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
The amended claims filed on October 9, 2025, have been acknowledged. Claims 2-4, 7-10, 12-15, 17-20, 28-30, 32-39, 41-43, and 45 were cancelled. Claim 23 was amended. Claims 1, 5-6, 11, 16, 21-27, 31, 40, 44, and 46-50 are pending and examined on the merits.
Priority
The applicant claims domestic priority from U.S. provisional application No. 62/750,972, filed on October 25, 2018. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1, 5-6, 11, 16, 21-27, 31, 40, 44, and 46-50 receive domestic benefit from U.S. provisional application No. 62/750,972, filed on October 25, 2018.
Information Disclosure Statement
The information disclosure statements (IDS) filed on September 4, 2025, and November 14, 2025, have been considered.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims23 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of Applicant’s amendments to claim 23 to recite the oncolytic adenovirus.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 5-6, 16, 24, 46, 48, and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Wing et al. (Cancer Immunol Res 6: 605-616. 2018; Published May 2018) in view of Farzad et al. (Molecular Therapy-Oncolytics 1: 1-9. 2014), Scarfo et al. (Journal for ImmunoTherapy of Cancer 5: 1-8. 2017), and Saha et al. (Oncoscience 4: 7-8. 2017), as evidenced by Fajardo et al. (Cancer Res 77: 2052-2063. 2017) and Fueyo et al. (Oncogene 19: 2-12. 2000). This rejection is repeated with regards to the rejection in the Non-final Office action mailed on June 16, 2025. The traversal is addressed below.
Regarding claim 1, Wing teaches a method of treating cancer comprising establishing xenograft tumors by subcutaneous injection of HCT116 (colon cancer) or Panc-1 (pancreatic cancer) tumor cells into the flanks of NSG mice. For Panc-1, a solution of 50% Matrigel (BD Biosciences) and 50% PBS was used. After mean tumor volume reached 100 mm3, mice were treated with one intratumoral injection of (i) OAd-BiTE (1x109 vp) or PBS. After 3 or 5 days, mice were treated with one intravenous injection of (iii) 1x107 CART cells (50%CAR+, 1:1CD4:CD8). In HCT116 tumors, a second CART-cell injection was performed after one week (page 607, column 1, paragraph 4 and page 607, column 2, paragraph 5). Wing teaches that bispecific T-cell engagers (BiTE) are immunotherapeutic molecules consisting of an anti-CD3 single-chain variable fragment (scFv) fused to an antitumor-associated antigen scFv via a flexible linker. Wing uses an ICO15K-cBiTE, an OAd [oncolytic adenovirus] that secretes an EGFR-targeting BiTE (OAd-BiTE) upon infection of malignant cells (page 605, column 2, paragraph 4-page 606, column 1, paragraph 2).
Wing does not teach wherein the virus comprising nucleic acid encoding an antigen-binding molecule is a helper-dependent adenovirus (HDAd).
However, Farzad teaches that oncolytic adenoviruses (Onc.Ads) produce significant antitumor effects but as single agents they rarely eliminate tumors. Investigators have therefore incorporated sequences into these vectors that encode immunomodulatory molecules to enhance antitumor immunity. Successful implementation of this strategy requires multiple tumor immune inhibitory mechanisms to be overcome, and insertion of the corresponding multiple functional genes reduces the titer and replication of Onc.Ads, compromising their direct ant-tumor effects. By contrast, helper-dependent (HD) Ads are devoid of viral coding sequences, allowing inclusion of multiple transgenes. HDAds, however, lack replicative capacity. Since HDAds encode the adenoviral packaging signal, they hypothesized that the coadministration of Onc.Ad with HDAd would allow to be amplified and packaged during replication of Onc.Ad in transduced cancer cells. This combination could provide immunostimulation without losing oncolytic activity. We now show that coinfection of Onc.Ad with HDAd subsequently replicates HDAd vector DNA in trans in human cancer cell lines in vitro and in vivo, amplifying the transgenes the HDAd encode. This combinatorial treatment significantly suppresses the tumor growth compared to treatment with a single agent in an immunocompetent mouse model. Hence, combinatorial treatment of Onc.Ad with HDAd should overcome the inherent limitations of each agent and provide a highly immunogenic oncolytic therapy (abstract). Replication machinery of Onc.Ad recognizes coinfected HDAd vector DNA in transduced cancer cells and replicates HDAd vector DNA in trans, leading to multiple cycles of production and release of both the oncolysis and the transgenes encoded in an HDAd. These vectors are packaged into newly synthesized Ad particles and distribute to surrounding cells including tumor stroma (Figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the oncolytic adenovirus viral vectors of Wing with the combinatorial helper dependent adenoviral vector and oncolytic adenoviral vector of Farzad to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Farzad teaches that oncolytic adenoviruses (Onc.Ads) produce significant antitumor effects but as single agents they rarely eliminate tumors. Incorporating additional sequences into these vectors that encode immunomodulatory molecules can enhance antitumor immunity but insertion of the corresponding multiple functional genes reduces the titer and replication of Onc.Ads, compromising their direct ant-tumor effects. By contrast, helper-dependent (HD) Ads are devoid of viral coding sequences, allowing inclusion of multiple transgenes. Farzad shows that coinfection of Onc.Ad with HDAd subsequently replicates HDAd vector DNA in trans in human cancer cell lines in vitro and in vivo, amplifying the transgenes the HDAd encode. This combinatorial treatment significantly suppresses the tumor growth compared to treatment with a single agent in an immunocompetent mouse model. Hence, combinatorial treatment of Onc.Ad with HDAd should overcome the inherent limitations of each agent and provide a highly immunogenic oncolytic therapy. As such, it would have been obvious to use HDAd viruses with oncolytic adenoviruses as this improves the efficacy of their anti-tumor activity. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Farzad teaches co-infection of an Onc.Ad with an HDAd encoding human GM-CSF and human IL-12p70 in tumor bearing mice and this combination significantly reduced tumor size (page 5, column 1, paragraph 2-column 2, paragraph 1).
