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 Amendments and Remarks filed 3/13/26 in response to the Office Action of 11/13/25 are acknowledged and have been entered.
Claims 1, 2, 4, 7, 9, 11, 13-15, 18, 19, 42, 58, 69-71, 168, 240, and 241 are pending.
Claim 168 has been amended by Applicant.
Claims 1, 2, 4, 7, 9, 11, 13-15, 18, 19, 42, 58, 69-71, 168, 240, and 241 are currently under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections Withdrawn
The rejection of claims under 35 U.S.C. 103 as being unpatentable over Kono et al (Cancer Sci, 2014, 105: 1049-1055) in view of Stadler et al (Nature Medicine, 2017, 23(7): 815-817) and Allen et al (WO 98/58630; 12/30/98) is withdrawn.
The rejection of claims under 35 U.S.C. 103 as being unpatentable over Kono et al (Cancer Sci, 2014, 105: 1049-1055) in view of Stadler et al (Nature Medicine, 2017, 23(7): 815-817) and Chen et al (International Journal of Pharmaceutics, 2015, 490: 173-179) is withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claims 1, 2, 4, 7, 11, 13, 18, 19, 42, and 58 remain rejected under 35 U.S.C. 103(a) as being unpatentable over Kono et al (Cancer Sci, 2014, 105: 1049-1055) in view of Stadler et al (Nature Medicine, 2017, 23(7): 815-817).
Kono et al teaches macrophages are classified as “M1 macrophages” that have antitumor potency due to expression of Th1 cytokines (e.g., IL-12, TNF-a, and IL-6) and “M2 macrophages” that show tumor-promoting effects due to expression of cytokines and pro-tumor factors, such as IL-10, VEGF, and MMPs (paragraph spanning columns on page 1049, in particular). Kono et al further teaches inhibition of NF-kB expression and activation can suppress the conversion of tumor-associated macrophages (TAMs; a “professional phagocyte”) to M2 macrophages and that inhibition of NF-kB using siRNA and NF-kB decoy oligonucleotides show the potential to convert the phenotype of TAMs from M2 macrophages to antitumor M1 macrophages (right column on page 1049, in particular). Kono et al further teaches a method of treating cancer by administering a composition comprising a TAM-targeting lipid formulation comprising a plurality of nanoparticles, each comprising targeting ligand (mannose) that binds mannose receptors on tumor associated macrophages (TAMs) and a polynucleotide (NF-kB decoy) that suppresses the conversion of TAMs to M2 macrophages and converts M2 macrophage TAMs from M2 macrophages to antitumor M1 macrophages, as evidenced by TAMs showing a decrease in IL-10 and an increased in Th1 cytokines upon exposure to the composition (pages 1053-1054 and Figure 5, in particular).
Kono et al does not specifically teach nucleic acids encoding first and second binding domains, as recited by instant claims. However, these deficiencies are made up in the teachings of Stadler et al.
Stadler et al teaches therapeutically treating a subject (ES-2/hCLDN6) with a cancer comprising human tumor cells expressing a cell surface human tumor associated antigen (TAA) comprising administering to the subject a lipid formulation comprising RNA encoding bi-specific T-cell engager antibodies (BiTEs) comprising a secretion signal wherein the BiTEs specifically bind a T cell receptor molecule (CD3; CD3 is a “cell surface protein expressed by a lymphocyte” and “immune cell activating epitope”) and the TAA (see Figure 2 and ONLINE METHODS, in particular). Stadler et al further teaches such BiTEs enhance immune responses by recruiting T cells to tumor cells (left column on page 815, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method comprising repeatedly treating just any subjects, including human subjects, with tumors that expresses a TAA by administering to the subjects a TAM-targeting lipid formulation of Kono et al wherein, in addition to a polynucleotide (NF-kB decoy) that suppresses the conversion of TAMs to M2 macrophages and converts M2 macrophage TAMs to antitumor M1 macrophages of Kono et al, the TAM-targeting lipid formulation comprises the RNA encoding secreted BITEs of Stadler et al that target the TAA because Kono et al teaches the TAM-targeted lipid formulations provide therapeutic benefit to subjects with cancer by suppressing the conversion of TAMs to M2 macrophages and converting M2 macrophage TAMs to antitumor M1 macrophages and delivering RNA encoding BITEs of Stadler et al with the TAM-targeting lipid formulation of Kono et al would have the benefit of tumor associated macrophage (TAM) secretion of BITEs in the tumor microenvironment where the BITEs would therapeutically interact with both T cells and tumor cells. This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine the prior art reference teachings to arrive at the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 3/13/26, Applicant submitted a declaration by Matthias Stephan. Applicant further indicates that because NF-kb inhibition would be expected to decrease and not stimulate or maintain immune responsiveness, one of ordinary skill in the art would not have looked to Kono as a starting point when seeking to stimulate and maintain immune system responsiveness by (1) recruiting additional immune cells to a treatment site, (2) remaining activated at the treatment site providing an on-going stimulator signal to other immune cells and (3) secreting multi-specific immune-cell engaging molecules that bind antigens on targeted cells at the treatment site and activate the recruited immune cells to destroy the bound cells as in the subject application. Applicant further argues a lack of motivation to modify Kono with Stadler because Kono teaches that TAM-targeted lipid formulations provide therapeutic benefit to subject with cancer…and BITEs would therapeutically interact with both T cells and tumor cells. Applicant further indicates it would not be considered obvious to administer combinations of reagents that are both known to treat cancer due to redundancy. Applicant further indicates the rejection is based on hindsight. Applicant further argues a lack of finite number of identified, predictable solutions, with a reasonable expectation of success. Applicant further argues Stadler does not mention tumor associated macrophages. Applicant further argues no reason has been provided to select Stadler over other methods of treating cancer. Applicant further argues motivation provided by the Office, “the benefit of tumor associated macrophage (TAM) secretion of BITEs in the