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 .
Claim Status
Claims 4-5, 7, and 12-20 have been cancelled and claims 1-3, 6, 8, 21, and 24-26 have been amended, as requested in the amendment filed on 12/19/2025. Following the amendment, claims 1-3, 6, 8-11, and 21-26 are pending in the instant application.
Claims 1-3, 6, 8-11, and 21-26 are under examination in the instant office action.
Drawings - Objection Withdrawn
Applicant has submitted replacement drawing sheets wherein the labels/text of Figures 5D/F are clear and legible. As such, the objection to the drawings is withdrawn.
Specification - Objection Withdrawn
Applicant has amended the specification to include symbol of trademarked terms indicating use in commerce and has noted that terms are appropriately capitalized. As such, the objection to the specification regarding the use of trade names and marks used in commerce is withdrawn.
Claim Objections - Withdrawn
Claim 1 was objected to for a typographical error. Applicant has amended claim 1 to correct said typographical error, and as such the objection to claim 1 is withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 8-11 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite. Specifically, claim 8 recited the term “cancer”, which is defined on Page 20 of the specification as “the physiological condition in mammals that is typically characterized by unregulated cell growth” and thus the claim was considered indefinite because it was unclear as to how cancer may be otherwise, i.e., atypically, characterized. Claim 8 has been amended to recite a specific group of cancers which may be treated by the method of claim 8. As such, claim 8 is now considered to be definite. Therefore, the rejection of claim 8 and subsequently dependent claims 9-11 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Claims 1-3, 6, 8-11, and 21-26 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement. Applicant has amended claim 1, and subsequently dependent claims, to recite “isolated” mesenchymal stem cells (MSCs); in view of this amendment the entire scope of the claims are now enabled. Therefore, the rejection of claims 1-3, 6, 8-11, and 21-26 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement, is withdrawn.
Claim 21 was rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim from which it depends. Applicant has amended claim 21 to recite a pharmaceutical composition comprising “(a) an isolated mesenchymal stem cell (MSC) selected from the group consisting of (i) an MSC infected with an oncolytic virus selected from respiratory syncytial virus (RSV), herpes simplex virus, vesicular stomatitis virus, poliovirus, reovirus, senecavirus, and RIGVIR (ii) an MSC that over-expresses interferon-beta and is IDO-deficient; and (iii) an MSC having both features of (i) and (ii); and(b) a pharmaceutically acceptable carrier or diluent”. As such, claim 21 now further limits the claim from which it depends. As such, the rejection of claim 21 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is withdrawn.
Claim Rejections - 35 USC § 103 - New
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
It is noted that claim rejections below still rely on the same prior art references and teachings presented in the previous Office Action, but have been updated to address the instantly amended claims. The addition of a new prior art reference to address the amended claims constitutes the new grounds of rejection presented below.
Claims 1, 6, 8, 11, and 21-26 are rejected under 35 U.S.C. 103 as being unpatentable over US 2009/0202479 A1 (previously cited on PTO-892; herein after referred to as "Shi") in view of non-patent literature by Ahn et. al. (PLOS ONE, 2013, 8(9), 1-11; previously cited on PTO-892; herein after referred to as "Ahn"), non-patent literature by Ling et. al. (Cancer Res., 2014, 74(5), 1576-1587; herein after referred to as “Ling”), and non-patent literature by Ed Davis (Technical Note retrieved from genecopoeia.com, published online in 2014; herein after referred to as “Davis”).
With regard to claim 1, Shi teaches a method for enhancing a local immune response involving administering to a subject in need of treatment an effective amount of iNOS-deficient
or IDO-deficient mesenchymal stem cells thereby enhancing a local immune response; in certain embodiments, the local immune response is to a tumor (Paragraph 0011), wherein Shi further teaches that chemical blockade of iNOS or IDO reverts immunosuppression (Paragraph 0019). A subject in need of treatment can be a mammal (e.g., a human, monkey, dog, cat, horse, etc.) with a particular disease or disorder associated with an adverse immune response wherein, in particular embodiments, the subject is human (Paragraph 0031). Subjects benefiting from treatment with the iNOS and/or IDO-deficient MSCs include a subject with a tumor, wherein iNOS and/or IDO-deficient MSCs provoke effective immune responses to tumors (Paragraph 0034). Interferon treatment has been indicated for use in the treatment of a several cancers including ovarian cancer and primary cancers of pleura and Shi presents data that indicates that the efficacy of IFN treatment or similar immune cancer therapies can be increased by suppressing NO production or IDO activity in the tumor microenvironment; accordingly, the invention also embraces a method for enhancing the efficacy of an immune therapy of cancer by administering to a subject receiving an immune therapy treatment an effective amount of a nitric oxide synthase (NOS) and/or IDO inhibitor (Paragraph 0035). Example 9 discloses that the combination of a NOS inhibitor with IFNγ promoted mouse melanoma therapy and Shi further indicates that inhibition of one or more of NO, IDO or PGE2 can dramatically enhance cancer treatment; therefore, when immunotherapies such as those based on cytokines, vaccination,
antibodies, dendritic cells, or T cells, are used to treat cancer, the tumor stromal cells might be responsible for the inability of these treatment to completely eradicate tumors in most cases and the combined used of inhibitors to iNOS and IDO with immunotherapies could provide effective ways to eradicate tumors (Paragraph 0074). Thus, Shi teaches MSCs that are IDO-deficient and their use in cancer treatment. However, Shi does not teach or suggest MSCs that overexpress interferon beta.
