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 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 August 14, 2025 for a Request for Continued Examination. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on August 14, 2025 has been entered.
This application is in response to the papers filed on August 14, 2025. Pursuant to the amendment filed on August 14, 2025, claims 1-2, 4,11-12, 14-20, 22-28, 30-37 and 40-43 are currently pending. Claims 1, 4, 20, and 40 have been amended, and claim 39 has been cancelled in Applicant’s amendment filed on August 14, 2025. No claims have been added.
Applicant’s election without traverse of Group I, claim(s) 1- 4, 11, 12, 14 – 22, 30 – 42 in the reply filed on July 19, 2024 was previously acknowledged.
Claims 23 - 28 and 43 were previously withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Therefore, claims 1-2, 4, 11, 12, 14-20, 22, 30-37, and 40-42 are currently under examination to which the following grounds of rejection are applicable.
***The Examiner for this Application has changed from Examiner Vyoma Tiwari, AU 1634 to Examiner Michael A. Riga, AU 1634. Please direct all future correspondence to Examiner Riga. Additional contact information can be found at the end of this paper.***
Information Disclosure Statement
The information disclosure statement (IDS) submitted on August 14, 2025 was filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Priority
The present application filed August 14, 2020, claimed the benefit of PCT/US2019/018324, filed February 15, 2019 which claims the benefit of Provisional Application, 62/631,747, filed February 17, 2018.
Therefore, the earliest priority date of the instant application is February 17, 2018.
Response to Arguments
Withdrawn Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Rejection - 35 USC § 112(d)
In view of Applicants’ amendment to the claims dated August 14, 2025, wherein claim 20 has been amended, the rejection to claim 20 rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends, is withdrawn.
Claim Rejection - 35 USC § 112(a)
In view of Applicants’ amendment to the claims dated August 14, 2025, wherein claims 1, 4, 20, and 40 have been amended, the rejection to claims 1, 2, 4, 11-12, 14-17, 18-20, 22, 30 – 37, and 40 – 42 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, are withdrawn. The reason for the withdrawal of the rejection is due to the amended claim 1 now reciting “wherein the fusogen comprises a paramyxoviral fusogen”. The examples provided include the HVJ-E fusogen that derives from the Sendai virus, a member of the Paramyxoviridae. Additionally, the Specification lists other fusogens of this viral family.
Claim Rejection - 35 USC § 112(b)
In view of Applicants’ amendment to the claims dated August 14, 2025, wherein claims 1, 4, 20, and 40 have been amended, the rejection to claims 1, 11– 12, 14 – 17, 19-20, 22, 30 –32, 34-35, 37 and 40 – 42 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, are withdrawn.
Applicants’ arguments are moot in view of the withdrawn rejection. A response to any argument pertaining to a new or maintained rejection can be found below.
Maintained Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Rejection - 35 USC § 112(b)
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.
Claim 2, 4,18, 33, and 36 remain 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 2 is indefinite in the recitation of “wherein the source cell is …., or a cell line” as it is unclear how the source cell is the entire cell line which is describing a population of cells. It appears the Applicant is intending to describing the source cell is a cell from a cell line.
Claim 4 remains indefinite because the amended claim does not properly describe the composition as the recitation of “one” can be understood as including both the structural and matrix proteins. The appropriate correction is “wherein the fusosome comprises a viral structural protein, a viral matrix protein, or a combination thereof.”
Claim 18 is indefinite for describing a target cell isolated from an organism in view of claim 17, for which the claim depends, describing the primary cell as being in an organism. Therefore, it is unclear if the limitation of being inside the organism is referring to only the location prior to isolation, or rather describing the cell is isolated and then administered back to the organism.
Claim 33 is indefinite because the claim states the fusosome can have up to three signaling domains, and then lists three groups of specific signaling domains, and therefore it is not clear if the listed specific signaling domains, groups (i) –(iii), are for each of the respective signaling domains, i.e. first signaling domain corresponding to group (i), second signaling domain corresponding to group (ii), and third signaling domain corresponding to group (iii), or rather options that can go with any of the three signaling domains.
