DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-3, 5, 8-9, 12, 14, 17, 20, 22-23, 25, 27-29, 32-33, 35, and 37 were previously pending.
Receipt is acknowledged of the amendments to the claims filed on 16 March, 2026. Claims 1, 2, 9, 12, 14, 17, 22, 23, 27, and 28 are amended. Claims 3, 8, and 25 are cancelled.
Applicant’s election without traverse of the invention of group I drawn to a method of making a primatized rodent or swine in the reply filed on 09 September, 2025 was previously acknowledged. Claims 29, 32-33, 35, and 37 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Therefore, claims 1-2, 5, 9, 12, 14, 17, 20, 22-23, and 27-28 are pending and are the subject of the present Official Action.
Priority
The present application claims priority to a United States Provisional Application No. 63/240,257 filed: 02 September, 2021. The earliest possible priority for the instant Application is 02 September, 2021.
Drawings
The drawings remain objected to because many of them are out of focus to the point of illegibility. Specifically, all of Fig. 5, Fig. 8A, Fig. 8B, Fig. 9C-F and J, Fig. 10, Fig. 12, Fig. 13A, Fig. 15B-C, Fig. 16A-D, Fig. 18A, C-D and F-G, Fig. 20A, Fig. 21B, Fig. 24A-B, Fig. 25A and D, and Fig. 28 are out of focus and illegible. Further, Fig. 8A, and 9A should to be rotated 90 degrees to the right. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Applicant stated that replacement drawings were submitted (Remarks, page 5). However, no such replacement drawings have been received. Therefore, Applicant’s response submitted on 16 March, 2026 is incomplete.
Claim Objections
Claim 1 remains objected to because of the following informalities: Amended claim 1 recites “the at least one portion of the thymus is 0.05 mm x 3 mm to 1 mm x 1 mm”. Both dimensional terms on either end of the continuum presented should be in either ascending or descending order. For example: 0.05 mm x 1 mm to 1 mm x 3 mm. Appropriate correction is required.
Claims 22-23 remain objected to because of the following informalities: Amended claim 22 recites “a a” before “NOG”. The claim should recite “a” only once. In addition, claims 22 and 23 have been amended to spell out abbreviations or acronyms but the claims were submitted in a form which renders the recitations illegible. Specifically, the amended language is in light grey and out of focus rendering the superscript information illegible. It is advised that Applicant submit marked-up copies of the claims without any change in color to the marked-up language. Appropriate correction is required.
Examiner’s Comment
Throughout the present Official Action, where reference is made to the instant specification, the Examiner will be citing to paragraphs of the corresponding published Application No. 20230112372.
Withdrawn Rejections in view of Applicant’s Amendments and Arguments
Claim Rejections - 35 USC § 112
The rejection of claims 1-2, 5, 9, 12, 14, 17, 20, 22-23, and 27-28 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 is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended the claims to remove all previously-identified issues of indefiniteness.
The rejection of claims 1-3, 5, 8-9, 12, 14, 17, 20, 22-23, 25, and 27-28 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for lacking enablement for the entire scope of the claimed invention is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended the claims to recite the previously-identified enabled claim scope.
Maintained Rejections in view of Applicant’s Amendments and Arguments
Claim Rejections - 35 USC § 103
Claims 1-2, 5, 9, 12, 14, 17, 20, 22-23, and 27-28 remain rejected under 35 U.S.C. 103 as being unpatentable over Brown et al. (Stem Cell Reports 10.4 (2018): 1175-1183. hereinafter “Brown”), in view of Verma et al. (Current protocols in pharmacology 89.1 (2020): e77. hereinafter “Verma”), Radtke et al. (Experimental hematology 70 (2019): 31-41. hereinafter “Radtke”) (of record in the IDS filed 07 April, 2023), Ishikawa et al. (Blood 106.5 (2005): 1565-1573. hereinafter “Ishikawa”), Binhazim et al. (Laboratory Investigation; a Journal of Technical Methods and Pathology 75.3 (1996): 339-348, hereinafter “Binhazim”) (of record in the IDS filed 07 April, 2023), and Yao et al. (Cancer Research 78.13_Supplement (2018): 5676-5676, hereinafter “Yao”). This rejection has been modified as necessitated by Applicant’s amendments to the claims.
Brown teaches a method of primatizing (humanizing) a rodent (mouse) comprising injecting CD34 enriched hematopoietic stem and progenitor cells (HSCs) in conjunction with transplantation of a neonatal human thymus fragment into the kidney capsule of an NSG mouse (Brown, “Summary”, page 1181, “Experimental Procedures”). Brown teaches a thymus fragment that is 1 mm x 1 mm and the injection of 0.5 x 105 to 1.5 x 105 CD34+ cells (Brown, page 1176, first paragraph). The result is a humanized mouse.