tumor microenvironment where the BITEs would therapeutically interact with both T cells and tumor cells” ignores teachings of both Kono and Stadler as a whole because Kono is not concerned with introducing a new and non-endogenous function to TAMs (Declaration, paragraph 10) and Stadler does not include TAMs and is not interested in localized delivery. Applicant further argues a lack of motivation with a reasonable expectation of success based on cited references because Stadler is directed towards exposing patients to bispecific antibodies at the same, systemic levels achieved using conventional intravenous bispecific antibody infusion and Stadler uses an immunodeficient NSG mouse model that lacks endogenous professional phagocytes where there are no phagocytes to transfect. Applicant further argues Kono does not describe secretion of a non-native protein by modified professional phagocytes. Applicant further argues existence of a secretory sequence for use in hepatocytes provides no evidence that such a process could be successfully used in professional phagocytes and that the Office relies on Applicant's own post-filing work to support the argument that a secretory signal could be used to secrete bispecific antibodies from professional phagocytes. Applicant further argues the inventors with the first to recognize that professional phagocytes could be repurposed as delivery and expression vehicles for therapeutic modality otherwise limited by systemic toxicity of Stadler. Applicant further agues there is nothing in Kono that would lead one of ordinary skill in the art to believe that professional phagocytes could be repurposed as delivery and expression vehicles. Applicant further argues even if Kono and Stadler were combined, there is no reasonable expectation that transfecting a different cell type in a different way to execute a different function would be successful.
The Declaration and the arguments found in the Reply of 3/13/26 have been carefully considered, but are not deemed persuasive. In regards to the indication that because NF-kb inhibition would be expected to decrease and not stimulate or maintain immune responsiveness, one of ordinary skill in the art would not have looked to Kono as a starting point when seeking to stimulate and maintain immune system responsiveness by (1) recruiting additional immune cells to a treatment site, (2) remaining activated at the treatment site providing an on-going stimulator signal to other immune cells and (3) secreting multi-specific immune-cell engaging molecules that bind antigens on targeted cells at the treatment site and activate the recruited immune cells to destroy the bound cells as in the subject application, Applicant is arguing limitations not recited by the claims of this rejection. The claims of this rejection do not recite (1) recruiting additional immune cells to a treatment site, (2) remaining activated at the treatment site providing an on-going stimulator signal to other immune cells and (3) secreting multi-specific immune-cell engaging molecules that bind antigens on targeted cells at the treatment site and activate the recruited immune cells to destroy the bound cells as in the subject application. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Further, one would be motivated to inhibit NF-kB when treating tumors because Kono et al teaches inhibition of NF-kB expression and activation can suppress the conversion of tumor-associated macrophages (TAMs; a “professional phagocyte”) to M2 macrophages and that inhibition of NF-kB using siRNA and NF-kB decoy oligonucleotides show the potential to convert the phenotype of TAMs from M2 macrophages to antitumor M1 macrophages (right column on page 1049, in particular).
In regards to the argument of a lack of motivation to modify Kono with Stadler because Kono teaches that TAM-targeted lipid formulations provide therapeutic benefit to subject with cancer…and BITEs would therapeutically interact with both T cells and tumor cells and that it would not be considered obvious to administer combinations of reagents that are both known to treat cancer due to redundancy, the examiner disagrees. The TAM-targeted lipid formulations provide therapeutic benefit to subject with cancer by converting M2 macrophage TAMs to antitumor M1 macrophages of Kono et al and the BITEs of the combined method provide an additional, not redundant, benefit of enhancing an anti-tumor immune response by therapeutically interacting with both T cells and tumor cells.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In regard to the arguments of a lack of finite number of identified, predictable solutions, with a reasonable expectation of success and lack of motivation with a reasonable expectation of success based on cited references because Stadler is directed towards exposing patients to bispecific antibodies at the same, systemic levels achieved using conventional intravenous bispecific antibody infusion and Stadler uses an immunodeficient NSG mouse model that lacks endogenous professional phagocytes where there are no phagocytes to transfect, and even if Kono and Stadler were combined, there is no reasonable expectation that transfecting a different cell type in a different way to execute a different function would be successful, the examiner disagrees. The examiner maintains one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method comprising repeatedly treating just any subjects, including human subjects, with tumors that expresses a TAA by administering to the subjects a TAM-targeting lipid formulation of Kono et al wherein, in addition to a polynucleotide (NF-kB decoy) that suppresses the conversion of TAMs to M2 macrophages and converts M2 macrophage TAMs to antitumor M1 macrophages of Kono et al, the TAM-targeting lipid formulation comprises the RNA encoding secreted BITEs of Stadler et al that target the TAA because Kono et al teaches the TAM-targeted lipid formulations provide therapeutic benefit to subjects with cancer by suppressing the conversion of TAMs to M2 macrophages and converting M2 macrophage TAMs to antitumor M1 macrophages and delivering RNA encoding BITEs of Stadler et al with the TAM-targeting lipid formulation of Kono et al would have the benefit of tumor associated macrophage (TAM) secretion of BITEs in the tumor microenvironment where the BITEs would therapeutically interact with both T cells and tumor cells.