Claim 36 is indefinite as it is not clear that the use of “heterologous relative to a naturally-occurring membrane protein” is in relation to the source cell membrane proteins.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
The rejection of claims 1-2, 4,11-12, 14-20, 22-28, 30-37 and 40-43 on the ground of nonstatutory double patenting as being unpatentable over claims 1-40 of U.S. Patent No. 11,576,872 B2 is maintained. Although the claims at issue are not identical, they are not patentably distinct from each other because both the issued claims and the instantly claimed invention are drawn to a fusosome comprising the following: (a) lipid bilayer; (b) lumen surrounded by the lipid bilayer; (c) an exogenous or overexpressed fusogen disposed in the lipid bilayer, that is more specifically a paramyxoviral fusogen, and (d) a payload agent (instant claims) or cargo as recited in the issued claims.
The instant claims differ from the issued claims in that the issued claims do not specifically define the term “cargo” as set forth in the instant claims. However, the specification of the of U.S. Patent No. 11,576,872 B2 teaches that the term “cargo” in the following manner: “e.g., a therapeutic agent, e.g., an endogenous therapeutic agent or an exogenous therapeutic agent.” (See col. 96, lines 4-35).In some embodiments, the cargo is a protein cargo. In embodiments, the cargo is an endogenous or synthetic protein cargo. In some embodiments, the fusosomes have (or are identified as having) at least 1, 2, 3, 4, 5, 10, 20, 50, 100, or more protein cargo molecules per fusosome. (See col. 22, lines 5-9).” Additionally, the specification teaches that the disclosed fusosome “delivers to a target cell at least 10, 50, 100, 500, 1,000....1,000,000,000 copies of a therapeutic agent.” (See col. 21, lines 18-22).
The term cargo is also defined in the following manner: (See col. 38, lines 46-60) “[I]n some embodiments, the fusosome comprises a cargo, e.g., a therapeutic agent, e.g., an endogenous therapeutic agent or an exogenous therapeutic agent. In some embodiments, the therapeutic agent is chosen from one or more of a protein, e.g., an enzyme, a transmembrane protein, a receptor, an antibody; a nucleic acid, e.g., DNA, a chromosome (e.g. a human artificial chromosome), RNA, mRNA, siRNA, miRNA, or a small molecule. In some embodiments, the therapeutic agent is an organelle other than a mitochondrion, e.g., an organelle selected from: nucleus, Golgi apparatus, lysosome, endoplasmic reticulum, vacuole, endosome, acrosome, autophagosome, centriole, glycosome, glyoxysome, hydrogenosome, melanosome, mitosome, cnidocyst, peroxisome, proteasome, vesicle, and stress granule. In some embodiments, the organelle is a mitochondrion.”
Additionally, the specification of the issued US Patent defines the fusosomes as: “[c]apable of delivering (e.g., delivers) a protein to a target cell, e.g., to transiently rescue a protein deficiency. Similarly, in some embodiments, a method herein comprises delivering a protein to a target cell. In embodiments, the protein is a membrane protein (e.g., a membrane transporter protein), a cytoplasmic protein (e.g., an enzyme), or a secreted protein (e.g., an immunosuppressive protein).” (Col. 16, lines 50-57).
Thus, the definition of the term “cargo” as defined in the disclosure of the issued US Patent clearly renders obvious the membrane protein payload agents as set forth in the instant claims. Therefore, the instant claims are rendered obvious over the claims of the issued US Patent in view of the definition of the term “cargo” as set forth in the disclosure of the issued US Patent.
As per MPEP 2111.01, “Further, those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application).
Response to Applicants’ Arguments as they apply to Double Patenting Rejection
At page 8 of the remarks filed on August 14, 2025, Applicants offer to provide a terminal disclaimer upon indication by the Examiner of allowable claims. However, Applicant’s request is not a proper response to the rejections of record as it neither traverses the grounds of rejection by providing specific arguments, nor indicates that a terminal disclaimer has been filed to overcome the rejection. As such, the rejections of record stand.
