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 1-10, 13, 15-21 are rejected.
Claims 11-12 are withdrawn.
No claims are allowed.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-10 and 13-21 in the reply filed on 02-Jun-2026 is acknowledged.
Accordingly, claims 11-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 12-Nov-2024 has been considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-10, 13 and 15-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites wherein the optional targeting moieties are configured to direct the nanoparticle to tumor-resident myeloid cells in a tumor microenvironment upon administration. The claim is indefinite since the scope of “configured to” is unclear. It is unclear whether the optional targeting moieties are configured to direct the nanoparticle to tumor-resident myeloid cells in a tumor microenvironment upon administration by virtue of its chemical composition or whether the optional targeting moieties need to be modified chemically or physically to fulfill the claimed function. To obviate this issue, it is suggested that the term “configured to” be removed.
Claim 7 recites wherein the shell is configured to shield the TLR9 agonist and the nucleic acid inhibitor of VISTA from degradation. The claim is indefinite since the scope of “configured to” is unclear. It is unclear whether the shell is configured to shield the TLR9 agonist and the nucleic acid inhibitor of VISTA from degradation by virtue of its chemical composition or whether the shell needs to be modified chemically or physically to fulfill the claimed function. To obviate this issue, it is suggested that the term “configured to” be removed.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The 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 pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claim(s) 1-10, 13, and 15-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (Immune-Checkpoint Protein VISTA Regulates Antitumor Immunity by Controlling Myeloid Cell–Mediated Inflammation and Immunosuppression, 01-Sep-2019) (hereinafter Xu) in view of Gindy et al. (WO2017192470 A1, Patent Publication: 09-Nov-2017) (hereinafter Gindy) and Mitchell (WO2017023753 A1, Patent: 09-Feb-2017) (hereinafter Mitchell).
With regards to Claim 1, Xu discloses that “[c]ombining VISTA-blocking mAb with the TLR vaccine resulted in tumor-free long-term survival in ~50% mice, whereas either monotherapy transiently delayed tumor growth without long-lasting effects” (Page OF7-OF9, Blocking VISTA augments the TLR/MyD88-mediated proinflammatory responses).
However, Xu does not teach a nanoparticle comprising a biocompatible lipid shell defining an outer layer and a core loaded with the TLR9 agonist, and with a nucleic acid inhibitor of VISTA. Xu’s VISTA inhibitor is a germline knockout or a protein blocking monoclonal antibody, and the CpG of Xu is administered as an bare oligonucleotide. For this reason, Gindy and Mitchell are added.
Gindy teaches a composition comprising “a) a lipid nanoparticle (LNP) comprising one or more cationic lipids and a poly(ethyleneglycol)-lipid(PEG-lipid); b) a Toll-like receptor 9 (TLR9) agonist CpG oligonucleotide; and c) an anti-IL-10 antibody or an antigen-binding fragment thereof” (Page 3, line 2-6). Gindy further teaches that the “LNP composition, LNP B, comprised compound 1-9, cholesterol, DSPC and PEG-DMG at a molar composition of 58:30: 10:2, respectively, and encapsulated Cytidine phospho-guanosine (CpG)-based phosphorothioate oligodeoxynucleotide, ODN1826, (InvivoGen, San Diego, CA). ODN 1826 (5'-tccatgacgttcctgacgtt-3') (SEQ ID NO: 22) is a mouse TLR9 specific agonist and is a class B type sequence” (Page 51, line 32 to Page 52, line 3). Gindy does not teach that the LNP is additionally loaded with a nucleic acid inhibitor of VISTA, instead Gindy’s third component is a protein antibody directed against IL-10.
Mitchell teaches that a VISTA antagonist may be “a single stranded or double stranded RNAi inhibitor of VISTA” (Page 11, line 25-26).
