcγR system and the biological effects of engaging the activating and inhibitory huFcγRs by IgG are required. Furthermore, the increasing number of Ab-based therapeutics being developed for the treatment of neoplastic, infectious, and autoimmune diseases requires a system in which evaluation of the consequences of huFcγR interactions be addressed. The FcγR humanized mice recapitulate huFcγR expression patterns and expression levels and are functional in a variety of huIgG-mediated models of inflammation, cytotoxicity, and tumor clearance (page 6181, column 2, paragraph 1).
Smith does not identify whether their knockout mouse model lacks mFcεRI. However, Inoue teaches a FCRγ-/- mouse (abstract) which the instant specification identifies that the FCRγ-/- mice of Inoue are FcR KO mice deficient in Fcer1g and Fcgr2b (Example 2). Additionally, Bruhns teaches that FCRγ-/- mice have abrogated expression of mFcγRI, mFcγRIII, mFcγRIV, and mFcεRI (page 28, column 2, paragraph 3-page 29, column 1, paragraph 1). Inoue teaches that they mated their FCRγ-/- mice with immunodeficient NOD mice and were able to generate successfully progeny for experimentation (whole document).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the G-CSF knock-in mouse of Ito with the FCRγ-/- mouse of Inoue to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to combine with a reasonable expectation of success because Ito 2018, Li, and Smith each teach that humanized immunodeficient mice are commonly used to recapitulate human immune systems to assess human immunology in relation to infectious diseases in an animal model and Li and Smith teach examining the efficacy of antibodies for treating various disorders, such as cancer and infectious diseases in humanized mice.
Furthermore, Li provides evidence that NOG mice comprise macrophages that express FcγRs that may be responsible for rapid antibody clearance. However, Li specifically identifies that one can circumvent this issue by using transgenic strains containing human FcRn or FcgR genes and serve as better animal models for preclinical evaluation of therapeutic antibodies and cites to Smith for teaching one of the mouse transgenic strains containing knockout of all murine FcγRs and insertion of human FcγRs into the mouse genome resulting in recapitulation of the unique profile of human FcγR expression. Similarly, Inoue teaches a FCRγ-/- mouse that is deficient in Fcer1g and Fcgr2b and has already been previously used to generate immunodeficient mice lacking FCRγ expression.
Additionally, Ito 2018 teaches that although human T or B lymphocytes significantly differentiate in human HSC-transferred humanized mice, myeloid lineage cells, especially granulocytes, do not fully develop in them. In this study, they generated a novel NOG mouse strain, human G-CSF knock.in mouse, to induce mature human neutrophils in their circulation. During weeks 4-12 of transplantation, human neutrophils and monocytes were significantly differentiated and detected in the peripheral blood of hG-CSF Kl mice compared to conventional NOG mice.
Therefore, it would have been obvious that one of ordinary skill in the art could combine the mice of Ito 2012 with the FCRγ-/- mice of Inoue and transgenic expression of human FCRγ genes as Li has already discussed the need for combining immunodeficient mice with knockout of mouse FCRγ genes and knockin of human FCRγ genes to produce a better animal model for translation to humans and the combination of mutations produce a mouse model that more accurately recapitulates the human immune system when humanized through better differentiation of myeloid cells and recapitulation of huFcγR expression patterns and expression levels that are functional in a variety of huIgG-mediated models of inflammation, cytotoxicity, and tumor clearance, Furthermore, this allows for better assessment of the efficacy of human antibodies to treat cancer or infection in an in vivo model. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 19, Ito teaches that their mouse would be useful to study innate host defense in human against bacterial infection (abstract). As such, Ito specifically contemplates that these mice could be infected with a bacterium to examine innate immunity.
Regarding claims 32-33, Ito 2018, as stated supra, teaches that they transplanted 104-105 human HSPCs into their G-CSF knock-in mouse after irradiating the mouse and generated circulating neutrophils (Section 4). As the human neutrophils are circulating are circulating in the irradiated G-CSF knockin mice, an immune response to the neutrophils was inactivated. Otherwise, there would be no neutrophils, as seen in the control NOG mice (Section 4).
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631