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 .
DETAILED ACTION
Applicant’s response and claim amendments filed on 7/23/2026 are received and entered.
In the response to the most recent action, claims 5, 7, and 17-20 were previously under examination of the merits. In the instant action, claims 5 and 19 are currently amended.
Claims 5, 7, and 17-20 are currently under examination of the merits.
Any rejections/objections NOT repeated/presented here are withdrawn.
New Objections
The drawings are objected to under 37 CFR 1.83(a) because they fail to show Brazil-SJRP/2016-184 and Nicaragua/2016 UCB 7420 (see Fig. 13A and 13B) as described in the specification (Applicant shows Zika A1 and A2, however, the specification does not establish what viral strain A1 and A2 corresponds with. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). 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.
New Rejections
Claim Rejections - 35 USC § 103
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.
Claims 5, 7, and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Arumugaswami et al. (US 2019/0192593 A1, published 6/27/2019) in view of Alexander et al. (US 2019/0038685 A1, published 2/7/2019), Zwernik et al. (AXL receptor is required for Zika virus strain MR-766 infection in human glioblastoma cell lines, Molecular Therapy Oncolytics, Volume 23, Pgs. 447-457, 2021), Mazar et al. (Zika virus as an oncolytic treatment of human neuroblastoma cells requires CD24, PLoS One, All pages, 2018), Martin et al. (Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization, Cell Reports, Volume 13, Issue 11, Pgs. 2456-2469, 2015), Michlmayr et al. (CD14+CD16+ monocytes are the main target of Zika virus infection in peripheral blood mononuclear cells in a paediatric study in Nicaragua, Nature Microbiology, Volume 2, Issue 11, pgs. 1462-1470, published 6/12/2018) and Vinton et al. (Simian Immunodeficiency Virus Infection of Rhesus Macaques Results in Delayed Zika Virus Clearence, ASM Journals, Volume 10, No. 6, all pages, published 12/3/2019).
Regarding claim 5, Arumugaswami teaches a method for inducing an oncolytic effect on a tumor, comprising administering a composition comprising a Zika virus (ZIKV) to a subject in need thereof to induce the oncolytic effect on the tumor, wherein the tumor expresses a flaviviral cell entry receptor selected from the group wherein AXL is included (see paragraph 0006). Fig 3A-3C of Arumugaswani teaches the oncolytic effect on Glioma cells by administering ZIKV.
Regarding claim 7, Arumugaswami teaches the method of administering an oncolytic zika virus to see an oncolytic effect (reduction in size) of an Axl-positive tumor, as described above. Furthermore, Arumugaswami teaches where the subject has been diagnosed with a tumor that expresses flaviviral cell entry receptor GRP78, SDC2, TYRO2, AXL, or combinations thereof (see paragraph 0063).
Regarding claim 17, Arumugaswami teaches where the tumor expresses flaviviral cell entry receptor AXL at least 1.1 fold to 10 fold higher than non-tumor cells (see paragraph 0055).
Regarding claim 18, Arumugaswami teaches, in various embodiments, the subject in need thereof is a subject who has been diagnosed with a tumor that expresses the flaviviral cell entry receptor AXL (see paragraph 0063).
Regarding claim 19, Arumugaswami teaches wherein the instructions can comprise administering the composition to a subject in need thereof to induce an oncolytic effect on a brain tumor, an ocular tumor, or reintoblastoma (see paragraph 0020). These tumors express a flaviviral cell entry receptor AXL (see paragraph 0020). Fig. 3A-3C show how administering ZIKV induces cell death and cell growth/size in Glioma cells (brain tumor).
Regarding claim 20, Arumugaswami teaches Fig. 3A-C which depicts the oncolytic effect of ZIKV on Glioma cells in accordance with various embodiments of the present invention. Fig. 3A shows glioblastoma cells rounded up and treated with and without ZIKV. In the ZIKV wells, mainly cellular debris was found wherein untreated wells formed tumoroids and filamentous cellular networks (see paragraph 102). Though Arumugaswami does not teach the limitations of 21 days or where the volume of the Axl-positive tumor, when measured at least 21 days following infection, is less than about 150% of a tumor volume prior to infection, Arumugaswami teaches the structural limitations of the tumor (that being a cancer cell that expresses AXL) and the method of administering a virus to achieve an oncolytic effect. The outcome claimed in the instant application is a byproduct that will naturally flow from the method step taught by Arumugaswami.
Regarding claim 5, Arumugaswami does not teach where the oncolytic zika virus is Nicaragua/2016 UCB 7420.
Regarding claim 5, Michlmayr teaches ZIKV strain Nica 2-16 was used for in vitro experiments and was initially isolated in early 2016 from a ZIKV-infected patient in Nicaragua (see section titled “Virus and in vitro infection of PBMCs and monocytes).