The combined teachings of Wing and Farzad do not teach wherein the HDAd further comprises nucleic acids encoding IL-12 and anti-PD-L1 antibody.
However, Scarfo teaches that one method to enhance CAR T-cell efficiency is to induce the local release of stimulatory factors that promote anti-tumor immune responses, such as IL-12. Combining CAR T-cells with IL-12 secretion showed complete eradication of tumor and prolonged persistence of CAR T-cells. Furthermore, Scarfo teaches that CAR T-cells are susceptible to PD-1 mediated suppression that the combination of CAR T-cells and PD-1 antibodies improved antitumor activity. Scarfo directly contemplates an alternative way of blocking immune checkpoints is to use genetic engineering strategies instead of administering immune checkpoint antibodies directly (page 4, column 2, paragraph 4-page 6, column 1, paragraph 2)
Furthermore, Saha teaches that oncolytic viruses that express IL-12 showed synergized with anti-PD-1 antibodies to improve survival in cancer patients (page 67, column 1, paragraph 2-column 2, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the helper dependent adenoviral vector of the combined teachings of Wing and Farzad by including IL-12 and anti-PD-L1 antibody genes in the HDAd vector to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Scarfo, Saha, and Farzad all teach that expressing additional immunomodulatory agents, such as IL-12 and anti-PD-L1, improve anti-tumor activity of CAR T-cells (Scarfo) and oncolytic viruses (Saha and Farzad). Furthermore, Farzad successfully reduced to practice that encoding IL-12p70 and GM-CSF in the HDAd for co-administration into tumor bearing mice significantly reduced tumor size and, as stated supra, teaches that incorporating additional sequences into oncolytic vectors that encode immunomodulatory molecules can enhance antitumor immunity but insertion of the corresponding multiple functional genes reduces the titer and replication of Onc.Ads, compromising their direct ant-tumor effects. By contrast, helper-dependent (HD) Ads are devoid of viral coding sequences, allowing inclusion of multiple transgenes. As such, it would have been obvious to incorporate IL-12 and anti-PD-L1 genes in the HDAd virus because this will improve anti-tumor activity and incorporating these genes in the oncolytic adenovirus risks negatively impacting its antitumor activity. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 5, Fajardo evidences that the ICO15K-cBiTE of Wing is arranged VLC225–VHC225–VHCD3–VLCD3. C225 is synonymous with EGFR (page 2053, column 1, paragraph 5).
Regarding claim 6, Wing teaches that bispecific T-cell engagers (BiTE) are immunotherapeutic molecules consisting of an anti-CD3 single-chain variable fragment (scFv) fused to an antitumor-associated antigen scFv via a flexible linker. Wing uses an ICO15K-cBiTE, an OAd [oncolytic adenovirus] that secretes an EGFR-targeting BiTE (OAd-BiTE) upon infection of malignant cells (page 605, column 2, paragraph 4-page 606, column 1, paragraph 2).
Regarding claim 16, Farzad teaches that the oncolytic adenovirus is an adenovirus 5 (ad5 virus) with a 24 bp deletion in the viral genome (page 7, column 2, paragraph 3). Farzad does not specifically state that the 24 bp deletion is the same amino acid sequence as SEQ ID NO: 105. However, Fueyo evidences that they constructed a tumor-selective adenovirus (ad5), Δ24, that carries a 24-bp deletion (LTCHEACF amino acid sequence) in the E1A region responsible for binding Rb protein. Immunoprecipitation analyses verified that this deletion rendered D24 unable to bind the Rb protein (abstract, page 2, column 2, paragraph 3, and Figure 1). The deleted sequence (LTCHEACF) is 100% identical to SEQ ID NO: 105 of the instant application (Figure 1). It is reasonable to conclude that the adenovirus of Farzad also has the same 24 bp deletion as shown in Fueyo.
Regarding claim 24, Wing teaches a method of treating HCT116 (colon cancer) or Panc-1 (pancreatic cancer) cancer (page 607, column 1, paragraph 4 and page 607, column 2, paragraph 5).
Regarding claim 46, as stated supra, Wing teaches that after 3 or 5 days, mice were treated with one intravenous injection of (iii) 1x107 CART cells (50%CAR+, 1:1CD4:CD8); CAR T cells expressed cancer antigens CD-19 or FR-α (page 606, column 1, paragraph 6-column 2, paragraph 1 and page 607, column 1, paragraph 4).
Regarding claims 48 and 50, Wing uses an ICO15K-cBiTE, an OAd [oncolytic adenovirus] that secretes an EGFR-targeting BiTE (OAd-BiTE) upon infection of malignant cells (page 606, column 1, paragraph 2). Wing teaches that the CAR T cells targeted folate receptor alpha (FR-α) or CD19. As such, the antigens are specific for non-identical cancer cell antigens.