Ahn teaches that adipose tissue-derived mesenchymal stem cells (AT-MSCs) are attractive cell-therapy vehicles for the delivery of anti-tumor molecules into the tumor microenvironment; the innate tropism of AT-MSCs for tumors has important implications for
effective cellular delivery of anti-tumor molecules, including cytokines, interferon, and pro-drugs (Abstract). IFN-β transduced canine AT-MSCs (cAT-MSC-IFN-β) inhibited the growth of LMeC canine melanoma cells in direct and indirect in vitro co-culture systems while in animal experiments using BALB/c nude mouse xenografts, which developed by injecting LMeC cells, the combination treatment of cAT-MSC-IFN-β and low-dose cisplatin significantly reduced tumor volume compared with the other treatment groups (Id.). The cytokine interferon-beta (IFN-β) is known to have potent pro-apoptotic effects and is capable of inhibiting both tumor growth and angiogenesis wherein several reports indicate that mesenchymal stem cells engineered to secrete IFN-β trafficked to and reduced the tumor burden of melanoma, breast carcinoma, prostate cancer, and lung metastases; it has been reported that the combination of IFN-β cytokine therapy with anti-cancer drugs synergistically suppressed the cell growth of hepatocellular carcinoma and melanoma (Pages 1-2). The authors present evidence of a significant tumor suppression by cAT-MSC alone on canine melanoma (LMeC) in vitro and in vivo which was enhanced further when cAT-MSC expressed IFN-β; the authors further investigated the effects of stem cell-mediated gene delivery of IFN-β in combination with systemic treatment with low doses of cisplatin in a canine malignant melanoma xenograft model wherein such a treatment combination resulted in a significant additive anti-tumor effect (Page 2, Column 1, Paragraph 2). Thus, Ahn implicates MSCs engineered to express (i.e., overexpress) IFN-β in therapeutic modalities, wherein IFN-β expression alone enhances MSC performance and IFN-β in combination with other therapeutic modalities results in additive anti-cancer effects.
However, neither Shi nor Ahn disclose CRISPR-mediated knock out of IDO.
Ling discloses that mesenchymal stem cells (MSC) are present in most, if not all, tissues and are believed to contribute to tissue regeneration and the tissue immune microenvironment; murine MSCs exert immunosuppressive effects through production of inducible nitric oxide synthase (iNOS), whereas human MSCs use indoleamine 2,3-dioxygenase (IDO) (Abstract). The authors established a novel humanized system to model human MSCs, using murine iNOS-/-MSCs that constitutively or inducibly express an ectopic human IDO gene, and in this system, inducible IDO expression is driven by a mouse iNOS promoter that can be activated by inflammatory cytokine stimulation in a similar fashion as the human IDO promoter; these IDO-expressing humanized MSCs (MSC-IDO) were capable of suppressing T-lymphocyte proliferation in vitro and in melanoma and lymphoma tumor models, MSC-IDO promoted tumor growth in vivo, an effect that was reversed by the IDO inhibitor 1-methyl-tryptophan (Id.). The authors found that MSC-IDO dramatically reduced both tumor-infiltrating CD8+ T cells and B cells and provide a new line of evidence that interventional targeting of IDO activity could be used to restore tumor immunity in humans, by relieving IDO-mediated immune suppression of MSCs in the tumor microenvironment as well as in tumor cells themselves (Id.). MSC administration significantly altered the distribution within tumor-infiltrating lymphocytes (Fig. 6D–I); in mice administered with either constitutive or inducible IDO-transfected MSCs, CD3+ T-cell numbers in tumors were reduced by 70% in comparison with the mice treated with negative control-transfected iNOS-/- MSCs, wherein the vast majority of this reduction was in the CD8+ T-cell fraction, rather than CD4+ T cells (Fig. 6E and F) (Page 1584; Column 1, Second Full Paragraph). Thus, the study of Ling indicates that in the context of MSCs, IDO expression suppresses T-lymphocyte proliferation and subsequently promotes tumor growth, whereas MSCs that do not express IDO or MSCs treated with IDO inhibitor 1-methyl-tryptophan reversed the suppression of T lymphocyte proliferation; Ling suggests targeting of IDO activity could be used to restore tumor immunity in humans, by relieving IDO-mediated immune suppression of MSCs in the tumor microenvironment as well as in tumor cells.