Regarding claims 5 and 7, Michlmayr discloses that AXL is a receptor that has been described as possible entry for ZIKV infection (see introduction section).
Regarding claim 5, Vinton teaches the Zika virus isolate Nicaragua/2016 UCB 7420, originally isolated from patient serum collected at the University of California, Berkley (see experimental model and subject details).
Regarding claim 7, Arumugaswami does not teach wherein the Axl-positive tumor comprises of cells expressing both Axl and CD24.
Regarding claim 7, Alexander teaches a method for treating a CD24 positive tumor in an individual in need of such treatment, the tumor comprising malignant cells characterized by the presence of CD24, the method comprising administering to the subject an effective amount of an oncolytic Zika virus (see paragraph 0021).
Regarding claim 7, Zwernik teaches where cells expressing AXL are permissive for ZIKV infection, while cells that do not express AXL are not (see abstract). Zwernik teaches where survival for patients with glioblastoma is low and where treatments have not evolved and survival has not improved with current cancer therapies (see introduction).
Regarding claim 7, Mazar teaches where permissive Zika virus infection in neuroblastoma cells directly correlates with CD24 expression (see results) and where most neuroblastoma will progress relentlessly despite aggressive chemotherapy, radiation, and even autologous transplantation (see introduction).
Regarding claim 7, Martin teaches where cancer cells can express both CD24(+) AXL(+), and where said cancer cells show a higher lung metastasis competence compared to their more epithelial counterparts (see Fig. 11).
It would have been obvious to one with ordinary skill in the art, before the effective filing date, to combine the methods taught in Arumugaswami, Alexander, Zwernik, Mazar, Martin, Michlmayr, and Vinton to administer a Nicaragua strain Zika virus 2016/UCB 7420 to target a cell tumor expressing both AXL and CD24, for the purpose of reducing the size of an AXL positive tumor.
One would expect a reasonable chance of success as the use of oncolytic Zika viruses to reduce the size of a tumor is well characterized in the art, as evidenced by Arumugaswami. Though Arugmugaswani does not teach the use of a Nicaragua Zika virus or where the strain is Nicaragua/2016 UCB 7420, a skilled artisan would recognize that the ability of a Zika virus to exhibit an oncolytic effect resides in the characteristics of the virus (such as recognizing AXL receptors) to enter the cell and is not a unique, strain-dependent characteristic. This is evidenced by the teachings of Arumugaswani who provides examples of an Asian genotype virus PRVABC59 targeting U-87 MG cell lines (see paragraph 0082-0084) but discloses the use of African Zika viruses as well (see paragraph 0040, Table 1) and Alexander, who tests Zika virus strains MR766 and IBH 30656 on CD 24 tumor cells (see paragraph 0148) which are African strains but also discloses a Brazilian strain as being recently discovered (see paragraph 0072). Michylmayr discloses that in 2016, a Zika pandemic was present in South America, and a strain of Zika virus has been tested in vitro for its ability to infect cell lines. Vinton further discloses that the specific strain, Nicaragua/2016 UCB 7420 was known in the art, prior to the effective filing date. Furthermore, tumor cells that express both CD24 and AXL are susceptible to Zika virus infection, as evidenced by the arts of Zwernik, Mazar, and Martin.
Absent evidence to the contrary, given that Zika virus Nicaragua/2016 UCB 7420 was known in the art prior to the effective filing date and exhibits the same ability as other known Zika viruses to infect cell lines (such as recognizing AXL receptors), a skilled artisan would expect that by administering a Nicaragua/2016 UCB 7420 strain to an AXL-positive tumor would yield predictable results.
One would be motivated to combine these methods to target a tumor cell expressing both AXL and CD24 as both Zwernik and Mazar teach where AXL and CD24 positively affect ZIKV ability to infect a cancer cell. Both Zwernik and Mazar also teach that cells that express these oncogenes are typically resistant to current treatment standards. Martin teaches that cancer cells can express both CD24 and AXL at the same time. Therefore, one would be motivated to combine these prior teachings in order to effectively use Zika viruses to target cancer cells when other known cancer therapies are insufficient and to provide a safe and effective means for treating tumor malignancies with little to no off-target effects (see Alexander, paragraph 0071).
Further motivation that would direct a skilled artisan to test such strains is that Alexander mentions where a Brazilian strain of Zika virus has been linked to major birth defects compared to other Zika virus strains, wherein a skilled artisan of ordinary creativity may determine that strains of Zika virus from a 2016 pandemic affecting South America (including Nicaragua) could have an improvement over the currently test strains (African and Asian strains) on the oncolytic effect against tumor cells. The Federal Circuit has recognized that an implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the “improvement” is technology-independent and the combination of references results in a product or process that is more desirable, for example, because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient. See DyStar Textilfarben GmBH & Co. Deutschland KG v. C. H. Patrick Co., 464 F.3d 1356, 1368 (Fed. Cir. 2006).