Response to Arguments
Applicant's arguments filed February 25, 2025, are acknowledged.
First, Applicant argues that it does not appear obvious to use both an oncolytic adenovirus and CAR T cells and questions whether there would be a reasonable expectation of success (page 7, paragraph 3-page 8, paragraph 1).
Applicant's arguments have been fully considered but are not persuasive.
As an initial matter, the rejection as written is towards the obviousness of encoding an antigen-binding molecule as part of a helper-dependent adenovirus (HDAd), not using oncolytic adenoviruses in combination with CAR T-cells.
However, Wing specifically identifies that they used oncolytic adenoviruses in combination with CAR T-cells to see whether this would improve CAR T-cell therapy and found that dual treatment resulted in increased T-cell activation, proliferation, and cytotoxicity in vitro and enhanced antitumor efficacy due to improved T-cell activation in xenograft mouse models. Therefore, the combination therapy of CART cells and an OAd-BiTE has the potential to overcome the limitations of CARs and BiTEs as monotherapies in solid tumors (page 606, column 1, paragraph 3). Therefore, it was already taught in the art that oncolytic adenoviruses can be used in combination with CAR T-cells to successfully improve treatment.
Second, Applicant argues that Applicant is not claiming a BiTE and an oncolytic adenovirus in combination with CAR T-cells. Instead, Applicant is claiming the combination of an HDAd and an Oad (page 8, paragraph 1).
Applicant's arguments have been fully considered but are not persuasive.
The term "comprising" is open-ended and allows for additional, unrecited elements in the claims. MPEP 2111.03 specifically sets forth that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). Applicant fails to specifically exclude the step of administering CAR T-cells in either the claims or the specification. As such, the CAR T-cells of Wing do not teach away from the present invention as claims use the term comprising which allows for non-recited components and there is no requirement to exclude the CAR T-cells.
Third, Applicant argues that the combination of an HDAd encoding a BiTE and an oncolytic adenovirus lacks a reasonable expectation of success as the outcome of using an oncolytic adenovirus and HDAd is not obvious as there is a potential for the oncolytic adenovirus kills all the cells before the HDAd’s purpose is accomplished. A more predictable outcome would be to use the HDAd first and then the oncolytic adenovirus. Applicant concedes that Farzad demonstrates that the combination can be successful when OAds are used in combination with HDAds that encode GM-CSF and IL-12p70. However, there is no teaching or suggestion that combination treatment would work with HDAds that encode a BiTE, as currently claimed. The Office has not provided a reference that successfully uses an HDAd that encodes the claimed BiTE. As previously presented, the application as filed and Morita et al. demonstrates that the invention works exceptionally well (page 8, paragraph 2).
Applicant's arguments have been fully considered but are not persuasive.
In regard to the reasonable expectation of success, Farzad identifies the concept of combinatorial treatment of Onc.Ad with HDAd (Figure 1) and specifically identifies multiple examples where co-infection of an Onc.Ad with HDAd improved expression of the transgenes of the HDAd in vivo (page 2, column 2, paragraph 3-page 6, paragraph 1). Although Farzad teaches using OAds in combination with HDAds that encode GM-CSF and IL-12p70, it would be well understood to one of ordinary skill in the art that other transgenes can be used in place of GM-CSF and IL-12p70 as Farzad has identified the scientific concept of using oncolytic adenoviruses in combination with HDAds encoding transgenes to drive the expression of the transgenes. Farzad identifies that helper-dependent adenoviral vectors (HDAds) are devoid of all viral-coding sequences, affording them a large transgene coding capacity (up to 32 kb) that is suited to insertion of multiple transgenes in a single vector (page 1, column 2, paragraph 1). Furthermore, although the transgenes being used in Wing and Farzad are different, both are used to improve anti-tumor activity. Additionally, it is well understood in the art that transgenes can be replaced or combined with other transgenes in the same vector backbone. In this manner, the key concept of Farzad is the benefit of using a HDAd vector backbone to express transgenes to improve anti-tumor activity compared to expressing them all in the OncAd (reduces the titer and replication of Onc.Ads). As this method has worked with one set of transgenes, there is a reasonable expectation that other anti-tumor transgenes would also achieve higher expression levels as part of this combinatorial treatment and improve treatment efficacy.
In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988) (citations omitted) (The court held the claimed method would have been obvious over the prior art relied upon because one reference contained a detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful.). Therefore, one of ordinary skill in the art could have pursued using oncolytic adenoviruses in combination with HDAds encoding their transgene of interest (in this case the BiTE of Wing). Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.
Regarding Applicant’s argument about the stated purpose of the HDAd, it is not clear what Applicant considers the stated purpose to be as one would presume that killing all cancer cells is the goal of the combined treatment. As identified by Farzad, the oncolytic adenovirus and HDAd combination therapy enhances the therapeutic effects compared to treatment with HDAd or Onc.Ad alone in an immunocompetent mouse model by improving the suppression of tumor growth. Therefore, Farzad has already shown co-infection does achieve the goal of improving cancer treatment efficacy and suppressing tumor growth and one of ordinary skill in the art would follow the successful method of Farzad.