In regards to the argument that Stadler does not mention tumor associated macrophages, the examiner agrees.
In regards to the argument that no reason has been provided to select Stadler over other methods of treating cancer, Stadler was selected because Stadler teaches BITEs that would predictably provide therapeutic benefit upon being targeted to a tumor microenvironment by macrophages of Kono et al.
In regards to the argument that motivation provided by the Office, “the benefit of tumor associated macrophage (TAM) secretion of BITEs in the tumor microenvironment where the BITEs would therapeutically interact with both T cells and tumor cells” ignores teachings of both Kono and Stadler as a whole because Kono is not concerned with introducing a new and non-endogenous function to TAMs (Declaration, paragraph 10) and Stadler does not include TAMs and is not interested in localized delivery, the examiner disagrees. Teachings of Kono and Stadler have not been ignored.
In regards to the arguments that Kono does not describe secretion of a non-native protein by modified professional phagocytes and existence of a secretory sequence for use in hepatocytes provides no evidence that such a process could be successfully used in professional phagocytes and that the Office relies on Applicant's own post-filing work to support the argument that a secretory signal could be used to secrete bispecific antibodies from professional phagocytes, it is again noted one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, RNA encoding BITEs of Stadler et al comprises a secretion signal (see Cloning of template vectors and in vitro transcription of mRNA portion of ONLINE METHODS, in particular), which would predictably result in secretion of the BITEs from TAMs expressing the BITEs (as evidenced by lines 4-5 on page 13 of Weiner et al (WO 99/64074; 12/16/1999)).
In regards to the argument the inventors with the first to recognize that professional phagocytes could be repurposed as delivery and expression vehicles for therapeutic modality otherwise limited by systemic toxicity of Stadler and there is nothing in Kono that would lead one of ordinary skill in the art to believe that professional phagocytes could be repurposed as delivery and expression vehicles, it is first noted that this is not an anticipation rejection. Further, the prior art of Choi et al (Biomaterials, 2012, 33: 4195-4203) demonstrates macrophages (professional phagocytes) were known to be repurposed as “Trojan horse” delivery vehicles for therapeutic modality otherwise limited by systemic toxicity (Abstract, in particular). Further, the prior art of Wagner et al (WO 2018/035303 A1; 2/22/18) demonstrates macrophages (professional phagocytes) were known as delivery and expression vehicles for therapeutic modality otherwise limited by systemic toxicity by expressing and secreting a therapeutic (the extracellular domain of PD-1) within a tumor environment and elicit a strong tumor-specific treatment ([0046], in particular).
Claim Rejections - 35 USC § 103
Claim(s) 1, 2, 4, 7, 9, 11, 13, 18, 19, 42, and 58 remain rejected under 35 U.S.C. 103 as being unpatentable over Kono et al (Cancer Sci, 2014, 105: 1049-1055) in view of Stadler et al (Nature Medicine, 2017, 23(7): 815-817) as applied to claims 1, 2, 4, 7, 11, 13, 18, 19, 42, and 58 above, and further in view of Michalk et al (PLOS ONE, 2014, 9(4)(e95517): 1-8).
Teachings of Kono et al and Stadler et al are discussed above.
Kono et al and Stadler et al do not specifically teach a BiTE that binds CD8. However, these deficiencies are made up in the teachings of Michalk et al.
