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 .
Status of Claims
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on 27 June, 2025. Claims 10 and 142 – 155 are currently pending. Claims 10, 142, 144, 148, 149, 150, 151, 152, 153, and 154 have been amended and claim 155 has been added by Applicants’ amendment filed on 6/27/2025. No claims have been canceled by the Applicant’s amendment filed 6/27/2025 (Claims 1 – 9, and 11 – 141 were previously canceled).
Claim 149 and 151 – 152 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
Therefore, claims 10, 141 – 154 are under consideration to which the following grounds of rejection are applicable.
Response to Applicants’ Arguments as they apply to species election requirement
At page 6 of the remarks filed on 27 June 2025, Applicants essentially argue that: (a) Applicant elected the species of a G protein as set forth in Seq ID No. 16, and claim 149 reads on elected species of Seq ID No. 16, because it is generic (pg. 6, second paragraph), and (b) No species election was required for F protein, and even if they were, claims 151 and 152 read on what Applicant elected at a species of the F protein (pg. 6, last paragraph).
Regarding (a), Applicant’s arguments is not found persuasive. In the response to Restriction, filed 24 July, 2023, Applicant elected without traverse the NIV-G protein as set forth in Seq ID No. 16, and the restriction was made final (pg. 13). Thus, only claim 150 reads on the elected species. Claim 149 reads of a Hendra virus G protein or a wild-type Nipah virus G (NiV-G) protein which is unclear how these G proteins are generic and read on the elected species, and thus, claim 149 was previously withdrawn.
Regarding (b), Applicant’s argument that no species election was required for F protein is not found persuasive. In the response to Restriction, filed 24 July, 2023, Applicant elected without traverse the NIV-F protein as set forth in Seq ID No. 23 in the interest of being responsive, and the restriction was made final (pg. 13). Thus, only claim 153 reads on the elected species. Claims 151 – 152 do not read on the elected species, and thus, was previously withdrawn.
Note that because the genus claim is not allowable as originally claimed, no other species will be rejoined for search and examination.
Thus, claims 149 and 151 – 152 remain withdrawn.
Therefore, claims 10, 141 – 148, 150 and 153 – 155 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed 30 March, 2021, claims the benefit of Provisional Application 63/154,341, filed February 26, 2021, and Provisional Application 63/003,168, filed March 31, 2020.
Therefore, the earliest effective priority date of the instant application is March 31, 2020.
Withdrawn Objections/Rejections
Claim objections
In view of Applicants’ amendment of claim 1, the objection to claim 1 has been withdrawn.
Claim Rejection - 35 USC § 112(b)
The rejection of claims 10, 142 – 148, 150, and 153 - 154 is withdrawn 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.
The claims have been amended to particularly point out and distinctly claim the subject matter.
In view of the withdrawn rejection, Applicant’s arguments are moot.
Maintained Objections/Rejections
Nonstatutory Double Patenting
The rejection of claim 10 is maintained on the ground of nonstatutory double patenting as being unpatentable over claims 1-40 of US Patent No. US 11576872 (B2) (Published: 14 February, 2023) (hereinafter ‘872) in view of Bannas et al. (hereinafter referred to as “Bannas” (Bannas P. et al. Nanobodies and Nanobody-Based Human Heavy Chain Antibodies As Antitumor Therapeutics. Front Immunol. 2017 Nov 22;8:1603. PMID: 29213270; PMCID: PMC5702627). Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims would make obvious the instant claims if they were available as prior art.
Claim 1 of ‘872 teaches a fusosome composition comprising a lipid bilayer, lumen, an exogenous fuosgen disposed in the lipid bilayer, wherein the fuosgen comprises the Nipa virus F and G proteins (interpreted as a lipid bilayer enclosing a lumen, a henipavirus F protein, and a henipavirus G protein, instant claim 1). Claim 13 of ‘872 teaches that the targeting moiety is specific for a cell surface marker on the target cell (interpreted as a cell surface marker, instant claims 1 and 142).
The ‘872 patent does not describe a sdAb binding domain which is attached to the C-terminus of the G protein.