Claims 1 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Wing et al. (Cancer Immunol Res 6: 605-616. 2018; Published May 2018) in view of Farzad et al. (Molecular Therapy-Oncolytics 1: 1-9. 2014), Scarfo et al. (Journal for ImmunoTherapy of Cancer 5: 1-8. 2017), and Saha et al. (Oncoscience 4: 7-8. 2017) as applied to claim 1 above, and further in view of Niemann et al. (Virus Genes 53: 700-706. 2017). This rejection is repeated with regards to the rejection in the Non-final Office action mailed on June 16, 2025.
The teachings of Wing, Farzad, Scarfo, and Saha are as discussed above.
The combined teachings of Wing, Farzad, Scarfo, and Saha do not teach wherein the virus comprising nucleic acid encoding an antigen-binding molecule comprises nucleic acid encoding an enzyme capable of catalysing conversion of a non- toxic factor to a cytotoxic form, and wherein the enzyme is selected from: thymidine kinase, cytosine deaminase, nitroreductase, cytochrome P450, carboxypeptidase G2, purine nucleoside phosphorylase, horseradish peroxidase and carboxylesterase.
However, Niemann teaches that oncolytic adenoviruses have shown to be safe tools to selectively infect and eliminate cancer cells. To compensate for insufficient tumor transduction, different effector genes have been incorporated into the viral genome to enhance cell death and viral spreading or to confer cytotoxicity to non-infected neighboring cells. These so-called ‘armed’ oncolytic viruses have been equipped with proapoptotic genes to enhance cell death. A further type of utilized genes are pro-drug activators, whose expression facilitates local enzymatic transformation of a systemically applied non-toxic pro-drug into a toxic agent, that is also delivered to non-infected, neighboring cells via gap-junctions leading to enhanced ‘bystander’ cell killing. Examples are viruses carrying the herpes simplex virus-1 thymidine kinase (HSV-tk) or the bacterial cytosine deaminase (CD). Expression of these genes leads to the conversion of pro-drugs, such as ganciclovir or 5-fluorocytosine, into toxic substances, significantly enhancing the anti-tumor activity compared to unarmed oncolytic virus (page 703, column 1, paragraph 2-column 2, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating cancer using BiTEs of the combined teachings of Wing, Farzad, Scarfo, and Saha by adding a nucleic acid encoding an enzyme capable of catalysing conversion of a non- toxic factor to a cytotoxic form to the HDAd viral vector as identified by Niemann to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Niemann teaches that to compensate for insufficient tumor transduction, different effector genes have been incorporated into the viral genome to enhance cell death and viral spreading or to confer cytotoxicity to non-infected neighboring cells. These so-called ‘armed’ viruses have been equipped with pro-drug activators, whose expression facilitates local enzymatic transformation of a systemically applied non-toxic pro-drug into a toxic agent, that is also delivered to non-infected, neighboring cells via gap-junctions leading to enhanced ‘bystander’ cell killing. Expression of these genes leads to the conversion of pro-drugs, such as ganciclovir or 5-fluorocytosine, into toxic substances, significantly enhancing the anti-tumor activity compared to unarmed oncolytic virus. Furthermore, as stated supra, Farzad teaches that adding genes to the oncolytic virus reduces titer and replication. As such, it would have been obvious to include these genes in the HDAd (and not the Onc.Ad) viral vector to improve anti-tumor activity especially in non-infected neighboring cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Response to Arguments
Applicant's arguments filed October 9, 2025, are acknowledged and have been addressed above.
Claims 1 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Wing et al. (Cancer Immunol Res 6: 605-616. 2018; Published May 2018) in view of Farzad et al. (Molecular Therapy-Oncolytics 1: 1-9. 2014), Scarfo et al. (Journal for ImmunoTherapy of Cancer 5: 1-8. 2017), and Saha et al. (Oncoscience 4: 7-8. 2017) as applied to claim 1 above, and further in view of Zakharova et al. (The Journal of Biological Chemistry 278: 43067-43073. 2003) and Cheon et al. (Semin Oncol 41: 156-173. 2014). This rejection is repeated with regards to the rejection in the Non-final Office action mailed on June 16, 2025.
The teachings of Wing, Farzad, Scarfo, and Saha are as discussed above.
The combined teachings of Wing, Farzad, Scarfo, and Saha do not teach wherein the oncolytic virus comprises nucleic acid having one or more binding sites for STAT1.
However, Zakharova teaches that they expressed STAT1 binding sites upstream of the adenovirus major late core promoter in a DNA template and found that when the DNA template was cultured with phosphorylated STAT1α, there was increased transcription of the DNA template (page 43069, column 1, paragraph 5-column 2, paragraph 2 and Figure 2). Zakharova teaches that STAT proteins are interferon (IFN)-induced DNA binding proteins that bind to sequences upstream of IFN-induced genes. These binding sites are capable of directing IFN-induced transcription of synthetic reporter genes in transfection experiments (page 43067, column 1, paragraph 1).