Double Patenting
Claims 1-2, 4,11-12, 14-20, 22-28, 30-37 and 40-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14, 15, 21, 22, 24, 32, 34, 36, 45-47, 50, 54-58 filed on July 18, 2025 of copending Application No. 18/154,618. (hereinafter ‘618).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the issued claims and the instantly claimed invention are drawn to a fusosome comprising the following: (a) lipid bilayer; (b) lumen surrounded by the lipid bilayer; (c) an exogenous or overexpressed fusogen disposed in the lipid bilayer, that is more specifically a paramyxoviral fusogen, and (d) a payload agent (instant claims) or cargo as recited in the ‘618 claims.
The instant claims differ from the issued claims in that the ‘618 claims do not specifically define the term “cargo” as set forth in the instant claims. However, the specification of ‘618 teaches that the term “cargo” in the following manner: “e.g., a therapeutic agent, e.g., an endogenous therapeutic agent or an exogenous therapeutic agent.” (See par 0291). In some embodiments, the cargo is a protein cargo. In embodiments, the cargo is an endogenous or synthetic protein cargo. In some embodiments, the fusosomes have (or are identified as having) at least 1, 2, 3, 4, 5, 10, 20, 50, 100, or more protein cargo molecules per fusosome. (See par 0259).” Additionally, the specification teaches that the disclosed fusosome “delivers to a target cell at least 10, 50, 100, 500, 1,000....1,000,000,000 copies of a therapeutic agent.” (See par 0256).
The term cargo is also defined in the following manner: (See par 0291) “[I]n some embodiments, the fusosome comprises a cargo, e.g., a therapeutic agent, e.g., an endogenous therapeutic agent or an exogenous therapeutic agent. In some embodiments, the therapeutic agent is chosen from one or more of a protein, e.g., an enzyme, a transmembrane protein, a receptor, an antibody; a nucleic acid, e.g., DNA, a chromosome (e.g. a human artificial chromosome), RNA, mRNA, siRNA, miRNA, or a small molecule. In some embodiments, the therapeutic agent is an organelle other than a mitochondrion, e.g., an organelle selected from: nucleus, Golgi apparatus, lysosome, endoplasmic reticulum, vacuole, endosome, acrosome, autophagosome, centriole, glycosome, glyoxysome, hydrogenosome, melanosome, mitosome, cnidocyst, peroxisome, proteasome, vesicle, and stress granule. In some embodiments, the organelle is a mitochondrion.”
Additionally, the specification of ‘618 defines the fusosomes as: “[c]apable of delivering (e.g., delivers) a protein to a target cell, e.g., to transiently rescue a protein deficiency. Similarly, in some embodiments, a method herein comprises delivering a protein to a target cell. In embodiments, the protein is a membrane protein (e.g., a membrane transporter protein), a cytoplasmic protein (e.g., an enzyme), or a secreted protein (e.g., an immunosuppressive protein).” (See par 0225).
Thus, the definition of the term “cargo” as defined in the disclosure of ‘618 clearly renders obvious the membrane protein payload agents as set forth in the instant claims. Therefore, the instant claims are rendered obvious over the claims of Application No. 18/154,618 in view of the definition of the term “cargo” as set forth in the disclosure of ‘618.
As per MPEP 2111.01, “Further, those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application).
New Grounds of Rejection:
Claim Objections
Claims 19, 20, 32, 33, and 37 are newly objected to because of the following informalities:
Claims 19-20 are Markush-type claims which should recite “selected from the group consisting of.” This phrase refers to the election of one or more choices. A proper Markush-type claim recites alternatives in a format such as “selected from the group consisting of A, B and C.” See Ex parte Markush, 1925 C.D. 126 (Comm’r Pat. 1925). It is unclear whether the phrase “wherein the target cell is selected from…” in claims 19 and 20 refers to a further selection in addition to the election of one or more choices required by the recitation of the Markush groups.
Claim 32 is objected to because the recited abbreviations, “scFv” and “Fab” should be spelled out at the first encounter in the claims. Appropriate correction is required.
Claim 33 appears to be describing a Markush group, but the claim is not written in the proper format. Refer to the objection to claims 19 and 20 listed above for such format.