Davis discloses genome editing, wherein changes the genetic code typically cause a “knockout”, or complete elimination of gene function; the process begins with creation of a double-strand break (DSB) in the chromosome, wherein two tools have been developed for generating DSBs with high efficiency: Transcription Activator-Like Effector Nucleases (TALENs), and Clustered, Regularly Interspaced Palindromic Repeat Associated (CRISPR-Cas) proteins (Page 2). CRISPR-Cas uses a site-specific, 20 nucleotide single guide RNA (sgRNA) to bring the Cas9 nuclease to its target locus and the nuclease cuts both DNA strands of the target; the break must be repaired or the cell will die, so eukaryotic cells respond by two major mechanisms (see Figure 2) wherein (i) non-homologous end joining (NHEJ), re-ligates the two free chromosome ends, but NHEJ is error-prone, often resulting in small insertions or deletions that can disrupt, or knock out, the gene, or (ii) cells can repair DSBs through homologous recombination (HR), which provides researchers more options for gene knockout (Id.). Through such methods, defined deletions can be introduced, insertional mutations can be created, or single bases can be changed, to name a few. Davis further compared genome editing to common knockdown methods using RNAi (e.g., shRNA or siRNA) in Table 1, reproduced below.
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Davis indicates that RNAi-mediated knockdown is preferable to genome editing when changing the genetic code is undesirable; for example, if it is desired to reduce gene function temporarily, one could transiently transfect siRNAs into cells and after a few generations, the siRNAs are lost, restoring normal gene function (Page 3). Alternatively, one can stably integrate shRNAs into the genome and express them from an inducible promoter, wherein the expression of the gene can be turned down and then back up repeatedly, at desired times, and/or in specific tissues. However, to make a true genetic null allele, genome editing is preferable, as well as if it is desirable to introduce a specific point mutation, or correct a pre-existing mutation back to wild type; these goals absolutely depend on genome editing methods (Id.). Thus, Davis establishes the CRISPR-Cas protein systems are established in the art for target gene knockout.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was to filed to (i) knockout IDO expression and (ii) overexpress IFN-β in MSCs. One would have been motivated to combine the teachings of Shi, Ahn, Ling, and Davis in order to develop isolated MSCs with enhanced therapeutic properties, because: (1) Shi recognizes that local immune response can be enhanced by IDO-deficient MSCs (IDO expression and/or activity is reduced by as much as 99%); (2) Ling discloses that MSCs that do not express IDO or MSCs treated with IDO inhibitor 1-methyl-tryptophan reversed the suppression of T lymphocyte proliferation and suggests targeting of IDO activity could be used to restore tumor immunity in humans, by relieving IDO-mediated immune suppression of MSCs in the tumor microenvironment as well as in tumor cells; (3) Ahn recognizes that MSCs engineered to over-express IFN-β enhances MSC performance, wherein in combination with other therapeutic modalities results in additive anti-cancer effects; and (4) Davis discloses that methods of gene knockout, including the CRISPR-Cas system, are known/established in the art. One of ordinary skill in the art would have a reasonable expectation of success because the cited references teach the established, successful methods both gene knockdown and gene knockout, teach that IDO-deficient, IDO-inhibited, and/or non-IDO-expressing MSCs promote T cell proliferation and subsequent immune response, and teach that MSCs engineered to over-express IFN-β when in combination with other therapeutic modalities result in additive anti-cancer effects.
With regard to claim 6, Shi further teaches that mesenchymal stem cells (MSC) are multipotent progenitors for a variety of cell types of mesenchymal cell lineage, including bone, cartilage, fat, tendon, nerve tissue, fibroblasts and muscle cells, wherein mesenchymal stem cells can be isolated and purified from tissue such as bone marrow, blood (including peripheral blood), periosteum, and dermis, and other tissues which have mesodermal origins; human mesenchymal stem cells can be isolated from various tissues and purified when cultured in a specific medium by their selective attachment, termed "adherence," to substrates wherein exemplary methods for deriving/isolating human MSCs are further provided (Paragraphs 0021-0023). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references. Furthermore, treating a human subject, as suggested by Shi (see Paragraph 0031), would be most effectively done with human MSCs to avoid/reduce immune system clearance of the foreign MSCs and so for this advantage choice of human cells is obvious.
