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 .
1. The Amendment filed July 9, 2026 in response to the Office Action of April 14, 2026, is acknowledged and has been entered. Claims 1-7 and 10-16 are pending and being examined. Claims 8 and 9 are canceled. Claims 1, 5, 7, and 10 are amended.
Maintained 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.
2. Claims 1-7 and 10-15 remain rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2019/0134174, Jones et al, claiming priority to June 3, 2016; in view of Chawla et al (JAMA Oncology, 2015, 1:1272-1280); Eilber et al (Journal of Clinical Oncology, May, 30, 2017, 35, no. 15_suppl, abstract 11051); and Mita et al (Invest New Drugs, 2015, 33:341-348).
Jones et al teach a kit ([397-399]) comprising combination therapy for treating cancer in a subject, the kit comprising:
(a) vaccine vectors encoding MUC1, CEA, Ras, and/or brachyury;
(b) haNK or tank cells (genetically modified NK cells expressing CD16 high affinity variant V158);
(c) ALT-803;
(d) cetuximab; and
(e) chemotherapeutic doxorubicin that is a DNA-damaging agent ([12-16]; [35]; [37]; [90]; [93-183]; [225-226]; [232-238]; [239-249]; [254-255]; [260-261]; [272-275]; [279-280]; [284-285]; [287-295]; [300-320]; [372]; Table 3);
wherein the taNK cell expresses a chimeric antigen receptor (CAR) that binds to a tumor associated antigen or tumor neoepitope ([35]; [244]);
wherein the vaccine vector encoding MUC1, CEA, Ras, and/or brachyury is an adenoviral vector ([29]; [36]; [53-57]; [97-99]; [104]; [119]; [128]; [131-181]; [239]; [249]; [275]);
wherein the agents in the kit can be administered simultaneously, sequentially (existing separately or independently), or co-administered and can be contained in individual containers or mixed ([249]; [368]; [384]; [399]).
Jones further teaches the high affinity CD16 expressed by the cytotoxic NK cells inherently binds to antibody Fc regions to induce ADCC ([245]), therefore it is expected the therapeutic composition comprising the combination of cetuximab (comprising as Fc region) and haNK or taNK cells (comprising high affinity CD16 that binds or “couples to” Fc), would comprise haNK or taNK cells “coupled to” antibody cetuximab that targets a tumor associated antigen EGFR.
It is noted that claims 13-15 further limit the tumor or patient for whom the kit is intended, however, the preamble recitation in claim 1 of “for treating a patient having a tumor” for the claimed kit is merely suggestive of an intended use and is not given weight for purposes of comparing the claims with the prior art. The claims read on the active ingredients per se, which are the immune therapeutic composition and chemotherapeutic composition (see MPEP 2111.02).
Jones et al do not teach:
the doxorubicin is in prodrug form of aldoxorubicin (claim 1).
Aldoxorubicin:
Chawla et al teach aldoxorubicin is a prodrug of doxorubicin. Aldoxorubicin is derivatized at its C-13 keto-position with a thiol-binding, pH-sensitive linker (6-maleimidocaproic acid hydrazide). On bloodstream entry, the linker rapidly and covalently binds primarily to the thiol group of cysteine-34 of endogenous albumin. The albumin-drug conjugate preferentially localizes to the tumor, and in the acidic tumor environment, the doxorubicin is released via cleavage of the acid-labile hydrazine bond between drug and carrier. This approach to drug delivery exploits the leaky vasculature and defective lymphatic drainage (enhanced permeability and retention) characteristics of tumor tissues that promote entrapment of macromolecules within tumors, thereby increasing drug uptake and retention (p. 1273, col. 1). Chawla et al teach and demonstrate single-agent aldoxorubicin therapy showed superior efficacy over doxorubicin by prolonging progression-free survival and improving rates of 6-month progression-free survival and tumor response in cancer patients (abstract; Figure 2).
Eilber et al teach aldoxorubicin has demonstrated superior anti-tumor efficacy and lack of cumulative cardiac toxicity in multiple studies (p. 2, at top).