Accordingly, it would have prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted Mitchell’s VISTA RNAi inhibitor for the anti-IL-10 antibody component of Gindy’s composition, then loading it into Gindy’s LNP core together with the CpG oligonucleotide. One would have been motivated to do so because Xu’s teaching that VISTA silencing and TLR9 agonism act in a synergistic fashion when reaching the same tumor resident myeloid cell rather than relying solely on the independent distribution of separately administered agents of Xu. A person having ordinary skill in the art would have selected a nucleic acid modality, rather than relying on Gindy's antibody, because encapsulating a second nucleic acid alongside Gindy’s already encapsulated CpG is a more directed application of Gindy’s own LMP than versus co-formulating a nucleic acid with a large protein antibody. This represents the combination of known prior art elements according to their established functions to yield predictable results.
With regard to claim 2, Xu discloses the CpG oligonucleotide as the TLR9 agonist tested in combination with the VISTA inhibitor (Fig. 6C).
With regard to claims 3-4, the VISTA targeting siRNA of Mitchell are discussed above. Further, Mitchell discloses that “The VISTA antagonist can be, for example, an agent that binds to and antagonizes VISTA” (Page 11, line 20-21) and “VISTA shows some sequence homology to the PD-1 ligand, PD-Ll, however the two immune checkpoint inhibitors are structurally different and have different signaling pathways. VISTA blockade has been shown to enhance antitumor immune responses in mice, while in humans, blockade of the related PD-1 pathway has shown great potential in clinical immunotherapy trials” (Page 27, line 9-13).
With regard to claim 5, Xu discloses administering a CpG oligonucleotide as the TLR9 agonist tested in combination with the VISTA inhibitor (Fig. 6C).
Xu does not teach that the VISTA inhibitor is an siRNA, nor that the two agents are coloaded into a nanoparticle core. For this reason, Gindy and Mitchell are added.
Gindy teaches that the “LNP composition, LNP B, comprised compound 1-9, cholesterol, DSPC and PEG-DMG at a molar composition of 58:30: 10:2, respectively, and encapsulated Cytidine phospho-guanosine (CpG)-based phosphorothioate oligodeoxynucleotide, ODN1826, (InvivoGen, San Diego, CA). ODN 1826 (5'-tccatgacgttcctgacgtt-3') (SEQ ID NO: 22) is a mouse TLR9 specific agonist and is a class B type sequence” (Page 51, line 32 to Page 52, line 3). Thus, Gindy teaches that a TLR9 agonist CpG oligonucleotide is physically encapsulated in an LNP. Gindy does not teach that the coloaded agent is a VISTA siRNA.
Mitchell teaches that a VISTA antagonist may be “a single stranded or double stranded RNAi inhibitor of VISTA” (Page 11, line 25-26).
Xu supplied the rationale for codelivery of both agents, stating that “[c]ombining VISTA-blocking mAb with the TLR vaccine resulted in tumor-free long-term survival in ~50% mice” (Page OF9, Blocking VISTA augments the TLR/MyD88-mediated proinflammatory responses). Further, Xu discloses that “whereas either monotherapy transiently delayed tumor growth
without long-lasting effects (Fig. 6C)” (Page OF9, Blocking VISTA augments the TLR/MyD88-mediated proinflammatory responses). Thus, to produce this durable antitumor effect from a single administered particle, a persona having ordinary skill in the art would be motivated to combine the specific CpG oligonucleotide of Gundy with the specific VISTA siRNA of Mitchell rather than a differently targeted or different modality as VISTA antagonist.
Accordingly, it would have prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have loaded the CpG oligonucleotide of Gindy with the VISTA siRNA of Mitchell into a single LNP core for the same reasonable expectation of success as discussed for claim 1.
With regard to claim 6, Xu discloses “This study uncovered a function of VISTA in regulating the TLR/TRAF6-mediated signaling axis and the effector function in myeloid cells. Blocking VISTA together with a TLR-agonistic vaccine abolished the suppressive functions of myeloid-derived suppressor cells (MDSC) and tumorigenic DCs and augmented the production of proinflammatory cytokine” (Page OF2, Introduction). Thus, Xu teaches that two payloads perform in distinct and separate biological functions with codelivery.