With regard to claim 8, Shi teaches a method for enhancing a local immune response involving administering to a subject in need of treatment an effective amount of iNOS-deficient
or IDO-deficient mesenchymal stem cells thereby enhancing a local immune response; in certain embodiments, the local immune response is to a vaccine or tumor (Paragraph 0011). A subject in need of treatment can be a mammal (e.g., a human, monkey, dog, cat, horse, etc.) with a particular disease or disorder associated with an adverse immune response wherein, in particular embodiments, the subject is human (Paragraph 0031). Shi further provides Example 9, wherein inhibition of one or more of NO, IDO or PGE2 can dramatically enhance cancer treatment; when immunotherapies such as those based on cytokines, vaccination, antibodies, dendritic cells, or T cells, are used to treat cancer, the tumor stromal cells might be responsible for the inability of these treatment to completely eradicate tumors in most cases, and the combined use of inhibitors to iNOS and IDO with immunotherapies could provide effective ways to eradicate tumors (Paragraph 0074). Ahn presents evidence of a significant tumor suppression by cAT-MSC alone on canine melanoma (LMeC) in vitro and in vivo which was enhanced further when cAT-MSC expressed IFN-β; the authors further investigated the effects of stem cell-mediated gene delivery of IFN-β in combination with systemic treatment with low doses of cisplatin in a canine malignant melanoma xenograft model wherein such a treatment combination resulted in a significant additive anti-tumor effect (Page 2, Column 1, Paragraph 2). Ling teaches that MSC administration (e.g., in melanoma and lymphoma models) significantly altered the distribution within tumor-infiltrating lymphocytes (Fig. 6D–I); in mice administered with either constitutive or inducible IDO-transfected MSCs, CD3+ T-cell numbers in tumors were reduced by 70% in comparison with the mice treated with negative control-transfected iNOS-/- MSCs, wherein the vast majority of this reduction was in the CD8+ T-cell fraction, rather than CD4+ T cells (Fig. 6E and F) (Page 1584; Column 1, Second Full Paragraph).
Thus, it would have been obvious to one of ordinary skill in the art that the IDO-deficient MSCs of Shi could be further modified such that (i) the MSCs are IDO-deficient via CRISPR-mediated knockout, and (ii) they are engineered to express (i.e., overexpress) IFN-β and that such MSCs would be useful in cancer therapy (e.g., therapy for melanoma and lymphoma) because (i) Shi teaches using IDO-deficient MSCs in patients (e.g., humans) with tumors to enhance immune response and further suggests the combined use of inhibitors to iNOS and IDO with immunotherapies (e.g., interferon treatment) could provide effective ways to eradicate tumors, (ii) Ahn indicates increased anti-tumor effects associated with MSCs engineered express IFN-β compared to those that are not and IFN-β in combination with other therapeutic modalities results in additive anti-cancer effects, and (iii) Ling discloses that MSCs that do not express IDO or MSCs treated with IDO inhibitor 1-methyl-tryptophan reversed the suppression of T lymphocyte proliferation and suggests targeting of IDO activity could be used to restore tumor immunity in humans, by relieving IDO-mediated immune suppression of MSCs in the tumor microenvironment as well as in tumor cells. As such, combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success; administering MSCs that are IDO-deficient via CRISPR-mediated knockdown and engineered to express (i.e., overexpress) IFN-β would be expected to be beneficial, with potentially enhanced or additive effects, in the context of anti-cancer therapy, as suggested by the combination of teachings from Shi, Ahn, Ling, and Davis
With regard to claim 11, Shi teaches that iNOS and/or IDO-deficient MSCs provoke effective immune responses to tumors (Paragraph 0034). Shi presents data that indicates that the efficacy of IFN treatment or similar immune cancer therapies can be increased by suppressing NO production or IDO activity in the tumor microenvironment; accordingly, the invention also embraces a method for enhancing the efficacy of an immune therapy of cancer by administering to a subject receiving an immune therapy treatment an effective amount of a nitric oxide synthase (NOS) and/or IDO inhibitor (Paragraph 0035). NO, IDO and chemokines mediate the immunosuppressive activity of MSCs (Paragraph 0018); immunosuppression by MSCs is exerted through the coordinated action of cytokine-induced chemokines and NO, wherein in vitro chemical blockade of iNOS or IDO reverts immunosuppression (Paragraph 0019). The roles of IDO and NO in the inhibition of T cell proliferation by MSCs from mouse and human were analyzed in a side-by-side comparison; it was found that inhibition of NO by L-NMMA completely reversed immunosuppression by mouse MSCs, whereas the inhibition of peripheral blood mononuclear cell proliferation by human MSCs was reversed by 1-MT, indicating that MSCs from humans utilize IDO as the major effector of immunosuppression, in comparison to mouse MSCs which utilize NO (Paragraph 0059). Thus, Shi indicates that IDO-deficient MSCs are not immunosuppressive and are capable of enhancing an immune response on their own, and immune cancer therapies can be increased by suppressing NO production or IDO activity in the tumor microenvironment and embraces a method for enhancing the efficacy of an immune therapy of cancer by administering to a subject receiving an immune therapy treatment an effective amount of a nitric oxide synthase (NOS) and/or IDO inhibitor. Additionally, Ling discloses that mesenchymal stem cells (MSC) are present in most, if not all, tissues and are believed to contribute to tissue regeneration and the tissue immune microenvironment; murine MSCs exert immunosuppressive effects through production of inducible nitric oxide synthase (iNOS), whereas human MSCs use indoleamine 2,3-dioxygenase (IDO) (Abstract). The authors established a novel humanized system to model human MSCs, using murine iNOS-/-MSCs that constitutively or inducibly express an ectopic human IDO gene, and in this system, inducible IDO expression is driven by a mouse iNOS promoter that can be activated by inflammatory cytokine stimulation in a similar fashion as the human IDO promoter; these IDO-expressing humanized MSCs (MSC-IDO) were capable of suppressing T-lymphocyte proliferation in vitro and in melanoma and lymphoma tumor models, MSC-IDO promoted tumor growth in vivo, an effect that was reversed by the IDO inhibitor 1-methyl-tryptophan (Id.). The authors found that MSC-IDO dramatically reduced both tumor-infiltrating CD8+ T cells and B cells and provide a new line of evidence that interventional targeting of IDO activity could be used to restore tumor immunity in humans, by relieving IDO-mediated immune suppression of MSCs in the tumor microenvironment as well as in tumor cells themselves (Id.). Ling teaches that MSC administration (e.g., in melanoma and lymphoma models) significantly altered the distribution within tumor-infiltrating lymphocytes (Fig. 6D–I); in mice administered with either constitutive or inducible IDO-transfected MSCs, CD3+ T-cell numbers in tumors were reduced by 70% in comparison with the mice treated with negative control-transfected iNOS-/- MSCs, wherein the vast majority of this reduction was in the CD8+ T-cell fraction, rather than CD4+ T cells (Fig. 6E and F) (Page 1584; Column 1, Second Full Paragraph).
Thus, one of ordinary skill in the art would recognize the benefit of using (i) IDO-deficient MSCs, deficient by CRISPR-mediated knockout, and (ii) IDO inhibitors in cancer therapy, wherein IDO-deficient MSCs on their own can enhance an immune response and IDO inhibitors could serve to reduce IDO in the tumor microenvironment, from endogenous MSCs for example, and further promote therapeutic efficacy. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 21-23, Shi provides the above-referenced MSCs and cytokines in the form of a composition, e.g., a pharmaceutical composition suitable for administration to a subject in need of treatment with the same wherein the pharmaceutical composition typically contains at least one acceptable carrier (Paragraph 0029). The invention embraces, for example, a method for attenuating an immune response (an alternate embodiment/use of MSCs of the invention) by administering an effective amount of MSCs and cytokines to a subject in need of treatment; the MSCs are provided as a pharmaceutical composition, wherein the MSCs are formulated with a cytokine cocktail prior to administration wherein the MSCs and cytokines can be administered as individual components (Paragraph 0031). Thus, Shi suggests pharmaceutical compositions for methods of the invention comprising MSCs of the invention and additional components (e.g., cytokines) as necessitated by the method of interest. Shi also suggests using IDO-deficient MSCs and IDO inhibitors in cancer therapy, wherein IDO-deficient MSCs on their own can enhance an immune response and IDO inhibitors could serve to reduce IDO in the tumor microenvironment, which one of ordinary skill in the art would recognize as serving to further promote therapeutic efficacy. Thus, a pharmaceutical composition comprising (i) the IDO-deficient MSCs themselves or (ii) the IDO-deficient MSCs and an IDO inhibitor would be recognized by one of ordinary skill in the art as useful in the disclosed methods of enhancing an immune response. It is further noted that the addition of an IDO inhibitor generally fits the definition of an adjuvant wherein the IDO inhibitor serves a therapeutic function secondary/supplemental to the IDO-deficient MSCs. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 24-26, Shi teaches that iNOS-deficient or IDO-deficient MSCs can be generated by conventional mutagenesis methods or site-specific mutagenesis to delete all or a part of the iNOS or IDO open reading frame thereby decreasing the expression and activity of iNOS and/or IDO or, in an alternative embodiment, MSCs can be made iNOS- and/or IDO-deficient by treatment with iNOS- and/or IDO-selective inhibitors wherein suitable IDO inhibitors include, e.g., 1-methyltryptophan (1-MT, i.e., a tryptophan analog) and Exiguamine A (Paragraph 0034). MSCs that are deficient in iNOS and/or IDO activity are defined as MSCs that exhibit less than 30%, 40%, 50%, 60%, 70% or 80% IDO and/or iNOS activity as compared to wildtype MSCs (Id.); thus one of ordinary skill in the art would recognize that the MSCs of the invention generated by mutagenesis are knockdown MSCs, not knockout, because some IDO/iNOS expression/activity is still occurring by definition. Furthermore, Davis discloses that through genome editing methods (e.g., CRISPR-Cas system), defined deletions can be introduced, insertional mutations can be created, or single bases can be changed; to make a true genetic null allele, genome editing is preferable, as well as if it is desirable to introduce a specific point mutation, or correct a pre-existing mutation back to wild type (Pages 2-3). Thus, one of ordinary skill in the art would recognize that CRISPR-mediated IDO knockout can include gene deletion. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Claims 2-3 are rejected under 35 U.S.C. 103 as being unpatentable over US 2009/0202479 A1 (previously cited on PTO-892; herein after referred to as "Shi"), non-patent literature by Ahn et. al. (PLOS ONE, 2013, 8(9), 1-11; previously cited on PTO-892; herein after referred to as "Ahn"), non-patent literature by Ling et. al. (Cancer Res., 2014, 74(5), 1576-1587; herein after referred to as “Ling”), and non-patent literature by Ed Davis (Technical Note retrieved from genecopoeia.com, published online in 2014; herein after referred to as “Davis”), as applied to claims 1, 6, 8, 11, and 21-26 above, and further in view of WO 2014/160475 A1 (previously cited on PTO-892; herein after referred to as "Aboody").