In view of the foregoing, claims 5, 7, and 17-20 are rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
Response to Arguments
Applicant’s arguments filed on7/23/2026 have been fully considered but are not found persuasive. Applicant argues claim 5 is amended to recite wherein the oncolytic Zika virus is Nicaragua/2016 UCB 7420 and the teachings of Arumugaswami does not describe such a strain. Furthermore, the dependent claims 7 and 17-20 does not teach or provide reason on why a skilled artisan would have been motivated to select Nicaragua/2016 UCB 7420.
This argument is in rendered moot in view of the new rejection necessitated by amendments. However, to address the applicant’s concerns, the combined teachings above now use the art of Michylmayr and Vinton to alleviate the strain discrepancies. Looking at the combined arts of Arumugaswami and Alexander, the use of a Zika virus for an oncolytic effect is not dependent on strain, but a characteristic of the virus, such as recognizing AXL receptors or affecting CD24 positive tumors.
This is evidenced by Arumugaswami using an Asian genotype strain while Alexander uses MR-766, an African genotype strain. Alexander further mentions that a Brazilian strain of Zika virus has been discovered which shows increased incidence of Guillain-Barre syndrome and hydrocephalus in infants, which could suggest a more virulent strain (see paragraphs 0072 and 0092). While Michylmayr and Vinton does not disclose the use of a Nicaragua Zika virus 2016/UCB 7420 strain to target a tumor, Michylmayr and Vinton do disclose that Nicaragua had a Zika virus pandemic where the specific strain Nicaragua/2016 UCB 7420 was isolated and where Nicaragua zika virus strains can infect similar cell types by mechanisms such as recognizing AXL receptors. Absent evidence to the contrary, a skilled artisan would recognize that Nicaragua/2016 UCB 7420 Zika virus strain would likely exhibit the same cell entry and lysis characteristics of other art recognized Zika viruses and the use of such strain would merely be routine experimentation of testing different zika viruses on tumor cells.
One would be motivated to combine the arts above in order to test if the known Nicaragua/2016 UCB 7420 strain would exhibit an improved oncolytic effect. The Federal Circuit has recognized that an implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the “improvement” is technology-independent and the combination of references results in a product or process that is more desirable, for example, because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient. See DyStar Textilfarben GmBH & Co. Deutschland KG v. C. H. Patrick Co., 464 F.3d 1356, 1368 (Fed. Cir. 2006).
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 5 and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. US 10993975 B2 in view of Arumugaswami et al. (US 2019/0192593 A1, published 6/27/2019) in view of Alexander et al. (US 2019/0038685 A1, published 2/7/2019), Zwernik et al. (AXL receptor is required for Zika virus strain MR-766 infection in human glioblastoma cell lines, Molecular Therapy Oncolytics, Volume 23, Pgs. 447-457, 2021), Mazar et al. (Zika virus as an oncolytic treatment of human neuroblastoma cells requires CD24, PLoS One, All pages, 2018), Martin et al. (Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization, Cell Reports, Volume 13, Issue 11, Pgs. 2456-2469, 2015), Michlmayr et al. (CD14+CD16+ monocytes are the main target of Zika virus infection in peripheral blood mononuclear cells in a paediatric study in Nicaragua, Nature Microbiology, Volume 2, Issue 11, pgs. 1462-1470, published 6/12/2018) and Vinton et al. (Simian Immunodeficiency Virus Infection of Rhesus Macaques Results in Delayed Zika Virus Clearence, ASM Journals, Volume 10, No. 6, all pages, published 12/3/2019).
Regarding claim 5 and 7, the teachings of these prior arts show that cancer cells expressing AXL or CD24 are suitable targets for oncolytic Zika viruses (both naturally occurring and modified. Furthermore, Martin shows that AXL and CD24 are oncogenes that can be simultaneously expressed within cancer cells (see rejection above).
Regarding claims 5 and 7, Michlmayr discloses that AXL is a receptor that has been described as possible entry for ZIKV infection (see introduction section).
Regarding claim 5, Vinton teaches the use of Zika virus isolate Nicaragua/2016 UCB 7420, originally isolated from patient serum collected at the University of California, Berkley (see experimental model and subject details) (see rejection above)
Claim 1 of the issued patent recites “a method for reducing the size of a CD24 positive tumor in a subject in need thereof, the method comprising administering to the subject an effective amount of an oncolytic Zika virus, wherein the effective amount is an amount sufficient to reduce the size of the CD24 positive tumor”.
