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 18-19, 21, 25-27, 29 and 33-35 are under consideration.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2/13/2026 has been entered.
Rejections/Objections Withdrawn
All rejections of claims 22, 30, 39, 42 and 43 are rendered moot due to claim cancellation.
Rejections Maintained
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 18-19, 21, 25-27, 29 and 33-35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Andrews (Andrews, et al., WO 00/09145; Published 02/24/2000, of record) in view of Han (Han, et al., J. Exper. & Clin. Cancer Res (2017) 36:156, of record) and Zhang (Zhang, et al., World J Gastroenterology 2006 12(25):3977, of record)
Andrews teaches on the subject of methods of inducing regression of a tumor comprising treating a tumor cell ex vivo with a pro-apoptotic agent, placing the treated tumor cells in a diffusion chamber and inserting the chamber into a human for a therapeutically effective amount of time (Andrews, Abstract). Andrews teaches that the method of Andrews is capable of treating cancer using any tumor cells that undergo apoptosis and induce resistance or regression of tumor cells (Andres, p 6, lines 1-6). Andrews teaches that the pro-apoptotic agent of Andrews is a nucleic acid molecule directed against IGF-IR having the sequence of Andrews’ SEQ ID NO: 9 (same as instant SEQ ID NO: 1) (Andrews, p 7, line 20 – p 8, line 13). Regarding the “two or more” chambers limitation of claims 18 and 29 as well as the 10 to 30 chambers limitation of claim 19 and the 20 chambers limitation of claim 34, Andrews teaches that between five and 20 chambers are implanted in a single patient and the chambers can be removed after 24-30 hours after implantation, if desired (Andrews, p 12, lines 23-30). Regarding limitations i-ii of claim 29, Andrews teaches that the tumor sample is disaggregated with a scalpel, treated with collagenase/protease and then plated and allowed to attach 4-6 hr before washing (Andrews, p 17, lines 16-22), with the chopping with the scalpel converting the tissue into “morselized” tissue and the “sterile trap” being the sterile container the morselized tissue is in and the plating/attachment/ steps satisfying “harvesting adherent cells”. Regarding claim 33 as well as the irradiation limitations of claims 1 and 29, Andrews teaches that the adherent cells are then treated with IGF-IR antisense oligonucleotide for 6-10 hours, placed in a diffusion chamber and irradiated with 6 Gy prior to implantation (Andrews, p 17, line 22- p 18, line 8). Regarding claims 25 and 35, p 14, line 1 through p 26, line 18 of the Andrews reference teaches a detailed protocol used in a clinical trial for the method of Andrews and none of the steps described would expose the tumor cells to temperatures over body temperatures and no chemotherapy or radiation was used on the patients. Regarding claims 26-27, Andrews teaches that three patients who failed initial treatment were re-treated with a higher biological dose under FDA compassionate use (Andrews, p 24, lines 6-10) and while Andrews does not teach whether the cells were obtained after the first harvest or not, this does not matter as it has to be one or the other and claim 27 a) does not require non-response or recurrence.
Additionally, Andrews teaches that situations wherein the pretreated tumor cells undergo apoptosis in the diffusion chambers prior to implantation, the time between when the tumor cells are harvested from the plates until implantation should be an hour maximum, with preference being this time being as small as possible (Andrews, p 18, lines 10-21).
Andrews does not teach that the cancer being treated is hepatocellular cancer (HCC). Andrews does not teach that the chambers are implanted for 48 hours. Andrews does not teach that the tumor cells are encapsulated in the diffusion chamber with IGF-IR antisense.
Han teaches on the subject of whole cell tumor vaccines for HCC comprising HCC cells and a STAT3 decoy oligonucleotide (Han, Abstract- Background and Methods). Han teaches that whole cell vaccines often fail to demonstrate clinical benefit, with poor immunogenicity and immune tolerance/immunosuppression in the stromal microenvironment being possible explanations (Han, p 2, ¶ 2). Han teaches that STAT3 is overexpressed in many tumors and that previous findings confirmed blocking STAT3 signaling in HCC cells inhibited proliferation, promoted apoptosis and were sensitized to killing by NK cells, leading to the hypothesis that STAT3-blocked HCC cells could be used as a vaccine (Han, p 2, ¶ 3). Han teaches that vaccination with the decoy ODN yielded significantly smaller tumor volumes in BALB/c and C57BL/6 mice and longer survival times compared to scrambled ODN, lipofectamine or PBS (Han, Fig. 1).
