DETAILED ACTION
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 .
Claims 1-7, 16-28 have been canceled. Claims 8-15 remain pending and under consideration.
Applicant's arguments filed 6-25-25 have been fully considered but they are not persuasive.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Objections
While plasma of the mouse may contain about 20 pg/ml hIL15, and the genome of the mouse may express hIL15 in the plasma of the mouse at a level of about 20 pg/ml, the “genome of the mouse” does not “express hIL15 at a level of about 20 pg/ml” as required in claim 8.
Written description
Claims 8-15 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The specification lacks written description for mice whose genome “expresses huIL15 at a level of about 20 pg/ml” as required in claim 1. Fig. 2 shows expression of hIL15 in the plasma of the mice at a level that is just under 20 pg/ml.
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While plasma of the mouse may contain about 20 pg/ml hIL15, and the genome of the mouse may express hIL15 in the plasma of the mouse at a level of about 20 pg/ml, the “genome of the mouse” does not “express hIL15 at a level of about 20 pg/ml” as required in claim 8. Nor does the genome of the mouse express IL15 at a level of about 20 pg/ml in muscle, brain, kidney, pancreas, skin,… tissue as broadly encompassed by claim 8. Accordingly, the concept lacks written description other than in the plasma.
Claim Rejections - 35 USC § 103
A) Claims 8-10, 15 are rejected under 35 U.S.C. 103 as being unpatentable over Ito (WO 2016189799) or Ito (20180213755) supported by Kim (J. Translational Med., 2011, Vol. 9, No. 113, pg 1-7) in view of Cany (Oncoimmunology, July 2015, Vol. 4, No. 7, e1017701, pg 1-12).
Ito taught NOG mice whose genomes comprise a sequence encoding human IL-15. NOG mice have homozygous IL-2rgtm1Sug and Prkdcskid mutations (“(Preparation of NOD-scid, IL-2rγnull-hIL-15 Tg mice) The above NOD-IL-2rγnull-hIL-15 Tg mice (female) and NOD-scid, IL-2rγnull mice (hereinafter also referred to as "NOG mice") . NOD-IL-2rγnull-hIL-15 Tg mice were further transduced with a scid mutation that deficient in T and B cells, the primary cells responsible for the immune system, by mating with ) (males). , NOD-scid, IL-2rγnull-hIL-15 Tg mice (hereinafter also referred to as “NOG-hIL-15 Tg mice”). ) was made”).” pg 5 of the translation in the 9th full paragraph).
The range hIL15 concentration in the plasma of the mice was 47.7 ± 27.5 pg/ml (para 56; Fig. 3) which is 20.2 pg/ml. The mice of Ito are “non-obese diabetic” as required in claim 8 because they are homozygous for a Prkdcscid allele and homozygous for an “IL-2rg” mutation. The concentration of 20.2 pg/ml described by Ito is “at a level of about 20 pg/ml” as required in claim 8 because they are so close.
Ito administered human CD34+ hematopoietic stem cells (HSCs) to the mice determined that they differentiated into NK cells in vivo by hCD56 staining (Example 3) which is equivalent to mice that contain human NK cells as required in claim 8.
Ito implanted human tumor cells into the mice (“In vivo experiment on suppression of tumor growth” para 122-122, claim 5, 7,…) as required in claim 8.
Ito administered HSCs or peripheral blood to the mice is equivalent to a “test substance” as required in step c) 8.
The last two paragraphs of the translation show “assaying response of the” tumor which is equivalent to step c) of claim 8.
Ito is limited to a IL-2rgtm1Sug mutation and did not teach an IL-2rgtm1Wjl mutation as required in claim 8.
However, the IL-2rgtm1Wjl mutation was well-known in NSG mice (NOD.Cg-Prkdcskid IL-2rgtm1Wjl/Szj; pg 27, para 105) as evidenced by Cany. It was also well-known that NSG mice combined the IL-2rgtm1Wjl mutation with the Prkdcskid.mutation as required in claim 8. Cany added IL15 and IL12 to NSG mice to support human CD34+-derived NK cells in the mice (title; pg 11, col. 1).
Thus, it would have been obvious to express hIL-15 in an immunodeficient prkdcscid mice on a NOD background with an IL-2rg mutation as described by Ito using NSG mice (NOD.Cg-Prkdcskid IL-2rgtm1Wjl/Szj) described by Cany. Those of ordinary skill in the art at the time of filing would have been motivated to replace the IL-2rgtm1Sug mutation of Ito with the IL-2rgtm1Wjl mutation found in NSG mice described by Cany because Cany taught NSG mice supplemented with IL-15 supported the growth of human CD34+-derived NK cells in vivo.