Michalk et al teaches bispecific BiTEs that bind TAA and CD3, in addition to cross-linking target cells with CD8+ cytotoxic T cells, are able to cross-link target cells with CD4+ T cells that can lead to life-threatening cytokine storms (left column on page 2, in particular). Michalk et al further teaches targeting such bispecific constructs to CD8, instead of CD3, with pre-activated T cells can allow retargeting of CD8+ cytotoxic T cells and avoid cytokine storms from activation of CD4+ T cells (Abstract, in particular). Michalk et al further teaches such CD8-targeted bispecific constructs can be used in vivo to (i) retarget CD8+ T cells that have been ex vivo activated to target and kill target/cancer cells or (ii) retarget CD8+ T cells that are activated with IL-2 treatment to target and kill target/cancer cells (sentence spanning pages 6-7 and first full paragraph on page 7, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to avoid cytokine storms from multiple treatments of the combined method of Kono et al and Stadler et al by performing the combined method of Kono et al and Stadler et al wherein subjects are then subsequently administered the TAM-targeting lipid formulation of the combined method wherein the RNA encoding BiTEs of the TAM-targeting lipid formulation encode a CD8-binding domain in place of the CD3-binding domain because subjects of the combined method have pre-activated T cells and Michalk et al teaches targeting such bispecific constructs to CD8, instead of CD3, with pre-activated T cells can allow activation of CD8+ cytotoxic T cells and avoid cytokine storms from activation of CD4+ T cells. Further, such bispecific constructs can be used in the combined method to (i) retarget CD8+ T cells that have been ex vivo activated to target and kill target/cancer cells or (ii) retarget CD8+ T cells that are activated with IL-2 treatment to target and kill target/cancer cells. This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine the prior art reference teachings to arrive at the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 3/13/26, Applicant argues motivation provided by the Office to avoid a cytokine storm is defeated by the proposed combination of Kono, Stadler, and Michalk because pre-activated T cells of Stadler administered to an immunodeficient mouse results in graft versus host disease. Applicant further argues there is no reasonable expectation that the combination of Kono, Stadler, and Michalk would actually work because "Kono is not concerned with introducing a new and non-endogenous function to TAMs" (Declaration, paragraph 10), Stadler, which does not include TAMs, is not interested in localized delivery (Stadler, page 815, left hand column), Michalk only works with pre- activated cells, and states that it does not understand why it is less efficient, notes that the two bsAbs use different target signaling pathways, and that there are different affinities towards the effector cell side which may influence the interaction time interval, and that they merely "open the chance" to CD8+ T cell redirection (Michalk, page 6, right hand column). Applicant further argues none of these point to any reasonable expectation of success in making and use of a combined formulation.
The declaration and the arguments found in the Reply of 3/13/26 have been carefully considered, but are not deemed persuasive. In regards to the argument that motivation provided by the Office to avoid a cytokine storm is defeated by the proposed combination of Kono, Stadler, and Michalk because pre-activated T cells of Stadler administered to an immunodeficient mouse results in graft versus host disease, the rejection does not suggest administering pre-activated T cells of Stadler.
In regards to the arguments there is no reasonable expectation that the combination of Kono, Stadler, and Michalk would actually work because "Kono is not concerned with introducing a new and non-endogenous function to TAMs" (Declaration, paragraph 10), Stadler, which does not include TAMs, is not interested in localized delivery (Stadler, page 815, left hand column), Michalk only works with pre- activated cells, and states that it does not understand why it is less efficient, notes that the two bsAbs use different target signaling pathways, that there are different affinities towards the effector cell side which may influence the interaction time interval, and that they merely "open the chance" to CD8+ T cell redirection (Michalk, page 6, right hand column), and none of these point to any reasonable expectation of success in making and use of a combined formulation, the examiner disagrees. The examiner maintains one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to avoid cytokine storms from multiple treatments of the combined method of Kono et al and Stadler et al by performing the combined method of Kono et al and Stadler et al wherein subjects are then subsequently administered the TAM-targeting lipid formulation of the combined method wherein the RNA encoding BiTEs of the TAM-targeting lipid formulation encode a CD8-binding domain in place of the CD3-binding domain because subjects of the combined method have pre-activated T cells and Michalk et al teaches targeting such bispecific constructs to CD8, instead of CD3, with pre-activated T cells can allow activation of CD8+ cytotoxic T cells and avoid cytokine storms from activation of CD4+ T cells. Further, such bispecific constructs can be used in the combined method to (i) retarget CD8+ T cells that have been ex vivo activated to target and kill target/cancer cells or (ii) retarget CD8+ T cells that are activated with IL-2 treatment to target and kill target/cancer cells. This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine the prior art reference teachings to arrive at the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1, 2, 4, 7, 11, 13, 14, 18, 19, 42, 58, 69, 168, 240, and 241 remain rejected under 35 U.S.C. 103 as being unpatentable over Kono et al (Cancer Sci, 2014, 105: 1049-1055) in view of Stadler et al (Nature Medicine, 2017, 23(7): 815-817) as applied to claims 1, 2, 4, 7, 11, 13, 18, 19, 42, and 58 above, and further in view of Chistikov et al (Immunobiology, 2018, 223: 101-111).
Teachings of Kono et al and Stadler et al are discussed above.
Kono et al and Stadler et al do not specifically teach a nucleic acid encoding an interferon regulatory factor (IRF). However, these deficiencies are made up in the teachings of Chistikov et al.
Chistikov et al teaches IRF-5 as a protein that promotes M1 macrophage phenotype (Figure 2, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Kono et al and Stadler et al wherein, in addition to RNA encoding secreted BITEs of Stadler et al and a polynucleotide (NF-kB decoy) that suppresses the conversion of TAMs to M2 macrophages and converts M2 macrophage TAMs to antitumor M1 macrophages Kono et al, the TAM-targeting lipid formulation further comprises expression vectors comprising polynucleotides encoding IRF-5 in order to further therapeutically promote the M1 macrophage phenotype with both NF-kB decoy and IRF-5. This is an example of combining prior art elements according to known methods to yield predictable results. See MPEP 2141. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 3/13/26 argues the Office has provided no reason why additional M1 macrophage promotion is need (beyond what is provided in Kono alone) is desirable and, therefore, providing an additional macrophage promotion would be redundant and non-obvious.