Cheon teaches that plasmacytoid dendritic cells have been found to secrete high levels of IFN-α and IFN-β and this response has been identified in the T-cell zone of lymphatic tissue in tumors of various types (page 162, column 2, paragraph 1 and Figure 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the oncolytic adenovirus of the combined teachings of Wing, Farzad, Scarfo, and Saha by including STAT1 binding sites upstream of the major late core promoter, as identified by Zakharova to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Zakharova teaches that the STAT1 binding sites led to increased transcription when phosphorylated STAT1α was in the culture and that these binding sites are capable of directing IFN-induced transcription. Furthermore, Cheon teaches that plasmacytoid dendritic cells have been found to secrete high levels of IFN-α and IFN-β and this response has been identified in the T-cell zone of lymphatic tissue in tumors of various types. As such, the oncolytic adenovirus with STAT1 binding sites would have increased expressed of the adenoviral replication genes that the helper dependent adenovirus lacks. Increased expression of the adenoviral replication genes would increase expression of the BiTEs encoded by the helper dependent adenoviruses, increasing the likelihood of tumor killing. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Response to Arguments
Applicant's arguments filed October 9, 2025, are acknowledged and have been addressed above.
Claims 1 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Wing et al. (Cancer Immunol Res 6: 605-616. 2018; Published May 2018) in view of Farzad et al. (Molecular Therapy-Oncolytics 1: 1-9. 2014), Scarfo et al. (Journal for ImmunoTherapy of Cancer 5: 1-8. 2017), and Saha et al. (Oncoscience 4: 7-8. 2017) as applied to claim 1 above, and further in view of Miliotou et al. (Current Pharmaceutical Biotechnology 19. 5-19. 2018; Published April 2018). This rejection is repeated with regards to the rejection in the Non-final Office action mailed on June 16, 2025.
The teachings of Wing, Farzad, Scarfo, and Saha are as discussed above. Furthermore, Wing teaches a method of generating CAR T cells comprising:
primary lymphocytes from normal donors were provided by the University of Pennsylvania Human Immunology Core;
CD4+ and CD8+ T cells were cultured separately with CD3/CD28-activating Dynabeads at a bead-to-cell ratio of 3. Approximately 24 hours after activation, T cells were transduced with lentiviral vectors (expressing CARs for CD19 or FR-α) at an MOI of 5, by adding the virus supernatant to T-cell cultures;
Beads were removed from cultures at day 5, and T cells were counted and fed every day after day 5. T cells were cryopreserved when returning to the resting state, as determined by decreased growth kinetics and cell size (i.e. expansion). Although Wing does teach expanding the CART cells, this is not required by the claims as this is an optional step;
After 3 or 5 days, mice were treated with one intravenous injection of 1x107 CART cells (50%CAR+, 1:1CD4:CD8) (page 606, column 1, paragraph 6-column 2, paragraph 1 and page 607, column 1, paragraph 4).
The combined teachings of Wing, Farzad, Scarfo, and Saha do not teach wherein the cell is isolated from the subject receiving the cancer treatment.
However, Miliotou teaches a method of generating CAR T-cells using autologous cells isolated from a patient. Autologous T-cells, isolated through leukapheresis, are harvested and genetically modified ex vivo, using viral and non-viral transfection methods. Modified T-cells are then expanded in culture. When the CAR T cell product is prepared and passed all the quality control testing, the patient in most cases receives lymphodepleting chemotherapy, followed by CAR T-cell infusion (page 6, column 2, paragraph 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of generating CAR T cells of the combined teachings of Wing, Farzad, Scarfo, and Saha by using autologous T cells isolated from the patient, as identified by Miliotou to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Miliotou teaches that using autologous T cells from the patient is a well known procedure and avoids autoimmunity. As such, it would have been obvious that the method of Wing, Farzad, Scarfo, and Saha could be modified to use autologous T cells for modification and generation of CAR T-cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Response to Arguments
Applicant's arguments filed October 9, 2025, are acknowledged and have been addressed above.
Claims 1 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Wing et al. (Cancer Immunol Res 6: 605-616. 2018; Published May 2018) in view of Farzad et al. (Molecular Therapy-Oncolytics 1: 1-9. 2014), Scarfo et al. (Journal for ImmunoTherapy of Cancer 5: 1-8. 2017), and Saha et al. (Oncoscience 4: 7-8. 2017) as applied to claim 1 above, and further in view of Bai et al. (International Journal of Oncology 21: 685-694. 2002) and Feuerer et al. (Nature Medicine 7: 452-458. 2001). This rejection is repeated with regards to the rejection in the Non-final Office action mailed on June 16, 2025.
The teachings of Wing, Farzad, Scarfo, and Saha are as discussed above.
The combined teachings of Wing, Farzad, Scarfo, and Saha do not teach wherein the method of treating a cancer comprises: (a) isolating immune cells from the subject; (b) generating or expanding a population of immune cells specific for an oncolytic virus by a method comprising: stimulating the immune cells by culture in the presence of antigen presenting cells (APCs) presenting a peptide of the oncolytic virus, and; (c) administering at least one immune cell specific for the oncolytic virus to the subject.
Bai teaches an optimized ex vivo stimulation protocol for cancer reactive memory T-cells (MTC) based on autologous dendritic cells (DC). As source of tumor antigens we used lysates from unmodified tumor cells or from tumor cells infected with Newcastle Disease Virus (NDV) which contain IFN-α inducing viral dsRNA (an oncolytic virus). Supernatants from cocultures of MTC and TuN-L pulsed DC contained increased titers of IFN-a and IL-15. The results suggest that an autologous DC preparation pulsed with viral oncolysate includes danger signals (e.g. dsRNA, cytokines, HSP molecules) and is superior for MTC stimulation to a DC preparation pulsed with lysate from non-infected tumor cells (abstract). Bone marrow (BM) samples were taken from primary breast carcinoma patients during operation (page 686, column 1, paragraph 4). Tumor cell lysate (Tu-L) was produced by 5 cycles of shock-freezing and thawing of the cells followed by low speed centrifugation to remove subcellular particles. 104 DC were pulsed for 20 h with 200 μg Tu-L protein/lx106 cells/ml. Lysate from virus infected tumor cells (TuN-L) was produced in the same way as Tu-L except that the Tu cells were first infected for various length of time with NDV (page 687, column 1, paragraph 2). DCs pulsed with different antigens were co-incubated with autologous T cells for 40 hours (page 687, column 1, paragraph 5). Although Bai does not specifically teach that a peptide of the oncolytic virus is presented to the T cells by the dendritic cells, it would have been well understood that the tumor cell lysates from NDV infected cells would include NDV antigens that would be presented to the T cells.