Mita et al teach aldoxorubicin can be administered at doses several-fold higher than doxorubicin can, without associated acute cardiotoxicity (abstract). The benefits of doxorubicin-based regimens are diminished by dose-dependent, drug-related toxicities, particularly cardiotoxicity (p. 341, col. 2). Mita et al teach clinical treatment of several solid tumor types with aldoxorubicin including lung cancer, sarcoma, and glioblastoma (abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute the prodrug of doxorubicin, aldoxorubicin, for doxorubicin, in the kit for treating cancer taught by Jones et al. One would have been motivated to in order to gain the advantages of aldoxorubicin such as gaining superior efficacy over doxorubicin by prolonging progression-free survival and improving rates of 6-month progression-free survival and tumor response and reducing cumulative cardiac toxicity, as taught by Chawla et al, Eilber et al and Mita et al. One of ordinary skill in the art would have a reasonable expectation of success given aldoxorubicin has demonstrated successful treatment of cancer and superior treatment results over doxorubicin, as taught by Chawla et al, Eilber et al and Mita et al.
3. Claim(s) 16 remains rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2019/0134174, Jones et al, claiming priority to June 3, 2016; Chawla et al (JAMA Oncology, 2015, 1:1272-1280); Eilber et al (Journal of Clinical Oncology, May, 30, 2017, 35, no. 15_suppl, abstract 11051); and Mita et al (Invest New Drugs, 2015, 33:341-348); as applied to claims 1-7 and 10-15 above, further in view of US Patent 9,623,097, Palena et al, claiming priority to March 2011; and Bilusic et al (Cancer Immunol. Immunother. 2014, 63:225-234).
Jones, Chawla, Eilber, and Mita teach a kit comprising combination therapy for treating cancer in a subject, the kit comprising:
(a) vaccine vectors encoding tumor antigens MUC1, CEA, Ras, and/or brachyury;
(b) haNK or tank cells (genetically modified NK cells expressing CD16 high affinity variant V158);
(c) ALT-803;
(d) cetuximab; and
(e) aldoxorubicin, as set forth above.
Jones further teaches yeast vectors can be used to express the tumor antigens. ([202]); the vector can express all of MUC1, CEA, and Brachyury together ([116]); and K-ras (Ras) can be included as a tumor antigen epitope in the vaccine vector ([90]).
The combined references do not teach the vaccine vector is yeast and expresses all of brachyury, Ras, and CEA.
Palena teaches a yeast vector vaccine for treating cancer in a patient, wherein the yeast vector vaccine encodes one or more of brachyury, CEA, Ras and MUC1 tumor antigens (col. 2, lines 53-67; col. 3, lines 47 to col. 4, line 67; col. 35, lines 6-65; col. 37, line 65 to col. 39, line 7; claims 1-20). Palena et al suggest co-administering immunostimulatory or immunotherapeutic compositions including cytokines, chemotherapeutics, and recombinant virus-based immunotherapy (col. 29, line 14 to col. 31, line 7; col. 34, line 51 to col. 35, line 6; col. 37, lines 25-65; col. 38, lines 36-39). Palena demonstrates yeast vector vaccines encoding brachyury successfully treated cancer in vivo and teach administering the vaccine clinically (Examples 8, 11, and 12).
Bilusic teaches a yeast vector vaccine encoding CEA successfully induced antigen-specific T cell responses against CEA in cancer patients (abstract). Bilusic teaches the vaccine was able to break tolerance and induce antigen spreading, a process whereby a dynamic immune response leads to the targeting of tumor antigens not initially targeted by the vaccine, wherein the vaccine enhanced antigen-specific immune responses against brachyury and MUC1 (p. 232, col. 1; Table 3). Bilusic teaches a yeast vector encoding Ras is administered to treat cancer patients and in combination with chemotherapy (p. 226, col. 1-2). Bilusic teaches the yeast vector vaccine can be safely administered with chemotherapy in combination therapy regimens (p. 232, col. 2). Bilusic teaches the advantages of yeast vector vaccines (p. 226, col. 1- 2):
Numerous characteristics of Saccharomyces cerevisiae, a nonpathogenic yeast species, make it a desirable vector for vaccines. Yeast can be readily engineered to express antigens for infectious diseases or cancer. Heat-killed yeast is extremely stable and therefore easy to transport and store, and is generally easy to administer [18–20]. Recombinant heat-killed yeast has been shown to induce maturation of murine dendritic cells (DCs), and the yeast CEA vaccine can efficiently activate murine CEA-specific T cells in vitro [21, 22]. Previous studies have also shown that yeast-CEA can efficiently activate human DCs, resulting in increased surface expression of costimulatory molecules, MHC class I and II molecules, and increased