Bannas teaches that the antitumor effect of nanobodies can be enhanced by coupling nanobodies to proteins (Figure 6). (note: Bannas teaches that a functional target has been added to the C-terminus of a CD8 specific nanobody (pg. 7, right column, fourth paragraph) (i.e. a cell surface marker on the target cell). Bannas teaches that these antibodies are advantageous due to their small size, high solubility, high stability, and excellent tissue penetration in vivo (Abstract). Please note: the as-Filed Specification teaches that nanobodies and camelid VHH domains are examples of sdAbs (Paragraph [0171]).
Therefore, it would have been prima facia obvious for one of ordinary skill in the art to add the CD8 specific sdAbs to the G protein to enhance the therapeutic ability of the composition.
Response to Arguments
Applicant’s arguments filed 27 June, 2025 have been fully considered but they are not persuasive. Applicant essentially asserts that (a) that there is nothing in the claims of the ‘872 patent alone or in further view of Bannas that the claimed targeted lipid particles using a sdAb exhibit non-obvious highly advantageous properties including a 10-fold increased titer, higher surface expression of its sdAb, and higher binding to its target, as compared to the scFv (pg. 14, last paragraph).
Regarding (a), Applicant’s argument is not found persuasive. Applicant is reminded that this is a non-statutory double patent rejection, wherein the instantly recited claims do not disclose the advantageous properties, i.e. the claims do not teach a 10-fold increased titer, higher surface expression of its sdAb, or higher binding to its target. Thus, no such limitation exists in the claims as written. Hence the argument is not persuasive as they argue limitations that are not present in the claims.
Thus, the rejection is maintained for the reasons of record.
Claim Rejection - 35 USC § 103
The rejection of claims 10, 142 - 154 is maintained, and claim 155 is newly rejected under 35 U.S.C. 103 as being unpatentable over Costa et al. (hereinafter referred to as “Costa”) (US20190144885, published May 16, 2019), and further in view of Bannas et al. (hereinafter referred to as “Bannas”) (Bannas P. et al. Nanobodies and Nanobody-Based Human Heavy Chain Antibodies As Antitumor Therapeutics. Front Immunol. 2017 Nov 22;8:1603. PMID: 29213270; PMCID: PMC5702627).
Regarding claim 10, Costa teaches a pseudotyped retrovirus-like particle or retroviral particle comprising 1) a cell targeting fusion protein comprising a protein derived from an envelope glycoprotein G and a cell targeting domain, 2) one modulating fusion protein comprising an envelope glycoprotein G and a functional domain, and 3) a glycoprotein derived from an envelope glycoprotein F (Paragraph [0019]) (interpreted as a henipavirus F protein molecule, instant claim 10). Costa teaches that the protein F mediates the fusion of viral membranes with the cellular membranes of the host cell (Paragraph [0062]) (interpreted as a lipid bilayer enclosing a lumen and the F protein and the targeted enveloped protein are embedded in the lipid bilayer, instant claim 10). (Note: the as-Filed Specification teaches that the F glycoprotein that is involved in facilitating the merger or fusion of the two lumens of the lipid particle and the target cell membranes (Paragraph [0203]). Costa teaches that the C-terminus of the envelope glycoprotein G is fused via a linker to the N-terminus of the cell targeting domain, wherein the cell targeting domain is ScFv (Paragraph [0183] and [0026]) (interpreted as a targeted envelope protein comprising a henipavirus envelope attachment glycoprotein G and a binding domain, wherein the binding domain is attached to the C-terminus of the F protein via a peptide linker, instant claim 1). Costa teaches that the scFv is specific for CD8 (Paragraph [0163] (interpreted as the binding domain binds CD8, instant claim 10). Costa teaches that the invention related to a retroviral vector for use in immune therapy, and the in the prevention and treatment of cancer (Paragraph [0030]).
Costa does not specifically exemplify that the binding domain is a single domain antibody (sdAB) (instant claim 10 (in part)).