Feuerer teaches that DCs were pulsed with the lysates from autologous tumors, MCF-7 and HeLa cells or from U937 cells and PBMC (as a source of irrelevant antigens) followed by co-incubation with autologous bone-marrow–derived T cells or peripheral blood T cells (DC:T cell ratio = 1:5) for 20 h. The cell suspension containing T cells (5 × 106) and DCs (1 × 106) was injected (i.p.) into mice 16 d after tumor implantation (page 458, column 1, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method of treating cancer using BiTEs of the combined teachings of Wing, Farzad, Scarfo, and Saha with the ex vivo stimulation of T cells with and administration of autologous DCs and T stimulated T cells of Bai and Feuerer to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to combine with a reasonable expectation of success because Bai teaches that supernatants from cocultures of MTC and TuN-L pulsed DC contained increased titers of IFN-a and IL-15. The results suggest that an autologous DC preparation pulsed with viral oncolysate includes danger signals (e.g. dsRNA, cytokines, HSP molecules) and is superior for MTC stimulation to a DC preparation pulsed with lysate from non-infected tumor cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Response to Arguments
Applicant's arguments filed October 9, 2025, are acknowledged and have been addressed above.
Claims 1, 46, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Wing et al. (Cancer Immunol Res 6: 605-616. 2018; Published May 2018) in view of Farzad et al. (Molecular Therapy-Oncolytics 1: 1-9. 2014), Scarfo et al. (Journal for ImmunoTherapy of Cancer 5: 1-8. 2017), and Saha et al. (Oncoscience 4: 7-8. 2017) as applied to claims 1 and 46 above, and further in view of Maldini et al. (Nature Reviews Immuno 18:605-616.2018). This rejection is repeated with regards to the rejection in the Non-final Office action mailed on June 16, 2025.
The teachings of Wing, Farzad, Scarfo, and Saha are as discussed above.
The combined teachings of Wing, Farzad, Scarfo, and Saha do not teach wherein the CAR T cell comprises a CAR specific against the oncolytic virus.
However, Maldini reviews that CAR T cells specific against virus were well known (see entire document).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have included a CAR specific against the oncolytic adenovirus viral vectors of the combined teachings of Wing, Farzad, Scarfo, and Saha to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to choose this option with a reasonable expectation of success because Maldini teaches when the viral specific CAR T cells are exposed to the viral antigens robust CAR T cell proliferation and augmented antitumor activity is achieved in vivo (p. 608, col1, 3rd para.).
Response to Arguments
Applicant's arguments filed October 9, 2025, are acknowledged and have been addressed above.
Claims 25-27, 40, 44, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Wing et al. (Cancer Immunol Res 6: 605-616. 2018; Published May 2018) in view of Farzad et al. (Molecular Therapy-Oncolytics 1: 1-9. 2014), Scarfo et al. (Journal for ImmunoTherapy of Cancer 5: 1-8. 2017), and Saha et al. (Oncoscience 4: 7-8. 2017), as evidenced by Fajardo et al. (Cancer Res 77: 2052-2063. 2017). This rejection is repeated with regards to the rejection in the Non-final Office action mailed on June 16, 2025.
Regarding claim 25, Wing teaches a method of treating cancer comprising establishing xenograft tumors by subcutaneous injection of HCT116 (colon cancer) or Panc-1 (pancreatic cancer) tumor cells into the flanks of NSG mice. For Panc-1, a solution of 50% Matrigel (BD Biosciences) and 50% PBS was used. After mean tumor volume reached 100 mm3, mice were treated with one intratumoral injection of OAd-BiTE (1x109 vp) or PBS. After 3 or 5 days, mice were treated with one intravenous injection of 1x107 CART cells (50%CAR+, 1:1CD4:CD8). In HCT116 tumors, a second CART-cell injection was performed after one week (page 607, column 1, paragraph 4 and page 607, column 2, paragraph 5). Wing teaches that bispecific T-cell engagers (BiTE) are immunotherapeutic molecules consisting of an anti-CD3 single-chain variable fragment (scFv) fused to an antitumor-associated antigen scFv via a flexible linker. Wing uses an ICO15K-cBiTE, an OAd [oncolytic adenovirus] that secretes an EGFR-targeting BiTE (OAd-BiTE) upon infection of malignant cells (page 605, column 2, paragraph 4-page 606, column 1, paragraph 2).
Wing does not teach wherein the virus comprising nucleic acid encoding an antigen-binding molecule is a helper-dependent adenovirus (HDAd).