Claim 37 is objected to because it appears the recited “the membrane protein payload” is intended to be written as “the membrane protein payload agent” as recited in claim 1 from which the claim depends.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, 11, 14-17, 19-20, 22, 35, 36, 40, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Kaneda (Virosome: A novel vector to enable multi-modal strategies for cancer therapy, Advanced Drug Delivery Reviews, Volume 64, Issue 8, 2012, Pages 730-738) in view of Tang et al. (Therapeutic potential of CAR-T cell-derived exosomes: a cell-free modality for targeted cancer therapy." Oncotarget 6.42 (2015): 44179; of record).
Regarding claim 1, Kaneda teaches the HVJ-liposome that was developed by combining liposomes with fusion proteins derived from the hemagglutinating virus of Japan (HVJ), a paramyxovirus that is also known as the Sendai virus (Sec 1.2). Kaneda teaches the vector contains two HVJ glycoproteins, the HN (hemagglutinating) protein that is required for binding to target cell-surface sialic-acid receptors, and the F (fusion) protein that is required for cell fusion by associating with lipids. The HVJ-liposome is constructed to deliver DNA to the target cell cytoplasm after cell fusion, in which the HVJ-liposome comprises a lipid bilayer comprising a plurality of lipids wherein the lipids originate from the HVJ which would derive from a cell during viral infection. Fig. 1B shows the vector containing a lumen based on the containment of plasmid DNA. The fusogen of the HVJ-liposome (F protein) is exogenous as it originates from the HVJ or Sendai virus. The vector harbors no nucleus as depicted in Fig. 1B, and includes the targeting domains of the HN and F proteins for binding to target cell plasma membrane.
Kaneda Figure 1B:
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Kaneda Figure 2:
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Additionally, Kaneda teaches an updated HVJ vector, the HVJ-envelope vector (HVJ-E) that has the advantages in view of production and fusion rates (Sec. 1.5). This vector does not use a liposome and involves inactivation via UV followed by purification to remove viral RNA. Moreover, Kaneda describes a third vector, a tumor targeting HVJ-E vector utilizing transferrin (TF) without HN production, and further states that the vector should be investigated for other tumor-targeting molecules, e.g. CD19 antibody (Sec 1.6, Fig 2. (above)). Lastly, Kaneda-2 states the HVJ vectors can be used to deliver various molecules including proteins (abstract).
Kaneda is expected to teach the fusosome as comprising a membrane protein payload agent because transferrin interacts with the target cell membrane. In further support the instant Specification lists transferrin as a specific membrane-associated protein that is a transmembrane protein, and states that “As used herein, “membrane protein payload agent” refers to a cargo that is or comprises a membrane protein…A membrane protein is a protein which associates with (e.g., is localized in and/or on) or is capable of associating with a cell membrane.” (par 0855, 0676).
In further support of including a membrane protein payload agent, Tang et al. teaches CAR-T cell derived exosomes which responds better to the volatility and complexity of cancer (Abstract) (interpreted as the membrane protein payload agent). Tang teaches that these exosomes comprise lipid bilayer membrane, wherein the exosomes carry a complex cargo including nucleic acids, proteins and lipids (pg. 44180, right column, second paragraph). Engineered CARs can provide non-HLA restricted recognition of cell surface components and do not require antigen processing and presentation by HLA (pg. 44184, left column, first paragraph). Additionally, Tang describes the exosomes resemble liposomes consisting of a bi-lipid membrane and an aqueous core (pg. 44185, left column, first paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the membrane protein payload agents of the fusosomes taught by Kaneda based on teaching the vectors as comprising different types of cargo, e.g. DNA, RNA, and proteins, and due to providing the example of using transferrin that is known to interact with target cell membranes for transport. Therefore, there is a reasonable expectation that the vector taught by Kaneda can be modified to include other membrane protein agents that are capable of delivery after fusion to a target cell via fusion protein/fusogen. Furthermore, Tang provides further support in describing exosomes with CAR that are capable of fusing with target or recipient cells for CAR delivery, and therefore it would be obvious to include CAR with the claimed fusosomes since it has been done in a similar system.