Comparing the claims, both claim a method for reducing the size of a tumor expressing the claimed oncogene (being AXL or CD24). The specification of issued patent and instant application define administration as being administered intravenously (Column 4, line 42 of the issued patent and Pg. 20 of the instant application) and both define a Zika virus as a naturally occurring Zika virus (see claim 7 of the issued patent and Pg. 16 of the instant specification). The issued patent does not recite wherein the oncolytic zika virus is Nicaragua/2016 UCB 2016.
It would have been obvious to one with ordinary skill in the art, before the effective filing date, to combine the methods taught in Arumugaswami, Alexander, Zwernik, Mazar, Martin, Michlmayr, and Vinton to administer a Nicaragua strain Zika virus 2016/UCB 7420 to target a cell tumor expressing both AXL and CD24, for the purpose of reducing the size of an AXL positive tumor.
One would expect a reasonable chance of success as the use of oncolytic Zika viruses to reduce the size of a tumor is well characterized in the art, as evidenced by Arumugaswami. Though Arugmugaswani does not teach the use of a Nicaragua Zika virus or where the strain is Nicaragua/2016 UCB 7420, a skilled artisan would recognize that the ability of a Zika virus to exhibit an oncolytic effect resides in the characteristics of the virus (such as recognizing AXL receptors) to enter the cell and is not strain dependent. This is evidenced by the teachings of Arumugaswani who provides examples of an Asian genotype virus PRVABC59 targeting U-87 MG cell lines (see paragraph 0082-0084) but discloses the use of African Zika viruses as well (see paragraph 0040, Table 1) and Alexander which tests Zika virus strain MR766 and IBH 30656 on CD 24 tumor cells (see paragraph 0148) which are African strains but also disclose a Brazilian strain (see paragraph 0072). Michylmayr discloses that in 2016, a Zika pandemic was present in South America, and a strain of Zika virus has been tested in vitro for its ability to infect cell lines. Vinton further discloses that the specific strain, 2016 UCB 7420 was known in the art, prior to the effective filing date. Furthermore, tumor cells that express both CD24 and AXL are susceptible to Zika virus infection, as evidenced by the arts of Zwernik, Mazar, and Martin.
Absent evidence to the contrary, given that Zika virus Nicaragua/2016 UCB 7420 was known in the art prior to the effective filing date and exhibits the same ability as other known Zika viruses to infect cell lines (such as recognizing AXL receptors), a skilled artisan would expect that by administering a Nicaragua/2016 UCB 7420 strain to a AXL-positive tumor would yield predictable results.
One would be motivated to combine these methods to target a tumor cell expressing both AXL and CD24 as both Zwernik and Mazar teach where AXL and CD24 positively affect ZIKV ability to infect a cancer cell. Both Zwernik and Mazar also teach that cells that express these oncogenes are typically resistant to current treatment standards. Martin teaches that cancer cells can express both CD24 and AXL at the same time. Therefore, one would be motivated to combine these prior teachings in order to effectively use Zika viruses to target cancer cells when other known cancer therapies are insufficient and to provide safe and effective means for treating tumor malignancies with little to no off-target effects (see Alexander, paragraph 0071).
Response to Arguments
Applicant's arguments filed 7/23/2026 have been fully considered but they are not persuasive. Applicant argues that the amendments of claim 5 now recite wherein the oncolytic Zika virus is Nicaragua/2016 UCB 7420. In view of the new rejection necessitated by amendments, examiner argues that the use of Nicaragua/2016 UCB 7420 would merely be routine optimization of testing an art known Zika virus strain against tumor cells. Furthermore, examiners assert that the ability for Zika virus to infect and lyse tumor cells is not associated with strain type, but a characteristic that is shared amongst Zika viruses of various genotypes, as evidenced by Arumugaswami and Alexander (see rejection above).
Motivation to test such a strain would be to see if the known Nicaragua/2016 UCB 7420 strain would exhibit an improved oncolytic effect. The Federal Circuit has recognized that an implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the “improvement” is technology-independent and the combination of references results in a product or process that is more desirable, for example, because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient. See DyStar Textilfarben GmBH & Co. Deutschland KG v. C. H. Patrick Co., 464 F.3d 1356, 1368 (Fed. Cir. 2006).
Further motivation that would direct a skilled artisan to test such strains is that Alexander mentions where a Brazilian strain of Zika virus has been linked to major birth defects compared to other Zika virus strains, wherein a skilled artisan of ordinary creativity may determine that strains of Zika virus from a 2016 pandemic affecting South America (including Nicaragua) could have an improvement over the currently test strains (African and Asian strains) on the oncolytic effect against tumor cells.
Conclusion
No claims are 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.
/D.T.Y./Examiner, Art Unit 1635
/RAM R SHUKLA/ Supervisory Patent Examiner, Art Unit 1635
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