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 .
Election/Restrictions
Applicant's election with traverse of I. Claims 1-14 drawn to a method of treating cancer comprising administering MSCs to stimulate the immune system in the reply filed on 02/04/2025 is acknowledged. The traversal is on the grounds that the applicant disagrees and the Office has not demonstrated that the related inventions are distinct and the office has not made a showing of undue burden. This is not found persuasive because the examiner has explained how the inventions are distinct and simply stating that one disagrees with the distinction does not provide any evidence to the contrary. The examiner has stated the reasons there would be serious search or examination burden in the restriction at the top of page 4.
Examiner would like to make the record clear that there was a typographical error in the restriction requirement. Group I drawn to administering MSCs to stimulate the immune system should include claims 1-13 and not 14. Claim 14 is drawn to a treatment with MSC-derived exosomes belongs with Group II drawn to administering exosomes.
The requirement is still deemed proper and is therefore made FINAL.
Claims 14-20 withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable generic or linking claim.
Status of Claims
Claims 1-13 and 21-23 are under examination.
Claim 14-20 are withdrawn.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
The following rejection is maintained from the previous Office Action and modified in view of Applicant’s amendments filed 9/22/2025.
Claims 1-7 and 9-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shah (Advanced Drug Delivery Reviews, 2011).
Regarding claim 1, Shah teaches a treatment of cancer via engineered MSCs which after implantation which have suppressed the immune system (page 740, left column). Shah teaches future administration of the MSCs into humans (page 745, section 6).
Regarding claim 2, Shah teaches transplantation of MSCs engineered to express interleukin-18 where the immune modulation is enhanced T cell infiltration (page 741, left column). Shah further teaches that the delivery of interleukins via MSCs by activated cytotoxic lymphocytes and Natural killer cells (page 741, left column).
Regarding claim 3, Shah teaches the altering of T cells via the interleukin expressing MSCs injected into the tumor which increases the density of intratumoral T cells resulting in increased animal survival (page 741, section 3.1).
Regarding claim 4, Shah teaches the delivery of interleukins via MSCs improve the anti-cancer immune surveillance by activating cytotoxic lymphocytes and natural killer cells (page 741, section 3.1).
Regarding claim 5, Shah teaches MSCs as a carrier for oncolytic adenovirus and delivery for infection and replication in malignant cells to eradicate tumors (page 742, section 3.4)
Regarding claim 6, Shah teaches local radiotherapy for tumor treatment where there is sequential tumor irradiation (page 743, section 4).
Regarding claim 7, Shah teaches that the heterogeneity of tumors requires various treatment regimens which combine MSC based therapies with anti-tumor agents (page 743, section 4). Shah teaches the combined approach of MSC-mediated delivery of the therapeutic TRAIL gene delivery factor with XIAP inhibition to suppress metastatic growth of pancreatic carcinomas. Shah also teaches the further supplementation of micro-RNA inhibitors targeting micro-RNA 21 and PI3-kinase inhibitors. Shah further teaches numerous fusion variants that contained therapeutic (TRAIL) and diagnostic (luciferase). Shahs various approaches for delivery of anti-proliferative agents and novel stem-cell based proapoptotic therapies to improve various cancer treatments (page 745, section 5.1). Shah also teaches the delivery of IFN-α is frequently used as an adjuvant (page 741, section 3.2).
Regarding claim 9, Shah teaches the prevention of tumor formation during a synergistic approach using MSC based therapeutics with other anti-tumor agents (page 743, section 4).
Regarding claim 10, Shah teaches the treatment of subjects with engineered MSCs resulted in reduction in tumor volumes (page 742, section 3.3).
Regarding claim 11, Shah teaches the intratumoral injection of MSCs (page 741, section 3.1) and sequential treatment of radiation followed by engineered UCB-MSCs to enhance apoptosis in glioma cells (page 743, section 4).
Regarding claim 12, Shah teaches the delivery of interleukins via MSCs improve the anti-cancer immune surveillance by activating cytotoxic lymphocytes and natural killer cells (page 741, section 3.1). Shah further teaches the treatment of tumors with engineered MSCs provide sustained expression of interferon (IFN)-γ in sera and tumor sites. Shah teaches the treatment w resulted in a higher density of intratumoral T-cells in rats receiving combined therapies (page 741, section 3.1).