production by DCs of cytokines and chemokines such as IL-12p70, TNF-α, IFN-γ, and IL-8 [23]. Human DCs treated with yeast-CEA can efficiently generate and activate CEA-specific T cell lines in vitro that are capable of lysing CEA+ human tumor cells. Gene profiles of human DCs treated with yeast-CEA showed increased expression of numerous genes involved in the production of chemokines and cytokines and their receptors, as well as genes related to antigen uptake, antigen presentation, and signal transduction [23]. Furthermore, repeat administration of the vaccine in CEA-Tg mice demonstrated enhanced T cell responses after each vaccination, indicating that repeated vaccination could boost the immune response [23]. In addition, since this is a killed vector and does not actively infect cells, it is possible that an anti-vector antibody response could facilitate uptake by antigen presenting cells rather than a neutralizing response as may be seen with live vectors. In sum, recombinant heat-killed yeast serves as a delivery vehicle for a tumor antigen that is efficiently taken up by DCs, resulting in the release of protein in the cytoplasm for processing and MHC loading for T cell activation [20, 24]. Heat-killed yeast vaccines have demonstrated a good safety and tolerability profile in multicenter trials in patients with hepatitis C [18, 19] and in pancreatic cancer patients treated with yeast-ras (mutated) [25, 26] in combination with chemotherapy. An added benefit is that heat-killed yeast can be administered repeatedly without inducing host neutralizing activity [22]. In preclinical studies, vaccination of CEA-Tg mice bearing CEA+ carcinomas with yeast-CEA vaccine resulted in CEA-specific T cell responses, decreased tumor growth, and increased survival with no evidence of autoimmunity [22].
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the vector vaccine of the combined references to comprise a yeast vector encoding all of brachyury, Ras, and CEA. One would have been motivated to, and have a reasonable expectation of success to: (1) because Jones suggests utilizing a yeast vector to encode tumor antigens and suggests the vaccine encode one or more of CEA, brachyury, and Ras tumor antigens for the treatment of cancer in combination therapy; (2) Palena suggests a yeast vector vaccine for treating cancer in a patient, wherein the yeast vector vaccine encodes one or more of brachyury, CEA, Ras and MUC1 tumor antigens and is administered in combination therapies; (3) Bilusic teaches numerous advantages to utilizing a yeast vector to encode tumor antigens for the treatment of cancer and teaches the safety of combining these vaccines with chemotherapy; and (4) Palena and Bilusic teach and demonstrate the known success of yeast vector vaccines encoding CEA, Ras, or brachyury in inducing tumor antigen-specific immune responses and treating cancer.
Response to Arguments
4. Applicants argue that Jones mentions cetuximab once and in the context of patients that it was previously administered to or patients that have progressed on therapy. Applicants argue Jones does not teach including cetuximab in a kit.
5. The arguments have been considered but are not persuasive. Contrary to arguments, Jones does suggest combining cetuximab with the immune therapeutic composition. Cetuximab is also known as antibody C225. Jones teaches:
[270] It is further contemplated that other agents that increase the sensitivity of a hyperproliferative cell to apoptosis, such as the antibody c225, could be used in combination with pharmaceutical compositions described herein to improve the treatment efficacy.
Jones further teaches:
[372] A particular disease stage or progression may be selected, for example, patients with one or more of a metastatic, recurrent, stage III, or stage IV cancer may be selected for therapy with the methods and compositions as described herein. In some embodiments, patients may be required to have received and, optionally, progressed through other therapies including but not limited to fluoropyrimidine, irinotecan, oxaliplatin, bevacizumab, cetuximab, or panitumumab containing therapies. In some cases, individual's refusal to accept such therapies may allow the patient to be included in a therapy eligible pool with methods and compositions as described herein. In some embodiments, individuals to receive therapy using the methods and compositions as described herein may be required to have an estimated life expectancy of at least, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 18, 21, or 24 months.
In either case, Jones teaches administering cetuximab to the same cancer patients as the other kit components for the same purpose to treat cancer, rendering obvious its inclusion in the combination of drugs for treating cancer.