Brown does not explicitly teach use of a rodent that lacks mature T cells, B cells, and NK cells or “which immune deficient rodent expresses human interleukin-3(IL3) or human granulocyte-macrophage colony-stimulating factor (GM-CSF)” as required by amended claim 1.
However, Verma teaches that mice lacking T, B and NK cells are preferred models for humanization (Verma, page 14, col. 2). Further, the generation of mouse strains carrying a mutation of IL2rγ (for example: NOD/Shi-scid-IL2rγnull (NOG) or NOD/LtSz-scid IL2rγnull (NSG)) results in mice deficient in T, B, and NK cells (Ishikawa, page 1565, last partial paragraph, page 1567, “Results” first paragraph). Thus, in teaching an NSG mouse, Brown teaches a mouse lacking mature T, B, and NK cells. Verma also teaches that human immune system reconstituted mice are valuable tools for recapitulating the interactions between immune components and tumors of human origin and that transgenic expression of human IL-3 and GM-CSF in NOG mice improves engraftment of CD34+ cells, supporting enhanced myeloid lineage development while preserving T-cell development (Verma, “INTRODUCTION”).
The combined teachings of Brown, Verma, and Ishikawa do not teach to source the population of CD34+ cells or the portion of thymus from a non-human primate.
Radtke teaches the engraftment of rhesus macaque (nonhuman primate (NHP)) CD34+ hematopoietic stem and progenitor cells in immune deficient mice to produce “monkeynized” mice (Radtke, Title, page 32, third full paragraph). Radtke also teaches that the NHP mouse model can significantly reduce the cost of large-animal transplantations and facilitate high-throughput screening of therapeutic strategies in vivo (Radtke, page 40, third full paragraph). Thus, a person having ordinary skill in the art would have been motivated to generate NHP mouse models to significantly reduce the cost of large-animal transplantations and facilitate high-throughput screening of therapeutic strategies in vivo. Radtke also teaches that mice transplanted with similar numbers of NHP CD34+ hematopoietic stem and progenitor cells and human CD34+ cells exhibit comparable engraftment patterns and have comparable levels of chimerism highlighting the preclinical relevance of NHP mouse models (Radtke, page 40, first full paragraph). Thus, a person having ordinary skill in the art would have reasonably expected from the teachings of Radtke that they would have success in utilizing NHP CD34+ HSCs to generate NHP mouse models because Radtke teaches that mice transplanted with similar numbers of NHP and human CD34+ cells exhibit comparable engraftment patterns and have comparable levels of chimerism.
The combined teachings of Brown, Verma, Ishikawa and Radtke do not teach transplantation of a non-human primate thymus.
Binhazim teaches the creation of rhesus macaque xenograft mice (Binhazim, “Summary”). Binhazim specifically teaches the transplantation of fetal liver and thymus into the kidney capsule of immunodeficient mice (Binhazim, page 345, third full paragraph). Binhazim also teaches the harvest of the entire liver and thymus from fetal Rhesus macaques and the processing of these tissues into at least 1mm2 pieces prior to transplantation (Binhazim, page 345, third full paragraph).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have used cells and thymic tissue sourced from NHPs as taught by Radtke, and Binhazim in the method of generating a primatized rodent of Brown and it would have been prima facie obvious to have expressed human IL-3 and GM-CSF as taught by Verma in the rodent of Brown and to have arrived at the invention claimed in instant claim 1 with a reasonable expectation of success because they would have been motivated to do so to significantly reduce the cost of large-animal transplantations, facilitate high-throughput screening of therapeutic strategies in vivo, and improve engraftment of CD34+ cells, supporting enhanced myeloid lineage development while preserving T-cell development. There would have been a reasonable expectation of success in doing so insofar as a person having ordinary skill in the art would have reasonably expected from the teachings of Radtke that they would have success in utilizing NHP CD34+ HSCs as opposed to human-sourced cells to generate NHP mouse models because Radtke teaches that mice transplanted with similar numbers of NHP and human CD34+ cells exhibit comparable engraftment patterns and have comparable levels of chimerism. Further, they would have been motivated to use any mouse strain carrying a mutation of IL2rγ in combining the teachings of Brown, Radtke, and Binhazim because Verma teaches that mice lacking T, B and NK cells are preferred models for humanization and Ishikawa teaches that NSG mice are one such example of a mouse lacking IL2rγ.
Regarding claim 2, the method of Radtke results in mice having phenotypical B cells, NK cells, and T cells (Radtke, page 34, first full paragraph).
Regarding claim 5, a Rhesus macaque is a monkey.