Zhang teaches on the subject of IGF-IR inhibition in HCC (Zhang, Abstract). Zhang teaches that downregulation of IGF-IR function by antisense and dominant negative techniques reduces the growth and tumorigenicity of several cancer cell lines, thus rendering IGF-IR an attractive therapeutic target based on the hypothesis that inhibition would result in apoptosis and growth inhibition in tumor cells (Zhang, p 3978, ¶ 1). Zhang teaches that HepG2 HCC cells and Chang normal liver cells were treated with the IGF-IR inhibiting antibody aIR3 (Zhang, p 3978, ¶ 1-3). Zhang teaches that aIR3 both decreased cell growth (Zhang, Table 1) and increased apoptotic index (Zhang, Table 2) of the HepG2 HCC cells, both in dose-dependent manners.
It would be prima facie obvious to one of ordinary skill in the art to apply the biodiffusion method of Andrews to HCC in view of the teachings of Han and Zhang to arrive at a method of treating HCC comprising autologous HCC cells that have been transfected with the STAT3 decoy ODN of Han encapsulated in two or more of the biodiffusion chambers of Andrews with IGF-IR antisense in the biodiffusion chamber as well. One of ordinary skill in the art would be motivated to do this in order to better fight HCC. Andrews teaches that the biodiffusion chamber method of Andrews can be used to treat any form of cancer so long as the cells associated with that cancer undergo apoptosis and the resultant cells are capable of inducing an immune response. The teachings of Zhang demonstrate that inhibition of IGF-IR leads to apoptosis in HCC cells and the teachings of Han demonstrate that apoptotic HCC cells can create an anti-tumor response, and this creates a reasonable expectation of success with respect to the use of HCC cells in the biodiffusion chamber method of Andrews.
Andrews also teaches that is preferred to have the cells undergo apoptosis after the biodiffusion chamber has been implanted and this creates a time limit between when the tumor cells are harvested from the IGF-IR antisense treatment plate until implantation of one hour, with less time being better. This creates motivation to put IGF-IR antisense in the chamber with the cells, which one of ordinary skill in the art would reasonably assume would bypass this rush period and guarantee the cells undergo apoptosis in the patient with a reasonable expectation of success.
Regarding the 48-hour implantation limitation, Andrews teaches that the diffusion chambers of Andrews may be removed after 30 hours, if desired (Andrews, p 12, lines 23-30). This renders leaving the chambers in longer and reaching the 48-hour mark as obvious, as removing the chambers after 30 hours is optional. This leaves one of skill in the art the freedom to leave the chambers in longer than 30 hours in an attempt to amplify the effect via routine optimization. One of ordinary skill in the art would have a reasonable expectation of success leaving the chambers in for 48 hours because 1) Andrews teaches that removal of the chambers after 30 hours is optional and 2) one would reasonably deduce that leaving the chambers in longer would increase the effect of the chambers.
Response to Arguments
Applicant's arguments filed 2/13/2026 have been fully considered but they are not persuasive. Applicant argues that the combined teachings of Andrews, Han and Zhang do not teach every element of the instant claims, citing Graham v Deere, 383 US 1 (1960) and pointing to the amendments to claims to specify that the liver cancer is selected from HCC and cholangiocellular carcinoma (“CC”), wherein the HCC is selected from the group consisting of stage I, stage II, stage III and stage IV HCC. This argument is not persuasive because both the Han and Zhang references are on the subject of HCC in general and every case of HCC is selected from the group consisting of stage I, stage II, stage III and stage IV HCC.