6. Applicants argue claim 1 is amended to recite aldoxorubicin, and argue the combination of claimed kit components produces unexpected synergistic results. Applicants argue that the state of the art teaches away from combining aldoxorubicin, and the instant specification teaches aldoxorubicin has not been combined with the claimed immune therapeutic composition previously. Applicants argue the specification teaches ([0008]): "[a]ldoxorubicin has not been used in combination with immune therapeutic agents, presumably due to suspected adverse effects from DNA damage response, and epigenetic and transcriptomic deregulation in various cells exposed to doxorubicin." Applicants argue that the claimed combination produces unexpected synergistic results. Applicants argue that the specification discloses that the combination of aldoxorubicin with immune therapeutic compositions produces synergistic, more-than-additive effects, pointing to paragraph [0027]: "[t]he inventors have now discovered that the effectiveness of immune therapeutic compositions and a chemotherapeutic agent including aldoxorubicin can be enhanced, in some cases even synergistically (i.e., to a more-than-additive extent), by co-administration of those two agents to a cancer patient." Applicants argue that specification provides clinical examples (Examples I and II) demonstrating effective treatment of metastatic cancers with the claimed combination. Applicants argue that these unexpected synergistic results rebut the prima facie case of obviousness.
7. The arguments have been considered but are not persuasive. As stated in the rejection, Jones teaches the combination of cancer therapeutic agents includes doxorubicin, therefore, the combination of immune therapeutics with doxorubicin is taught by the prior art, and the art does not teach away from this combination. The secondary references render obvious administering the known pro-drug form of doxorubicin, aldoxorubicin, instead of doxorubicin, for the reasons of record:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute the prodrug of doxorubicin, aldoxorubicin, for doxorubicin, in the kit for treating cancer taught by Jones et al. One would have been motivated to in order to gain the advantages of aldoxorubicin such as gaining superior efficacy over doxorubicin by prolonging progression-free survival and improving rates of 6-month progression-free survival and tumor response and reducing cumulative cardiac toxicity, as taught by Chawla et al, Eilber et al and Mita et al. One of ordinary skill in the art would have a reasonable expectation of success given aldoxorubicin has demonstrated successful treatment of cancer and superior treatment results over doxorubicin, as taught by Chawla et al, Eilber et al and Mita et al.
Contrary to arguments, and as evidenced by the cited references in the rejection, the state of the art at the time of effective filing was such that combining doxorubicin with the claimed immune therapeutic composition was known, and substituting aldoxorubicin for doxorubicin in cancer treatment was known and predictable. Further, the cited prior art teaches aldoxorubicin is superior to doxorubicin as a cancer therapeutic.
Contrary to arguments, the instant specification does not present any data demonstrating synergistic or unexpected results from combining the claimed therapeutic agents in to a kit above and beyond what the cited prior art teaches. Examples I and II of the instant specification provide no results demonstrating synergistic or unexpected results by combining the claimed therapeutics. Paragraphs [105-110] each describe the results of treating a single cancer patient with various combinatorial therapies, none of which are described as the instantly claimed combination of agents, and none of which compare the results of combining doxorubicin in a kit with immune therapeutic composition versus combining aldoxorubicin in a kit with immune therapeutic composition. Therefore, there is no evidence provided to demonstrate the argued synergistic or unexpected results for combining aldoxorubicin with the claimed immune therapeutic composition in a kit.
Applicants are arguing results that are not commensurate in scope with the instant claims. MPEP 716.02(d) states:” Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.”
In the instant case, Applicants are arguing results for methods of administering a combination of therapeutic agents (and not necessarily the exact combination claimed), that were administered at specific doses by specific routes and at specific times to treat cancer. All of those variables affect unexpected and synergistic outcomes of cancer treatment, none of which are recited or required by the claimed kit. The claimed kit is simply a collection of drugs that all serve the same purpose of treating cancer, and the kit itself has no unexpected or synergistic properties. The claimed kit can be sitting on a shelf with each drug in a separate vial. Therefore, the claimed kit does not comprise the unexpected or synergistic results/properties argued by Applicants.
8. Applicants argue that the examiner's motivation to combine is improper. The secondary references Chawla, Eilber, and Mita teach aldoxorubicin's benefits as a standalone chemotherapeutic agent, including superior efficacy over doxorubicin and reduced cardiotoxicity. However, these references do not teach or suggest combining aldoxorubicin with immune therapeutics such as vaccines encoding brachyury, MUC1, or CEA; haNK cells; cetuximab; and ALT803. Applicants argue that Examiner's motivation addresses only why one might substitute aldoxorubicin for doxorubicin in chemotherapy regimens generally, but does not address why one of ordinary skill would combine aldoxorubicin with the specific immune therapeutic composition recited in claim 1. Applicants argue that the claimed combination is not a simple substitution of one chemotherapeutic for another - it is a multi-component kit comprising both immune therapeutic and chemotherapeutic compositions designed to work together synergistically.