Regarding claim 10 (in part), Bannas teaches that the inherent hydrophobic interactions of VH and VL domains of the scFv limits the stability and solubility of engineered antibodies, causing aggregation and mispairing of V-domains (Abstract). Bannas teaches that cannelids naturally produce antibodies comprised of heavy chains in which the target molecule is composed of a single variable domain (VHH or nanobodies (Nb)), wherein the advantages of these antibodies are their small size, high solubility, high stability, and excellent tissue penetration in vivo (Abstract). (Please note: the as-Filed Specification teaches that nanobodies and camelid VHH domains are examples of sdABs (Paragraph [0171]). Bannas teaches that nanobodies can be used in antitumor therapeutics (Abstract). Bannas teaches that CARs contain a scFv, but this relatively unstable scFv can be replaced by a stable nanobody (pg. 9, left column, first paragraph). Bannas teaches that the antitumor effect of nanobodies can be enhanced by coupling nanobodies to proteins (Figure 6). Bannas teaches that a functional target has been added to the C-terminus of a CD8 specific nanobody (pg. 7, right column, fourth paragraph).
Therefore, in view of the benefits of using nanobodies (e.g, a single domain antibody) in antitumor therapeutics as taught by Bannas, it would have been prima facia obvious for one of ordinary skill in the art to replace the sdABs of Bannas for the scFv of Costa with a reasonable expectation of optimizing the treatment of cancer. It would have been prima facia obvious to combine the cited references because Costa teaches the use of scFv specific CD8 in the retroviral particle to prevent and treat cancer, and Bannas teaches the disadvantages of using an scFv antibody, including aggregation and mispairing of V-domains of the scFv, and the use of a CD8 nanobody that overcomes these disadvantages, including small size, high solubility, high stability, and excellent tissue penetration in vivo for treatment of cancer.
Regarding claims 142 and 143, Costa teaches that the cell targeting domain is specific for CD3, CD8, or CD4 (Paragraph [0162]), rendering obvious T cells whose surface marker is CD8. .
Regarding claims 144 - 145, Costa teaches that the gene of interest is present in the retrovirus derived genome of said retroviral vector, wherein the gene of interest is a CAR (Paragraph [0280] and [0283]) (interpreted as the lipid particle further comprises an exogenous agent encoding a CAR, instant claims 144 and 145).
Regarding claim 146, Costa teaches that the gene of interest is present in the retro-virus derived genome of said retroviral vector, wherein the gene of interest is a CAR (Paragraph [0280] and [0283]) (interpreted as the exogenous agent is a nucleic acid comprising a payload gene for correcting a genetic deficiency, instant claim 146). (Note: the as-Filed Specification teaches that a CAR is an example of a “payload” (Paragraph [0308]).
Regarding claim 147, Costa teaches the linker can be a G4S (Paragraph [0191]) (interpreted as a GGGGS (Seq ID No. 43 and Seq ID No. 42), instant claim 147).
Regarding claim 148, Costa teaches that the retroviral vector is a lentiviral vector (Paragraph [0053]).
Regarding claims 150, Costa teaches the nucleic acid encoding a truncated and mutated NiV G protein fused to IL-7, wherein Seq ID No. 6 has a 100% alignment score to instant Seq ID No. 16 (See below).
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Regarding claim 153, Costa teaches that the NiV-F protein lacking 22 amino acids comprises Seq ID No. 16. Seq ID No. 16 has a 100% alignment score with instant Seq ID No. 23 (See below).
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Regarding claim 154, Costa teaches that NiV-F protein Seq ID is Seq ID NO. 16, which as a 100% alignment score to instant Seq ID No. 23 (see supra), and that the NiV G protein Seq ID is Seq ID No. 6, which as a 100% alignment score with Seq ID No. 16.
Regarding claim 155, Costa teaches that NiV-G may comprise at least two or at least three point wherein said point mutations are selected in the group consisting of E501A, W504A, Q530A and E533A (Paragraph [0108]).
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly rejected under 35 USC §103 as obvious over the art.
Response to Arguments as they apply to rejection of claims 10, 142 – 148, 150, and 153 - 155 under 35 USC § 103
Applicant’s arguments filed 27 June, 2025 have been fully considered but they are not persuasive. Applicant essentially asserts (a) the references do not teach any motivation to combine with reasonable expectation of success, wherein Bannas teaches the advantages of sdAB over scFv in the context of chimeric antigen receptors and their optimization (pg. 11, last paragraph), and (b) the working examples sufficiently demonstrate unexpected advantageous properties, including a 10-fold increased titer, higher surface expression, and higher binding to the target of the sdAB, compared to the scFv, as a result of incorporating sdAbs with the G protein (pg. 12 – 13, full pages).