Applicant then argues that the combined teachings of Andrews, Han and Zhang do not provide a person of ordinary skill in the art with a reasonable expectation of success. Applicant argues that “reasonable expectation of success” is premised on predictability. Applicant further argues that in order to have a reasonable expectation of success one must be able to predict the likely outcome of an experiment and, as such, if one cannot predict the likely outcome of an experiment one cannot have a reasonable expectation of success Applicant begins this argument pointing out that the “obvious to try” rationale supporting a conclusion of obviousness articulated in the KSR supreme court decision, emphasizing the language “predictable potential solutions” and “reasonable expectation of success” .. Applicant posits that the combined teachings of Andrews, Han and Zhang don’t provide a skilled artisan a reasonable expectation of success of obtaining the claimed subject matter, which, in the instant case, is a method of treating HCC (of any stage) or CC in a subject, said method comprising encapsulating tumor cells obtained from the subject in an implanted biodiffusion chamber in the presence of IGF-1R AS ODN because Andrews, Han and Zhang do not demonstrate that methods comprising encapsulating tumor cells obtained from a subject with IGF-1R AS ODN can be used to treat liver cancer whatsoever, let alone a liver cancer selected from CC, HCC stage I, HCC stage II, HCC stage III and HCC stage IV. Applicant argues Han only discloses STAT3 decoy oligonucleotide to treat HCC and Zhang only discloses the use of an anti-IGF-1R antibody to kill HCC cells, with neither Han nor Zhang teaching or suggesting the use of IGF-1R AS ODN, let alone the use of IGF-1R AS ODN as a treatment for a liver cancer selected from CC, HCC stage I, HCC stage II, HCC stage III and HCC stage IV. Applicant argues that a skilled artisan would also not have a reasonable expectation of success applying the biodiffusion chamber of Andrews to treat liver cancer because the criteria disclosed by Andrews for selecting a cancer includes “any cancer which undergoes apoptosis and induces an immune response, which is a very large genus, potentially including any known cancer and would require a very large group that requires experimental verification to achieve successful application.
Regarding the reasonable expectation of success argument, conclusive proof of efficacy is not required to show a reasonable expectation of success and that a reasonable expectation of success can be implicitly shown via the prior art teachings or obviousness analysis (See MPEP § 2143.02). In the instant case, Andrews lays two criteria for if a particular type of cancer can be treated using the biodiffusion chamber method of Andrews: 1) they must undergo apoptosis and 2) this must induce an anti-tumor immune response.
The work of Andrews mainly uses IGF-1R AS ODN as the pro-apoptotic agent in the method of Andrews. As such, using Andrews’ logic a tumor usable in this system should undergo apoptosis in the presence of IGF-1R AS ODN and that apoptosis should induce an anti-tumor immune response. The Zhang reference does use an anti-IGF-1R antibody and not an AS ODN but the Zhang reference does show that blocking the effect of IGF-1R on HCC cells causes the HCC cells to undergo apoptosis. It is well within the purview of one of ordinary skill in the art to deduce blocking the effect of IGF-1R via an AS ODN would also induce apoptosis in HCC cells. As such, HCC (of any stage) fits Andrews’ criterion “1”. Han shows HCC cells that have undergone apoptosis induced by an AS ODN were capable of inducing an immune response against HCC cells, thus fulfilling criterion “2” of Andrews. As such, one of ordinary skill in the art would reasonably expect that HCC cells implanted in the biodiffusion chambers of Andrews would undergo apoptosis due to the AS ODNs present in the chambers and the resulting apoptotic cells would induce an anti-HCC immune response. Additionally, the “obvious to try” rationale was not even invoked in the Office Action. There is a very clear combination of teaching, suggestion and motivation that would cause one of ordinary skill in the art to arrive at the instant claimed invention. Andrews provides an oncology platform that may be used to treat a variety of tumors and sets forth two broad but definite criteria for if a tumor is treatable with the method of Andrews. The teachings of Han demonstrate HCC (of any stage) fits one of those criterion and the teachings of Zhang demonstrate HCC fits the other criterion and, as such, one of ordinary skill in the art would have a reasonable expectation of success applying the method of Andrews to HCC (of any stage) in view of Han and Zhang. Additionally, the argument about the requirement for a large number of cancers to be tested to arrive at the claimed invention does not make sense. The claimed invention is an autologous cell-based immunotherapy. The cancer being treated comes from the cell line of cancer that the patient has.