However, Xu does not teach a ratio of siRNA to CpG loaded into a nanoparticle core. For this reason, Gindy and Mitchell are added.
Gindy discloses a dosing ratio of the LNP and its single encapsulated oligonucleotide such as “ODN 1826 control (0.5 mg/kg), ODN 1826 (0.5 mg/kg), Lipid Nanoparticle, LNP A (4.2 mg/kg), Lipid Nanoparticle (LNP) encapsulating ODN 1826, LNP B (4.2 mg/kg LNP /0.5 mg/kg ODN 1826), and Lipid 15 Nanoparticle (LNP)-encapsulating ODN 1826 control, LNP C (3.8 mg/kg LNP /0.5 mg/kg ODN 1826 control) were administered peritumoral (PT) only in right tumors on Days 0, 3, 7, and 12. "/" designates encapsulation” (Page 55, line 12-17). Thus, showing that payload loading ratios are a formulation variable Gindy actively manipulates and reports. Gindy does not teach a ratio between the two distinct co-loaded oligonucleotide.
Mitchell teaches that a VISTA antagonist may be “a single stranded or double stranded RNAi inhibitor of VISTA” (Page 11, line 25-26).
Accordingly, it would have prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at a workable siRNA:CpG loading ratio through routine experimentation because Gindy already establishes that payload loading ratios are a result-effective variable that formulators adjust and report, Mitchell establishes that VISTA antagonist may be double stranded RNAi, and Xu establishes that the two coloaded payloads perform distinct and independently tunable biological functions such that a person having ordinary skill in the art would have been able to balance their relative amounts to avoid under or over favoring one effect at the expense of the other
With regard to claim 7, the composition of Xu, Gindy, and Mitchell are discussed above. Gindy further discloses encapsulation in the lipid nanoparticle composition formulation (Page 49, line 26-29) and supports both limitation of shielding from degradation and release upon internalization.
With regard to claim 8-9, the composition of Xu, Gindy, and Mitchell are discussed above.
Gindy further discloses “[t]The lipid nanoparticle (LNP) composition, LNP A, comprised compound 1-9 in Table 3 (amino lipid 9 from WO201 l/022460), cholesterol, polyethylene glycol-lipid (PEG-DMG), and phospholipid (DSPC) at a specified molar composition of 58:30: 10:2 amino lipid:cholesterol:DSPC:PEG-DMG” (Page 49, line 26-29). Thus, Gindy discloses a phospholipid such as DSPC and cholesterol. Gindy goes on to disclose that “[i]n certain embodiments of the invention, the lipid nanoparticle comprises 34-59 mole% ionizable cationic lipid selected from the group consisting… 30-48 mole% cholesterol, 10-24% DSPC and 1-2 mole % PEG-DMG” (Page 6, line 3-8). Thus, Gindy discloses overlapping ranges.
With regard to claim 10 and 13, the composition of Xu, Gindy, and Mitchell are discussed above.
Gindy discloses that the “combination of ethanol volume fraction, reagent solution flow rates and t-mixer tubing ID utilized at this mixing stage had the effect of controlling the particle size of the LNPs between 30 and 300 nm” (Page 50, line 7-9). Thus, Gindy discloses overlapping range. Further, Gindy discloses “[e]ach therapeutic agent in a combination therapy of the invention may be administered either alone or in a medicament (also referred to herein as a pharmaceutical composition) which comprises the therapeutic agent and one or more pharmaceutically acceptable carriers, excipients and diluents, according to standard pharmaceutical practice” (Page 25-28). Thus, Gindy discloses that pharmaceutically acceptable carriers for the nanoparticles of instant claim 1.