9. The arguments have been considered but are not persuasive. As stated above, Jones already teaches combining doxorubicin with the claimed immune therapeutic composition, therefore, contrary to arguments, this is not a deficient limitation of the prior art. The secondary references teach aldoxorubicin is a known pro-drug form of doxorubicin, and teach the advantages of substituting aldoxorubicin for doxorubicin, for the reasons of record.
10. Applicants argue the rejection relies on impermissible hindsight reasoning to arrive at the claimed combination of agents. Applicants argue that this is evidenced by the Examiner’s rejection requiring a combination of four references (Jones, Chawla, Eliber, and Mita) to arrive at the claimed combination of claims 1-15 and six references for claim 16. Applicants argue the large number of references is evidence of impermissible hindsight to pick and choose references to bring together.
11. The arguments have been considered but are not persuasive. It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In the instant case, it is clear in the rejection of record that the combined references teach not only the suggestion but also the means and motivation to produce a kit comprising all of the claimed immune therapeutic agents and aldoxorubicin for the purpose of treating cancer.
In response to applicant’s implication that the examiner has combined an excessive number of references (i.e., 3 secondary references in the first rejection under 35 USC 103, and 2 additional references in the second “further in view of” rejection under 35 USC 103), reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991) (Court affirmed a rejection of a detailed claim to a candy sucker shaped like a thumb on a stick based on thirteen prior art references).
In the first rejection under 35 USC 103, the three secondary references, Chawla, Eliber, and Mita all teach and establish aldoxorubicin is the well-known prodrug and preferable form of the doxorubicin taught by Jones for cancer therapeutics. Therefore, the cited references establish across several publications that, prior to the effective filing date of the invention, aldoxorubicin was a well-known and preferable substitute for doxorubicin.
In the second rejection under 35 USC 103, only two additional references are cited, Palena and Bilusic, that render obvious a yeast vector encoding all of brachyury, Ras, and CEA for the reasons of record. The two references teach the same motivation and reasonable expectation of success to modify the yeast vaccine vector in the kit of Jones.
12. Applicants argue that similar claims have issued in US Patents 11,510,982 and 12,527,865, indicating non-obviousness of the instant claims.
13. The arguments have been considered but are not persuasive. Each application is treated and examined individually based upon its own merits, therefore prosecution during the application process for the US Patents is not applicable. Further, the US Patents 11,510,982 and 12,527,865 claimed inventions are directed to a different scope of invention, wherein both patents are directed to methods of treating a tumor in a subject, and are not directed to a kit comprising the instantly claimed agents.
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.
15. Claims 1-7 and 10-16 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12,527,865. Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent claims a method for treating cancer comprising administering a combination of therapeutics that render obvious the instantly claimed combination of therapeutics comprised in the claimed kit for treating cancer. The US Patent claims:
1. A method of treating a patient having a tumor, comprising:
providing an immune therapeutic composition comprising
(a) a vaccine component comprising a vector comprising a recombinant nucleic acid encoding at least one of brachyury, MUC1, and CEA,
(b) cetuximab,
(c) a cytotoxic cell component comprising at least one of a haNK cell, a taNK cell, and a T cell, wherein the haNK cell, the taNK cell or the T cell is genetically engineered to express a high affinity CD16 variant and/or a chimeric antigen receptor, and
(d) ALT803;
providing a chemotherapeutic composition comprising aldoxorubicin; and
administering the immune therapeutic composition and the chemotherapeutic composition in a dose and schedule sufficient to treat the tumor.
2. The method of claim 1, further comprising administering an antibody to the patient or a protein that interferes with or down-regulates checkpoint inhibition.
3. The method of claim 2, wherein the antibody is coupled to the cytotoxic cell component.
4. The method of claim 2, wherein the antibody specifically binds to at least one of a growth factor receptor, a blood vessel growth receptor, an immune checkpoint inhibitor, a tumor associated antigen, a tumor specific antigen, or a tumor- and patient-specific neoepitope.
5. The method of claim 2, wherein the protein that interferes with or down-regulates checkpoint inhibition is an antibody or an antagonist of CTLA-4, PD-1, TIM1 receptor, 2B4, or CD160.