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 18-19, 21, 25-27, 29 and 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. US 10,357,509 B2 in view of Andrews (Andrews, et al., WO 00/09145; Published 02/24/2000, of record) and Han (Han, et al., J. Exper. & Clin. Cancer Res (2017) 36:156, of record) and Zhang (Zhang, et al., World J Gastroenterology 2006 12(25):3977, of record).
Regarding claim 29 as well as the biodiffusion chamber referenced in claim 18, patented claim 1 is directed to a method of vaccinating a subject having brain cancer comprising steps that are identical to all of the step of claim 29 as well as patented SEQ ID NO: 1, which is the same as instant SEQ ID NO: 1. Regarding claims 19, 21 and 34, patented claim 3 is directed to a method comprising implanting 20 chambers for 48 hours. Regarding claim 33, patented claim 2 is directed toward a method of treating tumor cells for 18 hours prior to encapsulation. Regarding claims 25 and 35, the detailed method of treating brain cancer of patented claim 1 does not contain any steps that would elevate the cell temperature above body temperature or any steps comprising chemotherapy or radiation.
The ‘509 patent does not teach that the cancer treated is HCC. The ‘509 patent does not teach a second implantation using cells harvested at the same time as those of the first implantation or cells harvested after the first harvest, wherein the tumor has recurred or not responded.
Andrews teaches on the subject of methods of inducing regression of a tumor comprising treating a tumor cell ex vivo with a pro-apoptotic agent, placing the treated tumor cells in a diffusion chamber and inserting the chamber into a human for a therapeutically effective amount of time (Andrews, Abstract). Andrews teaches that the method of Andrews is capable of treating cancer using any tumor cells that undergo apoptosis and induce resistance or regression of tumor cells (Andres, p 6, lines 1-6). Andrews teaches that the pro-apoptotic agent of Andrews is a nucleic acid molecule directed against IGF-IR having the sequence of Andrews’ SEQ ID NO: 9 (same as instant SEQ ID NO: 1) (Andrews, p 7, line 20 – p 8, line 13). Andrews teaches that adherent cells are then treated with IGF-IR antisense oligonucleotide for 6-10 hours, placed in a diffusion chamber and irradiated with 6 Gy prior to implantation (Andrews, p 17, line 22- p 18, line 8). Andrews teaches that three patients who failed initial treatment were re-treated with a higher biological dose under FDA compassionate use (Andrews, p 24, lines 6-10).
Han teaches on the subject of whole cell tumor vaccines for HCC comprising HCC cells and a STAT3 decoy oligonucleotide (Han, Abstract- Background and Methods). Han teaches that whole cell vaccines often fail to demonstrate clinical benefit, with poor immunogenicity and immune tolerance/immunosuppression in the stromal microenvironment being possible explanations (Han, p 2, ¶ 2). Han teaches that STAT3 is overexpressed in many tumors and that previous findings confirmed blocking STAT3 signaling in HCC cells inhibited proliferation, promoted apoptosis and were sensitized to killing by NK cells, leading to the hypothesis that STAT3-blocked HCC cells could be used as a vaccine (Han, p 2, ¶ 3). Han teaches that vaccination with the decoy ODN yielded significantly smaller tumor volumes in BALB/c and C57BL/6 mice and longer survival times compared to scrambled ODN, lipofectamine or PBS (Han, Fig. 1).
Zhang teaches on the subject of IGF-IR inhibition in HCC (Zhang, Abstract). Zhang teaches that downregulation of IGF-IR function by antisense and dominant negative techniques reduces the growth and tumorigenicity of several cancer cell lines, thus rendering IGF-IR an attractive therapeutic target based on the hypothesis that inhibition would result in apoptosis and growth inhibition in tumor cells (Zhang, p 3978, ¶ 1). Zhang teaches that HepG2 HCC cells and Chang normal liver cells were treated with the IGF-IR inhibiting antibody aIR3 (Zhang, p 3978, ¶ 1-3). Zhang teaches that aIR3 both decreased cell growth (Zhang, Table 1) and increased apoptotic index (Zhang, Table 2) of the HepG2 HCC cells, both in dose-dependent manners.