Claim 1 is rendered obvious by Shi, Ahn, Ling, and Davis. However, none of the references teach or suggest MSCs that are infected with a virus, such as an oncolytic virus.
With regard to claims 2-3, Aboody teaches a method of killing a tumor cell wherein the method may include contacting the tumor cell with a tropic cell that carries a modified oncolytic virus, wherein the virus comprises a tumor selective element and/or a capsid protein that binds a tumor-specific cell surface molecule (Paragraph 0007; emphasis added). Aboody also teaches a method of treating cancer wherein the method may include administering a therapeutically effective amount of a pharmaceutical composition to a subject, wherein the pharmaceutical composition includes a tropic cell that carries a modified oncolytic virus, wherein the virus comprises a tumor selective promoter element and/or a capsid protein that binds a tumor-specific cell surface molecule; in some embodiments, the method may also include administering one or more additional therapeutic agents in combination with the pharmaceutical composition (Paragraph 0008). Tropic cells for use in the methods of the invention can include mesenchymal stem cells (Paragraph 0009). In an exemplary embodiment, a study showed that a neural stem cell (NSC)-based cell carriers (another topic cell embodiment) can effectively deliver anti-glioma oncolytic adenovirus to distant tumor sites, release the therapeutic payload at the target sites and increase median survival in a diverse range of orthotropic human glioma xenograft models that stand to recapitulate the heterogeneity of the human disease; it was demonstrated that the NSC-OV platform has the ability to extend survival in a multitude of invasive models of human glioma and target the therapeutic resistant and disease reinitiating glioma stem cell population, thereby fulfilling two important considerations for successful clinical translation and may serve as a future therapy that can complement the existing standard of care for glioblastoma (Paragraph 00298). Thus, Aboody teaches tropic cells, which can include MSCs, infected with modified oncolytic viruses that are useful in cancer therapeutic methods, either alone or in combination with other therapeutic modalities.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was to filed to further modify the MSCs rendered obvious by Shi, Ahn, Ling, and Davis such that they are infected with a modified oncolytic virus wherein a modified oncolytic virus could serve to specifically target and kill tumor cells, thereby treating cancer, as suggested by Aboody. Combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success; i.e., administering MSCs that are IDO-deficient, engineered to express (i.e., overexpress) IFN-β, and are infected with an oncolytic virus would be reasonably expected to be beneficial, with potentially enhanced or additive effects, in the context of anti-cancer therapy, as suggested by the combination of teachings from Shi, Ahn, Ling, Davis, and Aboody.
Claims 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over US 2009/0202479 A1 (previously cited on PTO-892; herein after referred to as "Shi"), non-patent literature by Ahn et. al. (PLOS ONE, 2013, 8(9), 1-11; previously cited on PTO-892; herein after referred to as "Ahn"), non-patent literature by Ling et. al. (Cancer Res., 2014, 74(5), 1576-1587; herein after referred to as “Ling”), and non-patent literature by Ed Davis (Technical Note retrieved from genecopoeia.com, published online in 2014; herein after referred to as “Davis”), as applied to claims 1, 6, 8, 11, and 21-26 above, and further in view of non-patent literature by Lokshin et. al. (Journal of the National Cancer Institute, 1995, 87(3), 206-212; previously cited on PTO-892; herein after referred to as “Lokshin”).
Claim 1 is rendered obvious by Shi, Ahn, Ling, and Davis. However, none of the references explicitly disclose using the MSCs in a method for treating lung cancer, and more specifically NSCLC. This deficiency is remedied by Lokshin.