The amendments to the claims, the declaration, and the arguments found in the Reply of 3/13/26 have been carefully considered, but are not deemed persuasive. In regards to the argument the Office has provided no reason why additional M1 macrophage promotion is need (beyond what is provided in Kono alone) is desirable and, therefore, providing an additional macrophage promotion would be redundant and non-obvious, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Kono et al and Stadler et al wherein, in addition to RNA encoding secreted BITEs of Stadler et al and a polynucleotide (NF-kB decoy) that suppresses the conversion of TAMs to M2 macrophages and converts M2 macrophage TAMs to antitumor M1 macrophages Kono et al, the TAM-targeting lipid formulation further comprises expression vectors comprising polynucleotides encoding IRF-5 in order to further therapeutically promote the M1 macrophage phenotype with both NF-kB decoy and IRF-5: The mechanisms by which NF-kB decoy and IRF-5 promote M1 macrophage phenotype are distinct, complementary, and non-redundant. This is an example of combining prior art elements according to known methods to yield predictable results. See MPEP 2141. The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395; B/E Aerospace, Inc. v. C&D Zodiac, Inc., 962 F.3d 1373, 1379, 2020 USPQ2d 10706 (Fed. Cir. 2020); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atl. & P. Tea Co. v. Supermarket Equip. Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950). See MPEP 2143.
Claim Rejections - 35 USC § 103
Claim(s) 1, 2, 4, 7, 11, 13-15, 18, 19, 42, 58, 69-71, 168, 240, and 241 remain rejected under 35 U.S.C. 103 as being unpatentable over Kono et al (Cancer Sci, 2014, 105: 1049-1055) in view of Stadler et al (Nature Medicine, 2017, 23(7): 815-817) and Chistikov et al (Immunobiology, 2018, 223: 101-111), as applied to claims 1, 2, 4, 7, 11, 13, 14, 18, 19, 42, 58, 69, 168, 240, and 241 above, and further in view of Zhang et al (Cancer Gene Therapy, 2010, 17: 334-343) and Yoo et al (The Journal of Gene Medicine, 2006, 8: 163-174).
Teachings of Kono et al, Stadler et al, and Chistikov et al are discussed above.
Kono et al, Stadler et al, and Chistikov et al do not specifically teach a nucleic acid encoding a tumor cell proliferation inhibitor. However, these deficiencies are made up in the teachings of Zhang et al and Yoo et al.
Zhang et al teaches expression of soluble TRAIL protein produced by bacterial cells in a tumor environment kills tumor cells reduces tumor cell growth rate (Abstract and Figures 2-4, in particular).
Yoo et al teaches generating a polynucleotide vector that drives expression of a secreted form of TRAIL (sTRAIL) that is secreted from cells and then induces apoptosis of cancer cells and inhibits growth of tumors in vivo (Abstract and Figures 1, 2, and 6, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Kono et al, Stadler et al, and Chistikov et al wherein, after performing the combined method of Kono et al, Stadler et al, and Chistikov et al, in addition to RNA encoding secreted BITEs of Stadler et al, a polynucleotide (NF-kB decoy) that suppresses the conversion of TAMs to M2 macrophages and converts M2 macrophage TAMs from M2 macrophages of Kono et al, and expression vectors comprising polynucleotides encoding IRF-5 in order to further therapeutically promote the M1 macrophage phenotype with both NF-kB decoy and IRF-5, the combined method of Kono et al, Stadler et al, and Chistikov et al is performed wherein the TAM-targeting lipid formulation further comprises an mRNA encoding a secreted protein that inhibits tumor cell proliferation and growth via pro-apoptotic effects because Zhang et al and Yoo et al teach soluble and secreted proteins that inhibits tumor cell proliferation and growth via pro-apoptotic effects provide therapeutic benefit when administered to subjects with cancer and TAM-targeting lipid formulation of the combined method of Kono et al, Stadler et al, and Chistikov et al would have the benefit of tumor associated macrophage (TAM) secretion of proteins in the tumor microenvironment where the proteins could induce apoptosis of the tumor cells. This is an example of combining prior art elements according to known methods to yield predictable results. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 3/13/26, Applicant argues the rejection impermissibly ignores teachings of Zhang et al and Yoo et al. Applicant argues Zhang states that the use of TRAIL is limited by its considerable liver toxicity (Zhang, Abstract). Applicant further argues Zhang disparages the methods of Yoo stating that "adenovirus or adeno- associated virus-based vectors (as in Yoo) may cause hepatotoxicity through innate and cell- mediated immune responses." (Zhang, Introduction, right hand column). Applicant further argues Yoo contains a problem that Zhang is attempting to solve. Applicant further argues Zhang discloses a specific method, the use of i.v. injected Escherichia DH5cx (E. DH5cx) expressing sTRAIL. Applicant further argues there is no teaching in Zhang that other delivery methods including localized delivery could be used to deliver soluble and secreted proteins that inhibit tumor cell proliferation and growth via pro-apoptotic effects without incurring significant cytotoxicity. Applicant further argues there is no reasonable expectation with an expectation of success that a composition could be achieved using the proposed combination of references because "Kono is not concerned with introducing a new and non-endogenous function to TAMs" (Declaration, paragraph 10), Stadler, which does not include TAMs, is not interested in localized delivery (Stadler, page 815, left hand column), Chistiakov provides a duplicate function, and Yoo requires a specific delivery method not disclosed by the other references. Applicant further argues modifying a Kono to secrete non-endogenous proteins changes the principle of operation of Kono (MPEP 2143). Applicant further argues in Kono, the ultrasound application collapses the Man-PEG bubble lipoplexes on the surface of the TAMs to introduce NF-kß oligonucleotides (Kono, page 1052, first paragraph left column) and that there is no reasonable expectation that such a delivery method could be used to concurrently deliver bispecific antibodies, IRF5, and Escherichia coli DH5cx (E. coli DH5cx) expressing sTRAIL.