However, Farzad teaches that oncolytic adenoviruses (Onc.Ads) produce significant antitumor effects but as single agents they rarely eliminate tumors. Investigators have therefore incorporated sequences into these vectors that encode immunomodulatory molecules to enhance antitumor immunity. Successful implementation of this strategy requires multiple tumor immune inhibitory mechanisms to be overcome, and insertion of the corresponding multiple functional genes reduces the titer and replication of Onc.Ads, compromising their direct ant-tumor effects. By contrast, helper-dependent (HD) Ads are devoid of viral coding sequences, allowing inclusion of multiple transgenes. HDAds, however, lack replicative capacity. Since HDAds encode the adenoviral packaging signal, we hypothesized that the coadministration of Onc.Ad with HDAd would allow to be amplified and packaged during replication of Onc.Ad in transduced cancer cells. This combination could provide immunostimulation without losing oncolytic activity. We now show that coinfection of Onc.Ad with HDAd subsequently replicates HDAd vector DNA in trans in human cancer cell lines in vitro and in vivo, amplifying the transgenes the HDAd encode. This combinatorial treatment significantly suppresses the tumor growth compared to treatment with a single agent in an immunocompetent mouse model. Hence, combinatorial treatment of Onc.Ad with HDAd should overcome the inherent limitations of each agent and provide a highly immunogenic oncolytic therapy (abstract). Replication machinery of Onc.Ad recognizes coinfected HDAd vector DNA in transduced cancer cells and replicates HDAd vector DNA in trans, leading to multiple cycles of production and release of both the oncolysis and the transgenes encoded in an HDAd. These vectors are packaged into newly synthesized Ad particles and distribute to surrounding cells including tumor stroma (Figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the oncolytic adenovirus viral vectors of Wing with the combinatorial helper dependent adenoviral vector and oncolytic adenoviral vector of Farzad to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Farzad teaches that oncolytic adenoviruses (Onc.Ads) produce significant antitumor effects but as single agents they rarely eliminate tumors. Incorporating additional sequences into these vectors that encode immunomodulatory molecules can enhance antitumor immunity but insertion of the corresponding multiple functional genes reduces the titer and replication of Onc.Ads, compromising their direct ant-tumor effects. By contrast, helper-dependent (HD) Ads are devoid of viral coding sequences, allowing inclusion of multiple transgenes. Farzad shows that coinfection of Onc.Ad with HDAd subsequently replicates HDAd vector DNA in trans in human cancer cell lines in vitro and in vivo, amplifying the transgenes the HDAd encode. This combinatorial treatment significantly suppresses the tumor growth compared to treatment with a single agent in an immunocompetent mouse model. Hence, combinatorial treatment of Onc.Ad with HDAd should overcome the inherent limitations of each agent and provide a highly immunogenic oncolytic therapy. As such, it would have been obvious to use HDAd viruses with oncolytic adenoviruses as improves the efficacy of their anti-tumor activity. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Farzad teaches co-infection of an Onc.Ad with an HDAd encoding human GM-CSF and human IL-12p70 in tumor bearing mice and this combination significantly reduced tumor size (page 5, column 1, paragraph 2-column 2, paragraph 1).
The combined teachings of Wing and Farzad do not teach wherein the HDAd further comprises nucleic acids encoding IL-12 and anti-PD-L1 antibody.
However, Scarfo teaches that one method to enhance CAR T-cell efficiency is to induce the local release of stimulatory factors that promote anti-tumor immune responses, such as IL-12. Combining CAR T-cells with IL-12 secretion showed complete eradication of tumor and prolonged persistence of CAR T-cells. Furthermore, Scarfo teaches that CAR T-cells are susceptible to PD-1 mediated suppression that the combination of CAR T-cells and PD-1 antibodies improved antitumor activity. Scarfo directly contemplates an alternative way of blocking immune checkpoints is to use genetic engineering strategies instead of administering immune checkpoint antibodies directly (page 4, column 2, paragraph 4-page 6, column 1, paragraph 2)
Furthermore, Saha teaches that oncolytic viruses that express IL-12 showed synergized with anti-PD-1 antibodies to improve survival in cancer patients (page 67, column 1, paragraph 2-column 2, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the helper dependent adenoviral vector of the combined teachings of Wing and Farzad by including IL-12 and anti-PD-L1 antibody genes in the HDAd vector to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Scarfo, Saha, and Farzad all teach that expressing additional immunomodulatory agents, such as IL-12 and anti-PD-L1, improve anti-tumor activity of CAR T-cells (Scarfo) and oncolytic viruses (Saha and Farzad). Furthermore, Farzad successfully reduced to practice that encoding IL-12p70 and GM-CSF in the HDAd for co-administration into tumor bearing mice significantly reduced tumor size and, as stated supra, teaches that incorporating additional sequences into oncolytic vectors that encode immunomodulatory molecules can enhance antitumor immunity but insertion of the corresponding multiple functional genes reduces the titer and replication of Onc.Ads, compromising their direct ant-tumor effects. By contrast, helper-dependent (HD) Ads are devoid of viral coding sequences, allowing inclusion of multiple transgenes. As such, it would have been obvious to incorporate IL-12 and anti-PD-L1 genes in the HDAd virus because this will improve anti-tumor activity and incorporating these genes in the oncolytic adenovirus risks negatively impacting its antitumor activity. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 26, Fajardo evidences that the ICO15K-cBiTE of Wing is arranged VLC225–VHC225–VHCD3–VLCD3. C225 is synonymous with EGFR (page 2053, column 1, paragraph 5). Bispecific T-cell engagers (BiTE) are novel immunotherapeutic molecules composed of two single-chain antibodies (scFV) connected through a flexible peptide linker. One of the scFV is specific for a tumor-associated antigen on target cells (EGFR), whereas the second scFV is specific for the CD3 T-cell coreceptor (page 2052, column 2, paragraph 2).