With regard to claims 9-10, Lokshin presents biochemical and molecular evidence that IFN-β is capable of affecting both growth and terminal squamous differentiation or programmed cell death in three representative NSCLC cell lines; tissue transglutaminase, the cytosolic enzyme that is activated in NSCLC cell lines in response to IFN-β is down-regulated during squamous differentiation in normal human bronchial epithelium cells and keratinocytes, but up-regulated during programmed cell death in several cell types (Page 209). The authors demonstrated that different mechanisms of programmed cell death exist in NSCLC cell lines, likely under differentiation-specific phenotypic control, suggesting a strong relationship between programmed cell death and terminal differentiation wherein the fact that differentiation and/or programmed cell death appears to be post-translationally regulated by IFN-β suggests that it occurs in a defined population within a given NSCLC cell line and that IFN-β alone in NSCLC may not be effective in controlling the tumor; this observation may direct the development of IFN-β as a therapeutic drug for lung cancer wherein if the characteristics of the inducible population can be identified, a strategy may be devised that will drive more cells into the differentiation/programmed cell death-inducible compartment and such a strategy would aid in the development of IFN-β as an effective anticancer agent through a defined mechanism (Page 211).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was to filed to further modify the method of treating cancer rendered obvious by Shi, Ahn, Ling, and Davis such that the cancer to be treated is lung cancer, and more specifically NSCLC, as suggested by Lokshin. Combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success; i.e., administering MSCs that are IDO-deficient and engineered to express (i.e., overexpress) IFN-β, and are infected with an oncolytic virus would be reasonably expected to be beneficial in cases of lung cancer, including NSCLC, because (i) MSCs are known to directly influence immune responses to tumors, (ii) engineering of said MSCs could provide more specific modulation of such immune responses (i.e., increase immune responses) to tumors by reducing MSC IDO expression/activity and increasing MSC IFN-β expression and (iii) IFN-β is capable of being beneficial in cases of NSCLC by regulating programmed cell death an terminal differentiation.
Double Patenting - Maintained
Claims 1, 6, 8-11, and 21-24 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 and 14-15 of U.S. Patent No. 11,607,426 (reference patent). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 1 of the reference patent discloses a mesenchymal stem cell (MSC) that is indoleamine 2,3-dioxygenase (IDO)-deficient due to CRISPR-mediated knockout of IDO and over-expresses interferon-beta. Reference patent claim 2 discloses that the MSC of claim 1 is a human MSC. Claims 3-6 of the reference patent discloses a method for treating cancer, comprising administering an effective amount of the MSC of claim 1 to a human or non-human animal subject in need thereof, wherein the cancer is lung cancer, the lung cancer is NSCLC, and the method further comprises administering an IDO inhibitor to the subject. Reference patent claims 14-15 disclose a composition comprising an MSC of claim 1 and a pharmaceutically acceptable carrier or diluent, wherein the composition may comprise an adjuvant.
As such, the reference patent discloses a MSC that is IDO-deficient and overexpresses interferon beta, wherein the MSC is IDO-deficient due to gene deletion and/or silencing, wherein the MSC is a human MSC and reads on instant claims 1, 6, and 24. The reference patent further discloses the use of such an MSC in the treatment of cancer, including lung cancer/NSCLC, which may further comprise administering an IDO inhibitor, and reads on instant claims 8-11. The reference patent also discloses a composition comprising the MSC, wherein the composition may further comprise an adjuvant and reads on instant claims 21 and 23. Furthermore, with regard to instant claim 22, it would be within the purview of one of ordinary skill in the art to combine the disclosures of the reference patent claims to include an IDO inhibitor in the composition of reference patent claims 14-15 (i.e., the IDO inhibitor is the adjuvant) because the reference patent discloses a method of treating cancer comprising administering (i) the MSCs of reference patent claim 1 and (ii) further administering an IDO inhibitor; “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).
Claims 2-3 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 and 14-15 of U.S. Patent No. 11,607,426 (reference patent) in view of WO 2014/160475 A1 (herein after referred to as "Aboody").
The limitations of instant claim 1 are disclosed by the reference patent claim 1. However, it is noted that the reference patent does not explicitly disclose that the MSCs are infected with a virus, such as an oncolytic virus. This deficiency is remedied by Aboody.