The declaration, the amendments to the claims, and the arguments found in the Reply of 3/13/26 have been carefully considered, but are not deemed persuasive. In regards to the argument that the rejection impermissibly ignores teachings of Zhang et al and Yoo et al, the examiner disagrees. Teachings of Zhang et al and Yoo et al have not been ignored by the Office.
In regards to the argument Zhang states that the use of TRAIL is limited by its considerable liver toxicity (Zhang, Abstract), the examiner agrees. However, the combined method provides a way to overcome such toxicity – by tumor-targeting macrophages delivering TRAIL to the tumor microenvironment. The prior art of Choi et al (Biomaterials, 2012, 33: 4195-4203) demonstrates macrophages were known to be repurposed in such as manner, as “Trojan horse” delivery vehicles, for therapeutic modality otherwise limited by systemic toxicity (Abstract, in particular).
In regards to the argument that Zhang disparages the methods of Yoo stating that "adenovirus or adeno- associated virus-based vectors (as in Yoo) may cause hepatotoxicity through innate and cell- mediated immune responses." (Zhang, Introduction, right hand column), the combined method does not suggest using adenovirus or adeno- associated virus-based vectors. The combined method uses macrophages as vectors.
The examiner acknowledges Applicant’s statements that Yoo contains a problem that Zhang is attempting to solve, Zhang discloses a specific method, the use of i.v. injected Escherichia DH5cx (E. DH5cx) expressing sTRAIL, and there is no teaching in Zhang that other delivery methods including localized delivery could be used to deliver soluble and secreted proteins that inhibit tumor cell proliferation and growth via pro-apoptotic effects without incurring significant cytotoxicity.
In regards to the argument that there is no reasonable expectation with an expectation of success that a composition could be achieved using the proposed combination of references because "Kono is not concerned with introducing a new and non-endogenous function to TAMs" (Declaration, paragraph 10), Stadler, which does not include TAMs, is not interested in localized delivery (Stadler, page 815, left hand column), Chistiakov provides a duplicate function, and Yoo requires a specific delivery method not disclosed by the other references, the examiner disagrees. The examiner maintains one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Kono et al, Stadler et al, and Chistikov et al wherein, after performing the combined method of Kono et al, Stadler et al, and Chistikov et al, in addition to RNA encoding secreted BITEs of Stadler et al, a polynucleotide (NF-kB decoy) that suppresses the conversion of TAMs to M2 macrophages and converts M2 macrophage TAMs from M2 macrophages of Kono et al, and expression vectors comprising polynucleotides encoding IRF-5 in order to further therapeutically promote the M1 macrophage phenotype with both NF-kB decoy and IRF-5, the combined method of Kono et al, Stadler et al, and Chistikov et al is performed wherein the TAM-targeting lipid formulation further comprises an mRNA encoding a secreted protein that inhibits tumor cell proliferation and growth via pro-apoptotic effects because Zhang et al and Yoo et al teach soluble and secreted proteins that inhibits tumor cell proliferation and growth via pro-apoptotic effects provide therapeutic benefit when administered to subjects with cancer and TAM-targeting lipid formulation of the combined method of Kono et al, Stadler et al, and Chistikov et al would have the benefit of tumor associated macrophage (TAM) secretion of proteins in the tumor microenvironment where the proteins could induce apoptosis of the tumor cells. This is an example of combining prior art elements according to known methods to yield predictable results.
In regards to the argument modifying a Kono to secrete non-endogenous proteins changes the principle of operation of Kono (MPEP 2143), secretion of non-endogenous antitumor proteins of the combined method does not change the principal operation of macrophages of Kono et al converted to antitumor M1 macrophages to treat tumors.