This is a two-way obviousness rejection. In the reverse, it would have been obvious to those of ordinary skill in the art at the time of filing to add human IL-15 to an NSG mouse as described by Cany using a transgene encoding human IL-15 as described by Ito. Those of ordinary skill in the art at the time of filing would have been motivated to insert the human IL-15 transgene into NSG mice instead of NOG mice so that the NSG mouse constitutively expressed human IL15, more closely reflected the human condition, and to enjoy the increased support of HSCs in the mouse.
Those of ordinary skill would have had a reasonable expectation of successfully expressing hIL-15 in an immunodeficient prkdcscid mice on a NOD background that lacked functional IL2RG protein as evidenced by Ito who did so in NOG mice.
Ito taught an “In vivo tumor growth suppression experiment”: “We investigated whether peripheral blood transplanted hIL-15 mice could exhibit cytotoxic activity against human tumors. Adult NOG-hIL-15 Tg mice were irradiated with 2.5 Gy of X-rays to induce bone marrow suppression. Human peripheral blood mononuclear cell (PBMC)-derived NK cells (2 × 10 NER182 cells) were intravenously transplanted within 1 day after irradiation to generate hu-PB-NK hIL-15 Tg mice. As a negative control, NK cell-untransplanted (hIL-15-Tg) mice were used. Four weeks after the transplantation of human PBMC-derived NK cells, 2.5 x 10 NER183 cells of the NK-sensitive human tumor cell line K562 were subcutaneously transplanted, and the tumor diameter was measured over time. The results are shown in Figure 17” (3rd to last paragraph of translation). This is equivalent to “comparing the response to a standard to determine the inhibitory effect of the test substance on the human tumor cells and/or solid or non-solid tumor, wherein an inhibitory effect of the test substance on the human tumor cells and/or solid or non-solid tumor identifies the test substance as having anti-tumor activity” as required in claim 9.
The human HSCs, peripheral blood, and NK cells are “immunotherapeutic agents” as required in claim 10.
The human HSCs, peripheral blood, and NK cells are “anti-cancer” test substances as required in claim 15.
Response to arguments
Applicants argue there was no reason to combine the references (pg 5). Applicants’ argument is not persuasive.
The examiner’s motivational statement is based on logic and science. It was well-known to mutate the IL2rg gene into an IL2rgtm1Sug or tm1Wjl mutation in an immunocompromised mouse as shown by Ito and Cany. Those of ordinary skill in the art at the time of filing would have been motivated to replace the IL-2rgtm1Sug mutation of Ito with the IL-2rgtm1Wjl mutation found in NSG mice described by Cany because Cany taught NSG mice supplemented with IL-15 supported the growth of human CD34+-derived NK cells in vivo. In the reverse, those of ordinary skill in the art at the time of filing would have been motivated to insert the human IL-15 transgene into NSG mice instead of NOG mice so that the NSG mouse constitutively expressed human IL15, more closely reflected the human condition, and to enjoy the increased support of HSCs in the mouse.
Applicants argue the results were not predictable (pg 5-7). Applicants’ argument is not persuasive. Pg 6, 1st full para, says NSG-hIL15 and NOG-hIL15 mice would be expected to have the same phenotype because they both lack IL2rg and both express hIL15. The paragraph concludes by say the phenotype of NSG-hIL15 and NOG-hIL15 mice without establishing what was expected or what results were obtained in NSG-hIL15 but not NOG-hIL15 mice.
Section 1 of the “unexpected results” argument entitled “Unexpectedly low and stable physiological levels of huIL15” (bridging pg 6-7 of the arguments) says NOG-hIL15 mice of Ito had serum hIL15 levels of about 50 pg/ml with a wide variability (47.7 ± 27..5 pg/ml) while NSG-hIL15 of the claimed invention had serum hIL15 levels of about 20 pg/ml. Applicants’ argument is not persuasive because 47.7-27.5 pg/ml described by Ito IS “about 20 pg/ml” hIL15 as required in claim 8. If applicants are attempting to argue their margin of error in expressing hIL15 is an unexpected result, then the amount of hIL15 expression in the serum is irrelevant, and the claim fails to capture an inventive concept of obtaining more consistent serum hIL15 levels in NOD-hIL15 vs NSG-hIL15 mice. Regardless, it cannot be denied that 47.7-27.5 pg/ml described by Ito IS “about 20 pg/ml” hIL15 which is all that is required in claim 8.