It would be prima facie obvious to one of ordinary skill in the art to apply the biodiffusion method of the ‘509 patent to HCC view of the teachings of Andrews, Han and Zhang to arrive at a method of treating HCC comprising IGF-IR antisense-treated HCC cells used in the biodiffusion chamber of the ‘509 patent, wherein the HCC cells have been transfected with the STAT3 decoy ODN of Han and wherein there is IGF-IR antisense in the biodiffusion chamber of the ‘509 patent. One of ordinary skill in the art would be motivated to do this in order to better fight HCC. The method of Andrews is nearly identical to the method of the ‘509 patent and Andrews teaches that the method of Andrews can be used to treat any form of cancer so long as the cells associated with that cancer undergo apoptosis and the resultant cells are capable of inducing an immune response. One of ordinary skill would reasonably assume that the method of the ‘509 patent would work for these cancers as well. The teachings of Zhang demonstrate that IGF-IR inhibition is capable of inducing apoptosis in HCC and the teachings of Han demonstrate that apoptotic HCC cells can induce anti-tumor responses, which would lead one of ordinary skill to have a reasonable expectation of success using HCC cells in the method of the ‘509 patent.
It would be further obvious to one of ordinary skill in the art to conduct a second implantation of the biodiffusion chamber of the ‘509 patent comprising HCC cells, wherein the HCC cells obtained after the first cell harvest in the event that the tumor does not respond to the first implantation. One or ordinary skill in the art would be motivated to do this in order to treat hepatocellular cancer that has not responded fully to the first implantation. One of ordinary skill would have a reasonable expectation of success doing this because Andrews teaches subsequent implantations and the method of Andrews is nearly identical to the method of the ‘509 patent.
Response to Arguments
Applicant's arguments filed 2/13/2026 have been fully considered but they are not persuasive. Applicant’s argument/logic for this NSDP rejection is identical to Applicant’s logic for the 35 USC § 103 rejection and, as such, the same counterarguments apply.
Claims 18-19, 21, 25-27, 29 and 33-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. US 10,772,904 B2 in view of Andrews (Andrews, et al., WO 00/09145; Published 02/24/2000, of record) and Han (Han, et al., J. Exper. & Clin. Cancer Res (2017) 36:156, of record) and Zhang (Zhang, et al., World J Gastroenterology 2006 12(25):3977, of record).
Regarding claim 29 as well as the biodiffusion chamber referenced in claim 18, patented claim 1 is directed to a method of vaccinating a subject having brain cancer comprising steps that are identical to all of the step of claim 29 as well as patented SEQ ID NO: 1, which is the same as instant SEQ ID NO: 1. Regarding claims 19, 21 and 34, patented claim 3 is directed to a method comprising implanting 20 chambers for 48 hours. Regarding claim 33, patented claim 2 is directed toward a method of treating tumor cells for 18 hours prior to encapsulation. Regarding claim 35, patented claim 9 is directed to methods wherein the tumor cells are not exposed to temperatures above body temperature. Regarding claim 25, the detailed method of treating brain cancer of patented claim 1 does not contain any steps comprising chemotherapy or radiation.
The ‘904 patent does not teach that the cancer treated is HCC. The ‘904 patent does not teach a second implantation using cells harvested at the same time as those of the first implantation or cells harvested after the first harvest, wherein the tumor has recurred or not responded.
Andrews teaches on the subject of methods of inducing regression of a tumor comprising treating a tumor cell ex vivo with a pro-apoptotic agent, placing the treated tumor cells in a diffusion chamber and inserting the chamber into a human for a therapeutically effective amount of time (Andrews, Abstract). Andrews teaches that the method of Andrews is capable of treating cancer using any tumor cells that undergo apoptosis and induce resistance or regression of tumor cells (Andrews, p 6, lines 1-6). Andrews teaches that the pro-apoptotic agent of Andrews is a nucleic acid molecule directed against IGF-IR having the sequence of Andrews’ SEQ ID NO: 9 (same as instant SEQ ID NO: 1) (Andrews, p 7, line 20 – p 8, line 13). Andrews teaches that adherent cells are then treated with IGF-IR antisense oligonucleotide for 6-10 hours, placed in a diffusion chamber and irradiated with 6 Gy prior to implantation (Andrews, p 17, line 22- p 18, line 8). Andrews teaches that three patients who failed initial treatment were re-treated with a higher biological dose under FDA compassionate use (Andrews, p 24, lines 6-10).