6. The method of claim 1, wherein the tumor is a solid tumor.
7. The method of claim 1, wherein the vaccine component and the cytotoxic cell component are separately administered by at least one day.
8. The method of claim 1, wherein the patient has a medical history of at least one of previous platinum-based chemotherapy and anti-PD-1/PD-L1 therapy.
9. The method of claim 1, further comprising determining a molecular profile of the patient, wherein the molecular profile comprises an HER2 expression level or a RAS mutation status.
10. The method of claim 1, wherein the tumor is metastatic Squamous Cell Carcinoma (SCC).
11. The method of claim 1, wherein the haNK cell is a NK-92 derivative cell with a high affinity CD16 variant or V158 variant.
12. The method of claim 1, further comprising a vaccine component comprising yeast vectors expressing brachyury, Ras, and CEA.
13. The method of claim 1, wherein the vaccine component comprises a nanoparticle as a core.
14. The method of claim 1, wherein the vector is a mRNA vector.
Thus, the US Patent claims recite and render obvious the instantly claimed compositions comprised by the instantly claimed kit.
16. Claims 1-7 and 10-16 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,510,982. Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent claims a method for treating cancer comprising administering a combination of therapeutics that render obvious the instantly claimed combination of therapeutics comprised in the claimed kit for treating cancer. The US Patent claims:
1. A method of treating a patient having a tumor, comprising:
providing an immune therapeutic composition comprising (a) a vaccine component comprising adenoviral vectors encoding brachyury, MUC1, and CEA, (b) cetuximab, (c) a cytotoxic cell component comprising NK92 cells genetically modified to express a high affinity CD16 variant, and (d) ALT803, and further providing a chemotherapeutic composition comprising aldoxorubicin; and
administering the immune therapeutic composition and the chemotherapeutic composition in a dose and schedule sufficient to treat the tumor.
2. The method of claim 1, further comprising administering an antibody to the patient or a protein that interferes with or down-regulates checkpoint inhibition.
3. The method of claim 2, wherein the antibody is coupled to the cytotoxic cell component.
4. The method of claim 2, wherein the antibody specifically binds to at least one of a growth factor receptor, a blood vessel growth receptor, an immune checkpoint inhibitor, a tumor associated antigen, a tumor specific antigen, or a tumor- and patient-specific neoepitope.
5. The method of claim 2, wherein the protein that interferes with or down-regulates checkpoint inhibition is an antibody or an antagonist of CTLA-4, PD-1, TIM1 receptor, 2B4, or CD160.
6. The method of claim 1, wherein the tumor is a solid tumor.
7. The method of claim 1, wherein the vaccine component and the cytotoxic cell component are separately administered by at least one day.
8. The method of claim 1, wherein the patient has a medical history of at least one of previous platinum-based chemotherapy and anti-PD-1/PD-L1 therapy.
9. The method of claim 1, further comprising determining a molecular profile of the patient, wherein the molecular profile comprises an HER2 expression level or a RAS mutation status.
10. The method of claim 1, wherein the tumor is metastatic Squamous Cell Carcinoma (SCC).
11. The method of claim 1, wherein the NK92 cells are high affinity NK (haNK) cells.
12. The method of claim 1, further comprising a vaccine component comprising yeast vectors expressing brachyury, Ras, and CEA.
Thus, the US Patent claims recite and render obvious the instantly claimed compositions comprised by the instantly claimed kit.
17. Claims 1-7 and 10-16 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,207,392 in view of Veluchamy et al (PLoS ONE; 2016; 11(6): e0157830; p. 1-16). Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent claims a method for treating cancer comprising administering a combination of therapeutics that render obvious the instantly claimed combination of therapeutics comprised in the claimed kit for treating cancer. The US Patent claims:
1. A method of providing a coordinated treatment regimen for treating a tumor, comprising:
reverting an escape phase of the tumor by administering at least a first pharmaceutical composition comprising-a drug that is bound to an albumin, and wherein the drug is selected from the group consisting of Bendamustine, Bortezomib, Cabazitaxel, Chlorambucil, Cisplatin, Cyclophosphamide, Dasatinib, Docetaxel, Doxorubicin, Epirubicin, Erlotinib, Etoposide, Everolimus, Gefitinib, Idarubicin, Hydroxyurea, Imatinib, Lapatinib, Melphalan, Mitoxantrone, Nilotinib, Oxiplatin, Paclitaxel, Pazopanib, Pemetrexed, Rapamycin, Romidepsin, Sorafenib, Vemurafenib, Sunitinib, Teniposide, Vinblastine, Vinorelbine, and Vincristine;
inducing an elimination phase of the tumor by administering natural killer cells and at least a second pharmaceutical composition comprising an immune stimulatory cytokine, wherein the natural killer cells are selected from the group consisting of aNK cells, haNK cells, and taNK cells [which express a CAR], and wherein the immune stimulatory cytokine is selected from the group consisting of IL-2, IL-7, IL-15, IL-17, IL-21, and an IL-15 superagonist;
maintaining an equilibrium phase of the tumor by administering at least a third pharmaceutical composition comprising a checkpoint inhibitor; and
administering low dose radiation to the tumor.