With regard to claim 15, Xu discloses “Combining VISTA-blocking mAb with the TLR vaccine resulted in tumor-free long-term survival in ~50% mice” (Page OF9, Blocking VISTA augments the TLR/MyD88-mediated proinflammatory responses) as discussed above. Further, Xu teaches administering a VISTA inhibitor in combination with a TLR agonist for treating cancer. Xu establishes that the VISTA pathway is treatment agnostic, “To exclude the possibility that this inflammatory response may be due to additional effects of the antibody (i.e., Fc receptor–mediated activation of myeloid cells), we examined WT and Vsir -/- tumor-bearing mice treated with CpG/R848 (Fig. 6G and I)” (Page OF9, VISTA controls the activation of MAPKs and NF-kB by regulating TRAF6). Xu demonstrates that by genetically removing VISTA expression combined with the CpG/R848 TLR agonist vaccine reproduces the same increased proinflammatory tumor microenvironment response that the antibody blockade produces when combined with the same vaccine.
Gindy teaches “co-administering to the subject 1) an effective amount of a composition comprising the LNP of the invention and TLR9 agonist; and 2) an anti-IL-10 antibody or antigen binding fragment thereof” (Page 6, line 16-18). Gindy does not teach administering the specific composition of instant claim 13.
Mitchell is discussed above.
Gindy demonstrated the method step of administering an effective amount of a LNP/TLR9 agonist containing composition to treat cancer. In order to produce the specific therapeutic outcomes that Xu observes, a person having ordinary skill in the art would apply Gindy’s administration method to the VISTA siRNA loaded composition rather than Gindy’s own anti IL-10 composition because Gindy’s method is drafted as a dosing regimen rather than limited to specific compositions.
Accordingly, it would have prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered the composition of claim 13 according to Gindy’s disclosed method of treating cancer, and to have expected the specific therapeutic results reported by Xu, since Gindy’s method is agnostic to the identity of the formulated biologic, and Xu independently confirms that a VISTA/TLR9 composition produces the claimed antitumor effect when administered.
With regard to claim 16, Xu teaches administration of the combination via subcutaneous and systemic administration (Page OF3, Murine tumor models, vaccine treatments, and examination of cytokines in tumor tissues).
With regard to claim 17-18, Xu discloses that VISTA inhibition in combination with TLR agonist enhances proinflammatory responses and produces increases in tumor infiltration T cells and expressly teaches a reduction tumor burden: “Combining VISTA-blocking mAb with the TLR vaccine resulted in tumor-free long-term survival in ~50% mice, whereas either monotherapy transiently delayed tumor growth without long-lasting effects (Fig. 6C). This stronger therapeutic effect correlated with significantly increased numbers of IFNγ-expressing tumor-infiltrating CD8+ and CD4+ T cells (Fig. 6D and E)” (OF7-OF9, Blocking VISTA augments the TLR/MyD88-mediated proinflammatory responses). As discussed above with respect to claim 15, one of ordinary skill would have reasonable expected the VISTA siRNA/TLR9 agonist nanoparticle composition to reprogram tumor resident myeloid cells and reduce tumor burden in the same fashion because Xu’s own gene knockout data confirms that the loss of VISTA expression is the mechanism in which siRNA operates , and reproduces the same proinflammatory response Xu attributes to antibody mediate blockade, independent of which modality is elected to achieve that loss.
With regard to claim 19-21, Xu teaches administering the VISTA-inhibitor/TLR9-agonist combination together with an additional cancer therapy (cf. claim 19), specifically an immunotherapy (cf. claim 20), and more specifically an immune checkpoint inhibitor in the form of a PD-L1 blocking antibody (cf. claim 21), citing that VISTA blockade synergizes with PD-L1 inhibitors in murine tumor models (Page OF12, Discussion).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WENHAN LI whose telephone number is (571)272-9143. The examiner can normally be reached Monday-Friday 7:30 am-5 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at (571)272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.L./Examiner, Art Unit 1614
/ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614
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