Regarding claim 4, dependent on claim 1, Kaneda teaches the HVJ vector as comprising a viral structural protein and viral matrix protein as depicted in Figure , e.g. HN a glycoprotein and M the matrix protein.
Regarding claim 11, dependent on claim 1, Kaneda teaches wherein the fusogen is active at a pH of 6- 8 as seen in describing “Since acidic pH is not necessary for the fusion of HVJ with the cell membrane, the fusion occurs at the cell surface at a neutral pH.” (Sec. 1.2).
Regarding claim 14, dependent on claim 1, the rejection to claim 1 makes obvious wherein the wherein the membrane protein payload agent is a membrane protein that is disposed in the fusosome lipid bilayer as seen with transferrin which is a transmembrane protein as taught by Kaneda, and furthermore, Tang teachings with CAR which are also integrated in plasma membranes.
Regarding claim 15, dependent on claim 1, the rejection to claim 1 makes obvious wherein the membrane protein payload agent is a nucleic acid that encodes the membrane protein as seen with transferrin and the HVJ vectors delivering DNA in the form of plasmids. Altogether, the vectors taught by Kaneda in view of Tang can comprise DNA or proteins as described above.
Regarding claim 16, dependent on claim 1, the rejection to claim 1 makes obvious wherein the membrane protein payload agent is or comprises a chimeric antigen receptor (CAR) as seen in the teachings of Tang in using exosomes to deliver CARs to target cells as described above.
Regarding claim 17, dependent on claim 1, Kaneda teaches wherein the target cell is in an organism by teaching chimeric HVJ vectors that target cancer cells in vivo (p 5, col 1; Fig. 3).
Regarding claim 19, dependent on claim 1, Kaneda teaches wherein the target cells are immortalized cell, e.g. HeLa cells, and HEK293 cells (p 5, col 1).
Regarding claim 20, Kaneda teaches the HVJ vectors can be used to target cancer cells, and further states the HVJ vector should be explored with anti-CD19 antibody that targets B-cell lymphoma (i.e. lymphocytes). Furthermore, Tang teaches “The results from early clinical trials have revealed a very encouraging therapeutic efficacy of CAR-mediated immunotherapy in a variety of cancers including acute and chronic lymphocytic leukemia [64, 65], lymphoma [66] and neuroblastoma [67].”, and then explores using CAR-T cell-derived exosomes for cancer treatments (p 4, col 1).
Regarding claim 22, dependent on claim 1, Kaneda teaches wherein the targeting domain interacts with a target cell moiety on the target cell as described in the claim 1 rejection above with the F protein binding to target lipids and HN binding to target sialic acid receptors (p 2, col 2).
Regarding claim 35, dependent on claim 20, Kaneda teaches the HVJ-E suppresses murine colon carcinoma (CT26) tumors growing in syngeneic Balb/c mice by activating cytotoxic T lymphocytes (CTL), and additionally, HVJ-E eradicates murine renal cancer in a mouse model by activating natural killer (NK) cells (Sec. 2.2.1). Therefore, it would be obvious to use the HVJ vectors that have been shown to activate different lymphocytes to further target these cells in delivering therapeutic agents, e.g. drugs, CARs, as a way to improve therapeutic outcomes related select diseases. There is a reasonable expectation that the HVJ vector would be successful in delivery based on the Kaneda teaching the fusion with other cell types, e.g. kidney cells, HeLa cells, cancers (Sec. 1.6). Lastly, Tang teaches T cell derived exosomes as depicted in Fig. 1 wherein T cells are engineered to express CAR, and then after expansion exosomes with the CARs are isolated for treatments. It would be obvious to not only use the isolated exosomes on treatments, but on other isolated T cells as a way to increase production of exosomes with CARs across blood samples.
Regarding claim 36, dependent on claim 1, Kaneda teaches using different signal sequences for delivery to particular regions of a cell, e.g. nucleus, as seen with a SV40 NLS or a “a non-classical nuclear localization signal peptide of heterogeneous nuclear ribonucleoprotein” (Sec. 1.1).