2. The method of claim 1, wherein the albumin is a nanoparticulate albumin.
3. The method of claim 2, further comprising an antibody or fragment thereof bound to the albumin.
4. The method of claim 3, wherein the antibody or fragment thereof is selected form the group consisting of Abciximab, Trastuzumab emtansine, Alemtuzumab, Basiliximab, Bevacizumab, Belimumab, Brentuximab vedotin, Certolizumab pegol, Cetuximab, Denosumab, Ibritumomab tiuxetan, Natalizumab, Obinutuzumab, Ofatumumab, Omalizumab, Panitumumab, Pertuzumab, Ramucirumab, Ranibizumab, Rituximab, Tositumomab, Trabectedin, and Trastuzumab.
5. The method of claim 4, wherein the antibody or fragment thereof binds specifically to a component of a necrotic cell.
6. The method of claim 1, wherein the first pharmaceutical composition comprises a drug that inhibits at least one of a T-reg cell, a myeloid derived suppressor cell, and a M2 macrophage.
7. The method of claim 6, wherein the drug is selected from the group consisting of cisplatin, gemcitabine, 5-fluorouracil, cyclophosphamide, doxorubicin, temozolomide, docetaxel, paclitaxel, trabectedin, and RP-182.
8. The method of claim 1, wherein the first pharmaceutical composition comprises a vascular permeability enhancer.
9. The method of claim 8, wherein the first vascular permeability enhancer comprises at least a portion of IL2.
10. The method of claim 1, wherein the second pharmaceutical composition comprises a recombinant bacterial vaccine, a recombinant viral vaccine, or a recombinant yeast vaccine.
11. The method of claim 10, wherein the recombinant bacterial vaccine, the recombinant viral vaccine, or the recombinant yeast vaccine is genetically engineered to express at least one of a tumor associated antigen and a patient and tumor specific neoepitope.
12. The method of claim 11, wherein the tumor associated antigen is selected from the group consisting of MUC1, CEA, HER2, Brachyury, and an oncogenic Ras mutant protein.
13. The method of claim 1, wherein the immune stimulatory cytokine is ALT-803.
14. The method of claim 13, wherein the natural killer cell is a haNK cell.
15. The method of claim 14 wherein the checkpoint inhibitor is a PD-1 inhibitor.
Thus, the US Patent claims recite and render obvious the instantly claimed compositions comprised by the instantly claimed kit of claims 1, 2, and 5-16.
With regards to claims 3 and 4, the US Patent does not claim the antibody cetuximab is coupled to the NK cells.
Veluchamy teaches and demonstrates that NK cells naturally bind to the Fc region of cetuximab through their CD16 region (abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the cancer treatment composition claimed by the US Patent comprising both NK cells and cetuximab to comprise cetuximab coupled to the NK cells. One would have been motivated to, and have a reasonable expectation of success to because Veluchamy teaches and demonstrates that the CD16 molecule expressed by NK cells naturally binds cetuximab Fc region when brought together in order to induce cytotoxic cell activity for cancer treatment.
Response to Arguments
18. Applicants request the double patenting rejections be held in abeyance.
19. No terminal disclaimers have been filed, therefore the rejections are maintained.
20. Conclusion: No claim is allowed.
21. All other rejections recited in the Office Action mailed April 14, 2026 are hereby withdrawn in view of claim amendments and canceling claims 8 and 9.
Conclusion
22. THIS ACTION IS MADE FINAL. 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.
23. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Laura B Goddard/Primary Examiner, Art Unit 1642
Prosecution Insights