With regard to claims 2-3, Aboody teaches a method of killing a tumor cell wherein the method may include contacting the tumor cell with a tropic cell that carries a modified oncolytic virus, wherein the virus comprises a tumor selective element and/or a capsid protein that binds a tumor-specific cell surface molecule (Paragraph 0007; emphasis added). Aboody also teaches a method of treating cancer wherein the method may include administering a therapeutically effective amount of a pharmaceutical composition to a subject, wherein the pharmaceutical composition includes a tropic cell that carries a modified oncolytic virus, wherein the virus comprises a tumor selective promoter element and/or a capsid protein that binds a tumor-specific cell surface molecule; in some embodiments, the method may also include administering one or more additional therapeutic agents in combination with the pharmaceutical composition (Paragraph 0008). Tropic cells for use in the methods of the invention can include mesenchymal stem cells (Paragraph 0009). Oncolytic viruses, such as the adenovirus, may be modified to increase specificity to a target tumor cell wherein such modifications to oncolytic viruses include, but are not limited to, (1) transductional targeting, which involves modifying one or more viral coat or capsid proteins to increase viral entry into a target cell and (2) non-transductional targeting, which involves modifying the viral genome so that it only replicates in cancer cells (Paragraph 0067). In an exemplary embodiment, a study showed that NSC-based cell carriers can effectively deliver anti-glioma oncolytic adenovirus to distant tumor sites, release the therapeutic payload at the target sites and increase median survival in a diverse range of orthotropic human glioma xenograft models that stand to recapitulate the heterogeneity of the human disease; it was demonstrated that the NSC-OV platform has the ability to extend survival in a multitude of invasive models of human glioma and target the therapeutic resistant and disease reinitiating glioma stem cell population, thereby fulfilling two important considerations for successful clinical translation and may serve as a future therapy that can complement the existing standard of care for glioblastoma (Paragraph 00298). Thus, Aboody teaches tropic cells, including MSCs, infecting with modified oncolytic viruses that are useful in cancer therapeutic methods, either alone or in combination with other therapeutic modalities.
The reference patent and Aboody are considered to be analogous to the present invention as they are in the same field of tropic cells (e.g., MSCs) and cancer therapeutics. Thus, it would have been obvious to one of ordinary skill in the art that the MSCs disclosed by the reference patent could be further modified such that they are infected with a modified oncolytic virus wherein a modified oncolytic virus could serve to specifically target and kill tumor cells, thereby treating cancer, as suggested by Aboody. Combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success; i.e., administering MSCs that are IDO-deficient, engineered to express (i.e., overexpress) IFN-β, and are infected with an oncolytic virus would be reasonably expected to be beneficial in the context of anti-cancer therapy, as suggested by the combination of disclosure of the reference patent and Aboody. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).
Claims 25-26 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 and 14-15 of U.S. Patent No. 11,607,426 (reference patent) in view of US 2009/0202479 A1 (herein after referred to as "Shi").
The limitations of instant claim 1 are disclosed by the reference patent claim 1. However, it is noted that the reference patent does not explicitly disclose that the MSCs can be IDO-deficient due to treatment with an IDO inhibitor. This deficiency is remedied by Shi.
With regard to claims 25-26, Shi teaches that iNOS-deficient or IDO-deficient MSCs can be generated by conventional mutagenesis methods or site-specific mutagenesis to delete all or a part of the iNOS or IDO open reading frame thereby decreasing the expression and activity of iNOS and/or IDO or, in an alternative embodiment, MSCs can be made iNOS- and/or IDO-deficient by treatment with iNOS- and/or IDO-selective inhibitors wherein suitable IDO inhibitors include, e.g., 1-methyltryptophan (1-MT, i.e., a tryptophan analog) and Exiguamine A (Paragraph 0034).
The reference patent and Shi are considered to be analogous to the present invention as they are in the same field of MSCs, particularly modified/engineered MSCs. Thus, it would have been obvious to one of ordinary skill in the art that the IDO-deficient MSCs of the reference patent could have been rendered IDO-deficient by way of treatment with an IDO inhibitor, such as the tryptophan analog 1-MT, as taught by Shi. The use of a known technique to improve similar products in the same way would be expected to yield predictable results with a reasonable expectation of success; i.e., using another known method to produce IDO-deficient cells would still be expected to yield IDO-deficient cells having the same function as those produced by a different known method.
Response to Arguments
Applicant’s arguments with respect to the rejections of claims 1-3, 6, 8-11, and 21-26 under 35 U.S.C. 103 as being unpatentable over Shi, Ahn, Aboody, and/or Lokshin have been fully considered but are moot because the new grounds of rejection above rely upon new prior art references to address the new, narrower claim limitation regarding CRISPR-mediated knock out of IDO, which is the limitation to which all arguments are drawn to. Thus, the new grounds of rejection address the argued deficiency of the previously applied prior art.
With regard to the claim rejections under nonstatutory double patenting over claims 1-6 and 14-15 of U.S. Patent No. 11,607,426 alone or in further view of Shi or Aboody, it is noted that no arguments against the claim rejections have been provided. Applicant has agreed to file a terminal disclaimer over U.S. Patent No. 11,607,426 once patentable subject matter is agreed upon. Seeing as no patentable subject matter has been agreed upon, the claim rejections under nonstatutory double patenting are maintained.
Conclusion
Claims 1-3, 6, 8-11, and 21-26 are pending. Claims 1-3, 6, 8-11, and 21-26 are rejected. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642