Regarding claim 13, Shah teaches antitumor properties of the MSCs (page 741, section 3.2), which read on MSC1 phenotype because they are proinflammatory and antitumorigenic. Shah et al. teach administration of MSCs expressing IFN-α which reduced the growth of melanoma cells and significantly prolonged survival (page 741, section 3.2). Shah teaches the anti-tumor effects of IFN-α when delivered via MSCs (page 741, section 3.2). Shah teaches administration of MSCs expressing IFN-α (page 741, section 3.2) which reads on administering one or more types of MSCs which results in at least one MSC in the one or more types of MSCs having an anti- tumorigenic MSC1 phenotype, wherein the at least one MSC having the anti-tumorigenic MSC1 phenotype secretes tumor necrosis factor-alpha (TNF-α).
Rejections maintained and rejection to newly added claim 21 below necessitated by amendment filed 09/22/2025:
Claims 1-2, 8, and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pittenger et al (WO2005/093044 A1).
Regarding claim 1, Pittenger teaches treatment of cancer in a subject by administering an effective amount of mesenchymal stem cells (page 28, claim 18). Pittenger teaches the MSCs administered alter the immune response in the subject (page, claim 14). Pittenger teaches the mammal can be a human (page 5, paragraph 2).
Regarding claim 2, Pittenger teaches MSCs interact with dendritic cells which leads to the secretion of IFN-β which acts as a tumor suppressor to treat cancer (page 8, final paragraph).
Regarding claim 8, Pittenger teaches an effective amount of mesenchymal stem cells (page 1, abstract) along with an acceptable pharmaceutical carrier can be injected to a subject(page 5, paragraph 3).
Regarding claim 21, Pittenger teaches the MSCs increase in IFN-y secretion from CD4+ cells (page 17, Figure 4).
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.
New rejections necessitated by amendment filed 9/22/2025:
Claims 22 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Shah (Advanced Drug Delivery Reviews, 2011) as applied to claim 1 above and in further view of Ruano et al. (Mol Ther., 2020).
Shah teaches a treatment of cancer administering engineered MSCs (page 740, left column), as in claim 1.
Regarding claim 22, Shah teaches a method for treatment of cancer and tumors. Shah does not teach MSCs are infected with ICOVIR-5 virus.
Ruano et al. teach Celyvir, an advanced therapy medicine that combines autologous mesenchymal stem cells (MSCs) carrying an oncolytic adenovirus (page 1033, abstract). Ruano et al. teach a first-in-human, first-in-child trial for patients with relapsed/refractory solid tumors using Celyvir (page 1033, abstract). Ruano et al. teach MSCs infected with ICOVIR-5 virus (page 1040, Manufacturing and Administration of Celyvir).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the teachings of Shah for a method of treating cancers and tumors by administering a composition with MSCs carrying an oncolytic adenovirus with the teachings of Ruano et al. for MSCs which carry the ICOVIR-5 oncolytic adenovirus. Ruano et al. provide motivation by teaching that ICOVIR-5 is a conditionally replicative oncolytic adenovirus, where the Arg-Gly-Asp (RGD) motif has been incorporated to enhance infectivity, and the virus does not replicate in healthy quiescent cells (page 1040, ICOVIR-5). Ruano et al. further teach the safety of ICOVIR-5 within their human trial (page 1033, abstract). One of skill in the art would have had a reasonable expectation of success at combining Shah and Ruano et al. because both teach methods of treating tumors utilizing MSCs as a carrier for oncolytic adenoviruses.
Regarding claim 23, Shah teaches treating a tumor via administration of MSCs. Shah does not teach administration with one or more additional agents which are chemotherapeutic drugs.
Ruano et al. teach Celyvir, an advanced therapy medicine that combines autologous mesenchymal stem cells (MSCs) carrying an oncolytic adenovirus (page 1033, abstract). Ruano et al. teach administration of Celyvir with other antitumoral agents including chemotherapeutics (page 1038, paragraph 5).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the teachings of Shah for a method of treating cancers and tumors by administering a composition with MSCs carrying an oncolytic adenovirus with the teachings of Ruano et al. for administration of the MSCs carrying an oncolytic adenovirus in combination with a chemotherapeutic agent. Ruano et al. provide motivation by teaching that non-lymphodepleting chemotherapeutics destroy cancer cells by mechanisms of action different to those of oncolytic viruses without hampering the contributing role of the adaptive immune system, and oncolytic virotherapy enhances tumor infiltration by immune cells, which optimizes the subsequent effects of checkpoint inhibitors (page 1038, paragraph 5). One of skill in the art would have had a reasonable expectation of success at combining Shah and Ruano et al. because both teach methods of treating tumors utilizing MSCs as a carrier for oncolytic adenoviruses.