Regarding claim 40, Kaneda teaches the wherein the paramyxoviral fusogen comprises a Sendai virus F protein as seen in Figure 1 and Sec. 1.2..
Regarding claim 41, Kaneda teaches the F protein is recognized by the asialoglycoprotein receptor on hepatocytes; and moreover describes the HVJ-E vector utilizing a chimeric F protein with transferrin to target cancer cells (Sec. 1.6).
Claims 1, 2, 37 are rejected under 35 U.S.C. 103 as being unpatentable over Kaneda (Advanced Drug Delivery Reviews, Volume 64, Issue 8, 2012, Pages 730-738) in view of Tang et al. (Oncotarget 6.42 (2015): 44179; of record) as applied to claim 1, and further in view of Watanabe et al. (Development, Growth & Differentiation 17.1 (1975): 61-69).
Regarding claim 1, the disclosure of Kaneda in view of Tang is applied as in the 103 rejections above, the content of which is incorporated above, in its entirety.
Regarding claim 2, the source cell would be the cell for which HVJ is propagated prior to combination with a liposome for the HVJ-liposome or inactivation with UV and purification for HVJ-E. Kaneda in view of Tang do not teach this method, and therefore the specific source cells.
Watanabe teaches the standard propagation of HVJ is injection into embryonated chicken eggs within the chorioallantoic membranes (CAM) wherein the virus infects allantoic epithelial cells which causes complete death of these cells and the release of newly produced viruses into the chorioallantoic fluid (p 61, par 2-3). Watanabe further describes cultured epithelial cells are highly susceptible to infection as opposed to cultured mesenchymal stem cells (abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have described the source cell as a primary cell based on Watanabe teaching viral propagation within embryonated chicken eggs, wherein it is shown that the primary epithelial cells are highly susceptible to infection by HVJ. Therefore, it would have been obvious for Kaneda to use such cells for the propagation of HVJ prior to forming the complete fusosome vector (HVJ-E, HVJ-liposome).
Regarding claim 37, Kaneda teaches the membrane protein payload is exogenous or overexpressed relative to the source cell based on Watanabe teaching the source cell as allantoic epithelial cells, and Kaneda teaching the loading of the vector with plasmid DNA after viral isolation, and therefore the payload which in this instance is plasmid DNA is exogenous to the host cell. Moreover, it would be obvious to overexpress the membrane protein payload based on known overexpression systems being known in the art and there being an obvious advantage to have a higher amount of the agent to be fused into the target cell.
Claims 1, 17, 18 are rejected under 35 U.S.C. 103 as being unpatentable over Kaneda (Advanced Drug Delivery Reviews, Volume 64, Issue 8, 2012, Pages 730-738) in view of Tang et al. (Oncotarget 6.42 (2015): 44179; of record) as applied to claims 1 and 7, and further in view of Kaneda et al. (Mol. Ther. 6 (2002) 219–226.; hereinafter ‘Kaneda-2’)
Regarding claims 1 and 17 the disclosures of Kaneda in view of Tang are applied as in the 103 rejections above, the content of which is incorporated above, in its entirety.
Regarding claims 18, dependent on claim 1, Kaneda describes using the HVJ vectors for in vivo applications, but does not teach using the HVJ vectors to target primary cells isolated from an organism as seen with ex vivo applications.
Kaneda-2 teaches using a HVJ vector for effective in vitro gene transfer to primary cells such as human aortic endothelial cells and mouse dendritic cells were (p 222, col 1; Table 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the vector taught by Kaneda and Tang to target primary cells isolated from an organism based on the same vector being shown to effectively transfect primary cells as described by Kang-2, and therefore there is a reasonable expectation of success in similar outcomes when using the vectors taught by Kaneda in view of Tang.
Claims 1, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Kaneda (Advanced Drug Delivery Reviews, Volume 64, Issue 8, 2012, Pages 730-738) in view of Tang et al. (Oncotarget 6.42 (2015): 44179; of record) as applied to claim 1, and further in view Lamb et al. (Virology, Volume 69, Issue 1, 1976, Pages 116-131).