In regards to the argument that in Kono, the ultrasound application collapses the Man-PEG bubble lipoplexes on the surface of the TAMs to introduce NF-kß oligonucleotides (Kono, page 1052, first paragraph left column) and that there is no reasonable expectation that such a delivery method could be used to concurrently deliver bispecific antibodies, IRF5, and Escherichia coli DH5cx (E. coli DH5cx) expressing sTRAIL, the examiner maintains one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method comprising treating human subjects with tumors that expresses a TAA by administering to the subjects a TAM-targeting lipid formulation of Kono et al wherein, in addition to RNA encoding secreted BITEs of Stadler et al, a polynucleotide (NF-kB decoy) that suppresses the conversion of TAMs to M2 macrophages and converts M2 macrophage TAMs from M2 macrophages of Kono et al, and expression vectors comprising polynucleotides encoding IRF-5 in order to further therapeutically promote the M1 macrophage phenotype with both NF-kB decoy and IRF-5, the combined method of Kono et al, Stadler et al, and Chistikov et al is performed wherein the TAM-targeting lipid formulation further comprises an mRNA encoding a secreted protein that inhibits tumor cell proliferation and growth via pro-apoptotic effects because Zhang et al and Yoo et al teach soluble and secreted proteins that inhibits tumor cell proliferation and growth via pro-apoptotic effects provide therapeutic benefit when administered to subjects with cancer and TAM-targeting lipid formulation of the combined method of Kono et al, Stadler et al, and Chistikov et al would have the benefit of tumor associated macrophage (TAM) secretion of proteins in the tumor microenvironment where the proteins could induce apoptosis of the tumor cells.
Claim Rejections - 35 USC § 103
Claim(s) 1, 2, 4, 7, 11, 13, 15, 18, 19, 42, and 58 remain rejected under 35 U.S.C. 103 as being unpatentable over Kono et al (Cancer Sci, 2014, 105: 1049-1055) in view of Stadler et al (Nature Medicine, 2017, 23(7): 815-817) as applied to claims 1, 2, 4, 7, 11, 13, 18, 19, 42, and 58 above, and further in view of Zhang et al (Cancer Gene Therapy, 2010, 17: 334-343) and Yoo et al (The Journal of Gene Medicine, 2006, 8: 163-174).
Teachings of Kono et al and Stadler et al are discussed above.
Kono et al and Stadler et al do not specifically teach a nucleic acid encoding a tumor cell proliferation inhibitor. However, these deficiencies are made up in the teachings of Zhang et al and Yoo et al.
Zhang et al teaches expression of soluble TRAIL protein produced by bacterial cells in a tumor environment kills tumor cells reduces tumor cell growth rate (Abstract and Figures 2-4, in particular).
Yoo et al teaches generating a polynucleotide vector that drives expression of a secreted form of TRAIL (sTRAIL) that is secreted from cells and then induces apoptosis of cancer cells and inhibits growth of tumors in vivo (Abstract and Figures 1, 2, and 6, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Kono et al and Stadler et al wherein, in addition to RNA encoding secreted BITEs of Stadler et al and a polynucleotide (NF-kB decoy) that suppresses the conversion of TAMs to M2 macrophages and converts M2 macrophage TAMs from M2 macrophages of Kono et al, the TAM-targeting lipid formulation further comprises an mRNA encoding a secreted protein that inhibits tumor cell proliferation and growth via pro-apoptotic effects because Zhang et al and Yoo et al teach soluble and secreted proteins that inhibits tumor cell proliferation and growth via pro-apoptotic effects provide therapeutic benefit when administered to subjects with cancer and TAM-targeting lipid formulation of the combined method of Kono et al and Stadler et al would have the benefit of tumor associated macrophage (TAM) secretion of proteins in the tumor microenvironment where the proteins could induce apoptosis of the tumor cells. This is an example of combining prior art elements according to known methods to yield predictable results. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 3/13/26, Applicant argues the rejection impermissibly ignores teachings of Zhang et al and Yoo et al. Applicant argues Zhang states that the use of TRAIL is limited by its considerable liver toxicity (Zhang, Abstract). Applicant further argues Zhang disparages the methods of Yoo stating that "adenovirus or adeno- associated virus-based vectors (as in Yoo) may cause hepatotoxicity through innate and cell- mediated immune responses." (Zhang, Introduction, right hand column). Applicant further argues Yoo contains a problem that Zhang is attempting to solve. Applicant further argues Zhang discloses a specific method, the use of i.v. injected Escherichia DH5cx (E. DH5cx) expressing sTRAIL. Applicant further argues there is no teaching in Zhang that other delivery methods including localized delivery could be used to deliver soluble and secreted proteins that inhibit tumor cell proliferation and growth via pro-apoptotic effects without incurring significant cytotoxicity. Applicant further argues there is no reasonable expectation with an expectation of success that a composition could be achieved using the proposed combination of references because "Kono is not concerned with introducing a new and non-endogenous function to TAMs" (Declaration, paragraph 10), Stadler, which does not include TAMs, is not interested in localized delivery (Stadler, page 815, left hand column), and Yoo requires a specific delivery method not disclosed by the other references. Applicant further argues modifying a Kono to secrete non-endogenous proteins changes the principle of operation of Kono (MPEP 2143). Applicant further argues in Kono, the ultrasound application collapses the Man-PEG bubble lipoplexes on the surface of the TAMs to introduce NF-kß oligonucleotides (Kono, page 1052, first paragraph left column) and that there is no reasonable expectation that such a delivery method could be used to concurrently deliver bispecific antibodies, IRF5, and Escherichia coli DH5cx (E. coli DH5cx) expressing sTRAIL.