Response to Arguments
Applicant’s Arguments: Applicant argues that Pittenger does not disclose administering an effective amount of a pharmaceutical composition and or formulation comprising one or more types of mesenchymal stem cells (MSCs).
Examiner’s Response: Pittenger in claim 18 teaches a method of treating cancer in an animal, comprising administering to said animal mesenchymal stem cells in an amount effective to treat cancer (page 28, claim 18). Pittenger teaches mesenchymal stem cells may be administered in conjunction with an acceptable pharmaceutical carrier. Pittenger further teaches the mesenchymal stem cells may be administered as a cell suspension in a pharmaceutically acceptable liquid medium for injection (page 5, paragraph 3).
Applicant argues, the cited portions of Shah make no mention of a pharmaceutical composition and/or formulation comprising MSCs, or administering an effective amount of such a composition and/or formulation. Applicant argues that Shah fails to disclose at least one of enhancing cytotoxicity of one or more CD8+ cytotoxic T lymphocytes (CTLs), enhancing cytotoxicity of one or more NK cells, increasing production of one or more cytokines in CD4+ Th1 lymphocytes, or increasing production of one or more cytokines in CD4+ Thl7 lymphocytes.
Examiner’s Response: Shah teaches MSC have inherent tumor-trophic migratory properties, which allows them to serve as vehicles for delivering effective, targeted therapy to isolated tumors and metastatic disease (page 739, abstract). The MSCs administered to a patient are a pharmaceutical composition which is delivered at an effective amount.
Applicant argues that Shah fails to disclose an increased number of cytotoxic NK cells expressing at least one of: interferon gamma (IFN-y), Fas ligand (FASL), and granzyme B.
Examiner’s Response: Shah teaches the delivery of interleukins via MSCs improve the anti-cancer immune surveillance by activating cytotoxic lymphocytes and natural killer cells (page 741, section 3.1). Furthermore, the activation of cytotoxic lymphocytes would perform their role in destroying infected or damaged cells and furthermore the proliferation of such cell would provide more cytotoxic cells thereby enhancing the cytotoxic function. Shah also teaches a recombinant protein which boosts the cytotoxicity in an environment(page 742, section 3.5).
Applicant argues Shah fails to disclose at least one MSC in the one or more types of MSCs having an anti- tumorigenic MSCI phenotype, wherein the at least one MSC having the anti-tumorigenic MSCI phenotype secretes tumor necrosis factor-alpha (TNF-a) and or interferon-gamma (IFN-y).
Examiner’s Response: Shah further teaches the treatment of tumors with engineered MSCs provide sustained expression of interferon (IFN)-γ in sera and tumor sites. Shah teaches the treatment resulted in a higher density of intratumoral T-cells in rats receiving combined therapies (page 741, section 3.1). This reads on an increased number of CD4+ helper T cells and an increased number of CD8+ cytotoxic T lymphocytes.
Applicant argues that a skilled artisan would not have been motivated to produce MSCs that express both IL-7 and IFN-y in the same cell as taught by Shah.
Examiner’s Response: Shah teaches antitumor properties of the MSCs (page 741, section 3.2), which read on MSC1 phenotype because they are proinflammatory and antitumorigenic. Shah makes obvious an MSC expressing IFN-γ. Shah provides motivation to produce MSCs that express both IL-7 and IFN-γ in the same cell because both IL-7 and IFN-γ in combination provide improved anti-tumor immunity, decreasing tumor volume (page 741, section 3.1). Therefore, one of ordinary skill in the art would have been motivated to combine these elements.
Sah further teaches a significant reduction in glioma volumes was seen as a result of combining peripheral immunization using interferon gamma (IFN-γ) transduced autologous tumor cells with local intratumoral delivery of MSC expressing interleukin 7 (page 741, section 3.1). Shah teaches human MSC expressing IL-12 have been shown to have anti-tumor effects and revealed sustained expression (IFN)-γ in sera and tumor sites (page 741, section 3.1). Shah teaches the anti-tumor effects of IFN-α when delivered via MSCs (page 741, section 3.2).
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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/C.L.M./Examiner, Art Unit 1638
/Anna Skibinsky/
Primary Examiner, AU 1635