Regarding (a), Applicant’s argument that Bannas does not teach incorporating a nanobody into targeted lipid particle and how to do so with a reasonable expectation of success is not found persuasive.
Applicant is reminded that none of the references has to teach each and every claim limitation. If they did, this would have been anticipation and not an obviousness-type rejection. 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). Applicant’s assertion that Bannas does not teach incorporating a nanobody into a targeted lipid particle is not found persuasive. The Applicant is reminded that the rejection of record is based on the combination of Costa and Bannas, wherein Costa teaches the use of scFv specific CD8 in the retroviral particle to prevent and treat cancer, and Bannas teaches the disadvantages of using an scFv antibody, including aggregation and mispairing of V-domains of the scFv, and the use of a CD8 nanobody that overcomes these disadvantages, including small size, high solubility, high stability, and excellent tissue penetration in vivo for treatment of cancer.
The Examiner acknowledges that Bannas teaches that CARs contain a scFv, but this relatively unstable scFv can be replaced by a stable nanobody. Bannas teaches that nanobodies can be fused genetically to other proteins and/or to smaller peptides, wherein both, the N- and C-terminus are available for fusion (Fig. 6A). The practitioner in the art would readily understand that a scFv of a CAR recognizes and binds a target molecule on the surface of a target cell. A sdAb recognizes and binds a target molecule on the surface of a target cell. There is no evidence provided by Applicants that attachment of the sdAb via a linker to a G-protein rather than a scFv would had impaired the recognition/ binding function of the sdAb. So if an unstable scFv can be replaced by a stable nanobody as disclosed by Bannas, the binding of a scFv and a sdAb should be reasonably expected to recognize/ bind a CD8+ cell or any other target molecule as both sdAb and scFv are the antigen-binding domain of an antibody. Thus, one of ordinary skill in the art would know how to replace the CD8 scFv as taught by Costa, with the CD8 sdAB as taught by Bannas, considering the advantages of the nanobody in the treatment of cancer.
Regarding (b), Applicant’s argument that there is evidence of unobvious or unexpected advantageous properties is not found persuasive. Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) and In re Baxter TravenoILabs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991). See MPEP § 716.02 - § 716.02(g). Evidence has not been provided that the "unexpected results" were unknown in the prior art. Further, the as-Filed Specification does not teach that these results were “surprising, advantageous, or unexpected.”
MPEP § 2112(II) indicates:
there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004)). ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention.") (underline added); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed.Cir.1999) (underline added).
MPEP 716.02(b) states:
the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (See also; In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977).
MPEP 716.02(c) indicates:
unexpected results must be weighed against evidence supporting a prima facie obviousness. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978); and where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977). “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
Bannas teaches the use of a CD8 nanobody (sdAB) provides advantages, compared to scFV, including small size, high solubility, high stability. Thus, one of ordinary skill in the art can expect that when the G protein, as taught by Costa, is linked with the CD8 sdAb, taught by Bannas, there would be a 10-fold increased titer, higher surface expression, and higher binding to the target of the sdAB, compared to the scFv.
The Applicant notes that there is nothing in the cited references that suggest a 10-fold increase in titer could be achieved by replacing an scFV with an sdAb (pg. 13, third paragraph). The Examiner notes that the instantly filed claims do not teach these advantages. Moreover, with respect to applicants' argument that, " median fluorescence intensity (MFI) of HEK 293 cells transfected with constructs containing a sdAb in the form of VHH binding modalities demonstrated higher surface expression as quantified by % of His+ cells (FIG. lA) than cells transfected with constructs containing scFv binding modalities” i (see page 12)," is not found persuasive because 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, 26USPQ2d 1057 (Fed. Cir. 1993).
Thus, the rejection is maintained for the reasons of record.
Conclusion
Claims 10, 142 – 148, 150, and 153 - 155 remain rejected.
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 extension fee 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VYOMA SHUBHAM TIWARI whose telephone number is (571)272-2954. The examiner can normally be reached M-F 8:30 - 5:30 EST.
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/VYOMA SHUBHAM TIWARI/Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634
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