Section 2 of the “unexpected results” argument entitled “Enhanced NK Cell Engraftment and Persistence” (pg 7) says 1x106 purified [human] NK cells engrafted into the NOG-hIL15 mice of Ito disappeared by week 16 while 1x105 human CD34+ HSCs showed sustained human NK cells up to 14 weeks. Applicants’ argument is not persuasive because it is an incongruous comparison and because NK cells lasted longer (16 weeks) in the NOG-hIL15 mice of Ito.
Section 3 of the “unexpected results” argument entitled “Superior NK Cell Cytotoxic Function” (pg 7) says “At a 10:1 E:T ratio, NSG-huIL-15-derived NK cells achieved -90% killing, compared to <50% for NK cells from NOG-huIL-15 mice. Notably, the NOG model required a huIL-2 transgene to reach similar killing capacity”. Applicants’ argument is not persuasive because it is unfounded.
Section 4 of the “unexpected results” argument entitled “Improved NK Cell Cell-Mediated Tumor Suppression” (pg 7) says “At 23 days post-engraftment, tumors were -600 mm3, regardless of CD8+ T-cell depletion-indicating NK-specific activity. In contrast, NOG-huIL-15 mice engrafted with K562 tumor cells showed tumors nearing 1,000 mm3 by day 21, with improved control only when a huIL- 2 transgene was added”. Applicants’ argument is not persuasive because it is unfounded.
B) Claims 11-14 remain rejected under 35 U.S.C. 103 as being unpatentable over Ito (WO 2016189799) or Ito (20180213755) supported by Kim (J. Translational Med., 2011, Vol. 9, No. 113, pg 1-7) in view of Cany (Oncoimmunology, July 2015, Vol. 4, No. 7, e1017701, pg 1-12) as applied to claims 8-10, 15 and further in view of Keck (WO 2016209865).
The combined teachings of Ito or Ito supported by Kim in view of Cany taught an administering human NK cells, a human tumor, and a “test substance” to an NSG-hIL15 mouse as required in claim 10 for reasons cited above.
The combined teachings of Ito or Ito supported by Kim in view of Cany did not teach administering an immune checkpoint inhibitor as required in claim 11, an antibody in claim 14.
However, administering checkpoint inhibitors to NSG mice with an inactivated IL-2RG gene that contain human HSCs or PBLs and a tumor was well-known in the art as described by Keck (NOD, NSG - claim 6; tumor cells – claim 13, 21; screening – claim 21; checkpoint inhibitors – pg 34, Example 7). PD-1, PD-L1 and CTLA4 inhibitors are contemplated on pg 5-8.
Thus it would have been obvious to those of ordinary skill in the art at the time of filing to screen whether an agent is capable of decreasing human tumor burden in an NSG hIL-15 IL-2rγnull mouse containing human HSCs or PBL as described by Ito or Ito supported by Kim in view of Cany using a checkpoint inhibitor as described by Keck. Those of ordinary skill in the art at the time of filing would have been motivated to screen checkpoint inhibitors in the model of Ito to determine whether they would decrease tumor burden. In the reverse, those of ordinary skill in the art at the time of filing would have been motivated to screen checkpoint inhibitors in an NSG IL-2rγnull mouse containing HSCs or PBL as described by Keck, wherein the mouse expressed hIL-15 to more closely reflect the human condition, i.e. the hIL-15 IL-2rγnull mouse of Ito is more humanized than the IL-2rγnull mouse of Keck.
Those of ordinary skill would have had a reasonable expectation of successfully screening checkpoint inhibitors as shown by Ito and Keck who both described how to monitor tumor burden and determine whether an immunotherapeutic agent was capable of decreasing tumor burden using immunodeficient mice containing human HSCs/PBL and human tumors.
Keck taught the checkpoint inhibitor was anti-PD1 antibody or anti-CTLA4 antibody (ipilimumab) (Fig. 16; pg 8, lines 1-5) or any of the other checkpoint inhibitors in Table 1 including nivolumab (pg 6-7) which is a PD1-inhibitor or CTLA-4 inhibitor as required in claim 12.
Keck taught the checkpoint inhibitor was nivolumab (Table 1 pg 6-7) as required in claim 13.
Keck taught anti-PD1 antibody, anti-CTLA4 antibody (ipilimumab), and nivolumab (Fig. 16; pg 8, lines 1-5; Table 1 pg 6-7) which are antibodies as required in claim 14.
Keck taught anti-PD1 antibody, anti-CTLA4 antibody (ipilimumab), and nivolumab (Fig. 16; pg 8, lines 1-5; Table 1 pg 6-7) which are also anti-cancer agents as required in claim 15.
Response to arguments
Applicants repeat the arguments above which are not persuasive for reasons set forth above.
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.
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Michael C. Wilson
/MICHAEL C WILSON/Primary Examiner, Art Unit 1638