Regarding claim 27, Wing uses an ICO15K-cBiTE, an OAd [oncolytic adenovirus] that secretes an EGFR-targeting BiTE (OAd-BiTE) upon infection of malignant cells (page 605, column 2, paragraph 4-page 606, column 1, paragraph 2).
Regarding claim 40, It is further envisaged that the pharmaceutical composition of the disclosure comprises the vectors defined herein above. The pharmaceutical composition of the present disclosure may further comprise a pharmaceutically acceptable carrier such as PBS as was suggested for the composition of Farzad (page 8, Animals and adenovirus injection, see also Fig. 4).
Regarding claim 44, Wing teaches a method of treating HCT116 (colon cancer) or Panc-1 (pancreatic cancer) cancer (page 607, column 1, paragraph 4 and page 607, column 2, paragraph 5).
Regarding claim 47, Wing teaches that they assessed whether the treatment with OAd-BiTE could enhance T-cell trafficking to tumors with low expression of the target antigen (Panc-1). Biodistribution studies in mice showed enhanced FR-CART–cell accumulation (>6-fold) at the tumor site in the presence of OAdBiTE at early time points after injection (page 612, column 1, paragraph 2 and Fig. 6C). As such, there would be a combination of helper dependent adenoviruses, oncolytic adenoviruses, and CAR T-cells in vivo.
Response to Arguments
Applicant's arguments filed October 9, 2025, are acknowledged and have been addressed above.
Claims 25 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Wing et al. (Cancer Immunol Res 6: 605-616. 2018; Published May 2018) in view of Farzad et al. (Molecular Therapy-Oncolytics 1: 1-9. 2014), Scarfo et al. (Journal for ImmunoTherapy of Cancer 5: 1-8. 2017), and Saha et al. (Oncoscience 4: 7-8. 2017), as applied to claim 25 above, and further in view of Niemann et al. (Virus Genes 53: 700-706. 2017). This rejection is repeated with regards to the rejection in the Non-final Office action mailed on June 16, 2025.
The teachings of Wing, Farzad, Scarfo, and Saha are as discussed above.
The combined teachings of Wing, Farzad, Scarfo, and Saha do not teach wherein the virus comprising nucleic acid encoding an antigen-binding molecule comprises nucleic acid encoding an enzyme capable of catalysing conversion of a non- toxic factor to a cytotoxic form, and wherein the enzyme is selected from: thymidine kinase, cytosine deaminase, nitroreductase, cytochrome P450, carboxypeptidase G2, purine nucleoside phosphorylase, horseradish peroxidase and carboxylesterase.
However, Niemann teaches that oncolytic adenoviruses have shown to be safe tools to selectively infect and eliminate cancer cells. To compensate for insufficient tumor transduction, different effector genes have been incorporated into the viral genome to enhance cell death and viral spreading or to confer cytotoxicity to non-infected neighboring cells. These so-called ‘armed’ oncolytic viruses have been equipped with proapoptotic genes to enhance cell death. A further type of utilized genes are pro-drug activators, whose expression facilitates local enzymatic transformation of a systemically applied non-toxic pro-drug into a toxic agent, that is also delivered to non-infected, neighboring cells via gap-junctions leading to enhanced ‘bystander’ cell killing. Examples are viruses carrying the herpes simplex virus-1 thymidine kinase (HSV-tk) or the bacterial cytosine deaminase (CD). Expression of these genes leads to the conversion of pro-drugs, such as ganciclovir or 5-fluorocytosine, into toxic substances, significantly enhancing the anti-tumor activity compared to unarmed oncolytic virus (page 703, column 1, paragraph 2-column 2, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating cancer using BiTEs of the combined teachings of Wing, Farzad, Scarfo, and Saha by adding a nucleic acid encoding an enzyme capable of catalysing conversion of a non- toxic factor to a cytotoxic form to the HDAd viral vector as identified by Niemann to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Niemann teaches that to compensate for insufficient tumor transduction, different effector genes have been incorporated into the viral genome to enhance cell death and viral spreading or to confer cytotoxicity to non-infected neighboring cells. These so-called ‘armed’ viruses have been equipped with pro-drug activators, whose expression facilitates local enzymatic transformation of a systemically applied non-toxic pro-drug into a toxic agent, that is also delivered to non-infected, neighboring cells via gap-junctions leading to enhanced ‘bystander’ cell killing. Expression of these genes leads to the conversion of pro-drugs, such as ganciclovir or 5-fluorocytosine, into toxic substances, significantly enhancing the anti-tumor activity compared to unarmed oncolytic virus. Furthermore, as stated supra, Farzad teaches that adding genes to the oncolytic virus reduces titer and replication. As such, it would have been obvious to include these genes in the HDAd (and not the Onc.Ad) viral vector to improve anti-tumor activity especially in non-infected neighboring cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Response to Arguments
Applicant's arguments filed October 9, 2025, are acknowledged and have been addressed above.
Conclusion
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.
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/KEENAN A BATES/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631