Regarding claim 9, Binhazim teaches harvesting the thymus and the liver from fetal Rhesus macaques, and as discussed above, a person having ordinary skill in the art would have understood that the liver fragments of Binhazim could instead be used to isolate CD34+ cells as are used in Radtke and Brown and that doing so would predictably produce CD34+ cells for transplantation. They would have been motivated to actually source the CD34+ cells from the liver according to Binhazim because doing so would be the simplest method of obtaining CD34+ cells considering that Binhazim teaches that one can harvest both from one macaque.
Regarding claim 12, Radtke teaches irradiating the NSG and the MISTRG mice prior to their use (Radtke, page 32, seventh full paragraph). Further, as discussed above, the NSG and the MISTRG mice are immune deficient as a result of genetic mutations.
Regarding claim 14, neither Brown, Verma, Ishikawa, Radtke, nor Binhazim teach a mouse expressing human IL-3, human GM-CSF, and human SCF as required by amended claim 14.
Yao teaches the NSG-SGM3 mouse model which produces higher myeloid and Treg populations when engrafted with CD34+ cells than NSG alone and teaches that NSG-SGM3 mice are an important platform for understanding human immune system interactions with tumors (Yao, whole paragraph). The NSG-SGM3 mice express human IL3, CSF2 (GM-CSF), and KITLG (SCF) (Yao, whole paragraph).
A person having ordinary skill in the art before the effective filing date of the claimed invention would have understood the NSG-SGM3 mice to have been an improved model for investigating human immune system interactions with tumors as taught by Yao and they would have been motivated to use the NSG-SGM3 mouse model as the rodent in the method of Brown, Verma, Ishikawa, Radtke, and Binhazim to improve CD34+ cell engraftment and produce a better model for understanding human immune system interactions with tumors.
Regarding claim 17, Brown teaches a thymus fragment that is 1 mm x 1 mm (Brown, page 1176, first paragraph).
Regarding claim 20, Brown teaches to enrich the CD34+ cells (Brown, page 1181, “Experimental Procedures”). Radtke teaches to enrich CD34+ cells using beads (Radtke, page 32, fourth full paragraph).
Regarding claims 22-23, Yao teaches and provides a motivation to use NSG-SGM3 mice.
Regarding claim 27, Binhazim teaches to use a fetal thymus and the CD34+ cells of Radtke are isolated insofar as they are enriched using beads and collected with a purity of 60-80% (Radtke, page 32, “Methods” first paragraph).
Regarding claim 28, Radtke teaches hematopoietic stem and progenitor cells (HPSCs) (Radtke, page 32, third full paragraph).
Response to Arguments
Applicant argues against the obviousness of the instant invention by arguing (1) that it is not obvious to use mice with transgenic human cytokines in the context of providing mice with non-human primal cells (Remarks, page 8), (2) that generally humanized mice are prepared by methods that only inject hematopoietic stem cells without tissue transplant (Remarks, page 8), (3) that the references individually do not render the invention obvious (Remarks, page 9), and (4) that there are unexpectedly beneficial properties which rebut the prima facie obviousness (Remarks, page 9). These arguments have been fully considered but have not been found persuasive for the following reasons.
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 “monkeynized” mice of Radtke are based on a MISTRG mouse model which expresses human cytokines (Radtke, page 32, seventh paragraph). Thus, the prior art does in fact teach to use mice expressing human cytokines as the base model for the transplantation of non-human primate CD34+ cells. Applicant ignores this teaching with their arguments by stating that Radtke is only “relied upon for teaching a source of CD34+ hematopoietic stem cells” without addressing the MISTRG mouse model used and relied upon in the instant rejection.
In response to the argument that generally humanized mice are prepared by methods that only inject hematopoietic stem cells without tissue transplant (Remarks, page 8), it is noted that this exact innovation is what Brown provides. Brown teaches a method of primatizing (humanizing) a rodent (mouse) comprising injecting CD34 enriched hematopoietic stem and progenitor cells (HSCs) in conjunction with transplantation of a neonatal human thymus fragment into the kidney capsule of an NSG mouse (Brown, “Summary”, page 1181, “Experimental Procedures”).
Finally, evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). “A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference.” In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential). See also MPEP 716.02e. In the instant case, Applicant only cites to figures within the instant disclosure without any attempt at a direct or indirect comparison to support the notion that the results would not have been predictable. In addition, it is noted that predictability is not what is required when a teaching- suggestion, or motivation to combine is the rationale relied upon but rather a reasonable expectation of success. It is further noted that the figures Applicant relies upon have been objected to for being illegible. Thus, even if Applicant had attempted a direct or indirect comparison, it would be impossible for the Examiner to evaluate the strength of such an argument.
Accordingly, the arguments have been fully considered but have not been found persuasive.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRENDAN THOMAS TINSLEY whose telephone number is (703)756-5906. The examiner can normally be reached Mon-Fri 8:00-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MARIA G LEAVITT can be reached at 571-272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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