Han teaches on the subject of whole cell tumor vaccines for HCC comprising HCC cells and a STAT3 decoy oligonucleotide (Han, Abstract- Background and Methods). Han teaches that whole cell vaccines often fail to demonstrate clinical benefit, with poor immunogenicity and immune tolerance/immunosuppression in the stromal microenvironment being possible explanations (Han, p 2, ¶ 2). Han teaches that STAT3 is overexpressed in many tumors and that previous findings confirmed blocking STAT3 signaling in HCC cells inhibited proliferation, promoted apoptosis and were sensitized to killing by NK cells, leading to the hypothesis that STAT3-blocked HCC cells could be used as a vaccine (Han, p 2, ¶ 3). Han teaches that vaccination with the decoy ODN yielded significantly smaller tumor volumes in BALB/c and C57BL/6 mice and longer survival times compared to scrambled ODN, lipofectamine or PBS (Han, Fig. 1).
Zhang teaches on the subject of IGF-IR inhibition in HCC (Zhang, Abstract). Zhang teaches that downregulation of IGF-IR function by antisense and dominant negative techniques reduces the growth and tumorigenicity of several cancer cell lines, thus rendering IGF-IR an attractive therapeutic target based on the hypothesis that inhibition would result in apoptosis and growth inhibition in tumor cells (Zhang, p 3978, ¶ 1). Zhang teaches that HepG2 HCC cells and Chang normal liver cells were treated with the IGF-IR inhibiting antibody aIR3 (Zhang, p 3978, ¶ 1-3). Zhang teaches that aIR3 both decreased cell growth (Zhang, Table 1) and increased apoptotic index (Zhang, Table 2) of the HepG2 HCC cells, both in dose-dependent manners.
It would be prima facie obvious to one of ordinary skill in the art to apply the biodiffusion method of the ‘904 patent to HCC view of the teachings of Andrews, Han and Zhang to arrive at a method of treating HCC comprising IGF-IR antisense-treated HCC cells used in the biodiffusion chamber of the ‘904 patent, wherein the HCC cells have been transfected with the STAT3 decoy ODN of Han and wherein there is IGF-IR antisense in the biodiffusion chamber of the ‘904 patent. One of ordinary skill in the art would be motivated to do this in order to better fight HCC. The method of Andrews is nearly identical to the method of the ‘904 patent and Andrews teaches that the method of Andrews can be used to treat any form of cancer so long as the cells associated with that cancer undergo apoptosis and the resultant cells are capable of inducing an immune response. One of ordinary skill would reasonably assume that the method of the ‘904 patent would work for these cancers as well. The teachings of Zhang demonstrate that IGF-IR inhibition is capable of inducing apoptosis in HCC cells and the teachings of Han demonstrate that apoptotic HCC cells are capable of eliciting an anti-tumor response, which would lead one of ordinary skill to have a reasonable expectation of success using HCC cells in the method of the ‘904 patent.
It would be further obvious to one of ordinary skill in the art to conduct a second implantation of the biodiffusion chamber of the ‘904 patent comprising HCC cells, wherein the HCC cells obtained after the first cell harvest in the event that the tumor does not respond to the first implantation. One or ordinary skill in the art would be motivated to do this in order to address the lack of response to the first implantation. One of ordinary skill would have a reasonable expectation of success doing this because Andrews teaches subsequent implantations and the method of Andrews is nearly identical to the method of the ‘904 patent.
Response to Arguments
Applicant's arguments filed 2/13/2026 have been fully considered but they are not persuasive. Applicant’s argument/logic for this NSDP rejection is identical to Applicant’s logic for the 35 USC § 103 rejection and, as such, the same counterarguments apply.
Conclusion
Claims 18-19, 21, 25-27, 29 and 33-35 are rejected.
No Claims are allowed.
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/SYDNEY VAN DRUFF/ Examiner, Art Unit 1643
/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643