The declaration, the amendments to the claims, and the arguments found in the Reply of 3/13/26 have been carefully considered, but are not deemed persuasive. In regards to the argument that the rejection impermissibly ignores teachings of Zhang et al and Yoo et al, the examiner disagrees. Teachings of Zhang et al and Yoo et al have not been ignored by the Office.
In regards to the argument Zhang states that the use of TRAIL is limited by its considerable liver toxicity (Zhang, Abstract), the examiner agrees. However, the combined method provides a way to overcome such toxicity – by tumor-targeting macrophages delivering TRAIL to the tumor microenvironment. The prior art of Choi et al (Biomaterials, 2012, 33: 4195-4203) demonstrates macrophages were known to be repurposed in such as manner, as “Trojan horse” delivery vehicles, for therapeutic modality otherwise limited by systemic toxicity (Abstract, in particular).
In regards to the argument that Zhang disparages the methods of Yoo stating that "adenovirus or adeno- associated virus-based vectors (as in Yoo) may cause hepatotoxicity through innate and cell- mediated immune responses." (Zhang, Introduction, right hand column), the combined method does not suggest using adenovirus or adeno- associated virus-based vectors. The combined method uses macrophages as vectors.
The examiner acknowledges Applicant’s statements that Yoo contains a problem that Zhang is attempting to solve, Zhang discloses a specific method, the use of i.v. injected Escherichia DH5cx (E. DH5cx) expressing sTRAIL, and there is no teaching in Zhang that other delivery methods including localized delivery could be used to deliver soluble and secreted proteins that inhibit tumor cell proliferation and growth via pro-apoptotic effects without incurring significant cytotoxicity.
In regards to the argument that there is no reasonable expectation with an expectation of success that a composition could be achieved using the proposed combination of references because "Kono is not concerned with introducing a new and non-endogenous function to TAMs" (Declaration, paragraph 10), Stadler, which does not include TAMs, is not interested in localized delivery (Stadler, page 815, left hand column), and Yoo requires a specific delivery method not disclosed by the other references, the examiner disagrees. The examiner maintains one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Kono et al and Stadler et al wherein, after performing the combined method of Kono et al and Stadler et al, in addition to RNA encoding secreted BITEs of Stadler et al and a polynucleotide (NF-kB decoy) that suppresses the conversion of TAMs to M2 macrophages and converts M2 macrophage TAMs from M2 macrophages of Kono et al, the combined method of Kono et al and Stadler et al is performed wherein the TAM-targeting lipid formulation further comprises an mRNA encoding a secreted protein that inhibits tumor cell proliferation and growth via pro-apoptotic effects because Zhang et al and Yoo et al teach soluble and secreted proteins that inhibits tumor cell proliferation and growth via pro-apoptotic effects provide therapeutic benefit when administered to subjects with cancer and TAM-targeting lipid formulation of the combined method of Kono et al and Stadler et al would have the benefit of tumor associated macrophage (TAM) secretion of proteins in the tumor microenvironment where the proteins could induce apoptosis of the tumor cells. This is an example of combining prior art elements according to known methods to yield predictable results.
In regards to the argument modifying a Kono to secrete non-endogenous proteins changes the principle of operation of Kono (MPEP 2143), secretion of non-endogenous antitumor proteins of the combined method does not change the principal operation of macrophages of Kono et al converted to antitumor M1 macrophages to treat tumors.
In regards to the argument that in Kono, the ultrasound application collapses the Man-PEG bubble lipoplexes on the surface of the TAMs to introduce NF-kß oligonucleotides (Kono, page 1052, first paragraph left column) and that there is no reasonable expectation that such a delivery method could be used to concurrently deliver bispecific antibodies, IRF5, and Escherichia coli DH5cx (E. coli DH5cx) expressing sTRAIL, the examiner maintains one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method comprising treating human subjects with tumors that expresses a TAA by administering to the subjects a TAM-targeting lipid formulation of Kono et al wherein, in addition to RNA encoding secreted BITEs of Stadler et al and a polynucleotide (NF-kB decoy) that suppresses the conversion of TAMs to M2 macrophages and converts M2 macrophage TAMs from M2 macrophages of Kono et al, the combined method of Kono et al and Stadler et al is performed wherein the TAM-targeting lipid formulation further comprises an mRNA encoding a secreted protein that inhibits tumor cell proliferation and growth via pro-apoptotic effects because Zhang et al and Yoo et al teach soluble and secreted proteins that inhibits tumor cell proliferation and growth via pro-apoptotic effects provide therapeutic benefit when administered to subjects with cancer and TAM-targeting lipid formulation of the combined method of Kono et al and Stadler et al would have the benefit of tumor associated macrophage (TAM) secretion of proteins in the tumor microenvironment where the proteins could induce apoptosis of the tumor cells.
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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/SEAN E AEDER/Primary Examiner, Art Unit 1642