Regarding claim 1, the disclosures of Kaneda in view of Tang are applied as in the 103 rejections above, the content of which is incorporated above, in its entirety.
Kaneda in view of Tang teach the HVJ vector capable of delivering DNA, e.g. plasmids, and proteins, e.g. CAR, but the references do not teach the total copy number of the cargo.
Lamb teaches the HVJ virus is composed of around 1000 NH proteins, 1000 F proteins (fusogen), 2600 nucleocapsid proteins (NP), and 3000 membrane proteins. Lamb further teaches that cellular proteins as opposed to viral products can be incorporated into the virion, wherein 1100 polypeptide 7 molecules were determined to be found in a virion when sourced from a cell (Table 1; p 119). Additionally, Kaneda teaches an updated HVJ-E vector wherein NH proteins are inactivated and replaced with transferrin, and therefore it could be seen that these viral vectors have the capacity to carry at least 1000 copies of an agent such as transferrin or a CAR when the NH protein is inactivated or not.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have described the vector taught by Kaneda and Tang as having a membrane protein payload agent at a copy number of at least 1,000 copies based on this capacity being known in the art for HVJ viruses for which the vector of Kaneda is directed. Moreover, there is clear motivation to include a high copy number near the capacity limit of the employed vector in order to increase the number of agents that are to be fused into the target cell.
Claims 1, 16, 30-34, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Kaneda (Advanced Drug Delivery Reviews, Volume 64, Issue 8, 2012, Pages 730-738) in view of Tang et al. (Oncotarget 6.42 (2015): 44179; of record) as applied to claim 1, and further in view Sadelain et al (Cancer discovery 3.4 (2013): 388-398).
Regarding claims 1 and 16, the disclosures of Kaneda in view of Tang are applied as in the 103 rejections above, the content of which is incorporated above, in its entirety.
Kaneda does not teach the membrane protein payload agent that comprises or encodes a chimeric antigen receptor (CAR).
Moreover, Tang teaches that the CARs are monoclonal antibody-based recombinant receptors that provide both antigen-binding and T-cell-activating functions (pg. 44181, right column, last paragraph) (referring to instant claim 31 and 42). Tang teaches that the targeting specificity of CAR-T cells is determined by an antibody-derived single-chain variable fragment (scFv) in the CAR structure (pg. 44183, right column second paragraph) (referring to instant claims 31 and 32). Tang teaches that CARs may comprise costimulatory domains of CD28, 4-1BB, DPA10, OX40, or ICOS (pg. 44182, right column, first paragraph) (referring to instant claim 33).
Tang does not teach the complete structure of chimeric antigen receptors, despite describing the different generation of CARs (p 44182, col 2).
Sadelain teaches the structures of CAR across three generations of CAR production, in which the second and third generations comprise activating receptors, transmembrane domains, and signaling domains wherein the third generation can have up to three or more (Fig. 1) (referring to instant claim 30 and claim 42). Moreover, Sadelain teaches wherein the one, two, or three signaling domains comprise a CD3 zeta domain and a 4-1BB domain as depicted in Figure 2, and with listed examples of references using CARs with such domains as listed in Table 1 (referring to instant claim 33 and 34).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the particular CAR domains included in the vector taught by Kaneda in view of Tang based on the options listed by Sadelain dependent on variables related to the treatment, subject, and form of cancer or disease being targeted. By doing so, there is a reasonable expectation that the vector harboring a CAR would function similarly in treatments for what has been shown in the art with such CAR.
Response to Applicants’ Arguments as they apply to rejection of the claims under 35 USC § 103
Starting on page 9 of the remarks filed on August 14, 2025, Applicants essentially argue the employed references fail to teach the amended claim 1, wherein the fusogen comprises a paramyxoviral fusogen.
Applicant’s arguments with respect to the claim have been considered but are moot because the new ground of rejection does not rely on the primary reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. For these reasons the rejections have been withdrawn, and new rejections are applied herein that do teach the amended claims, in particular wherein the fusogen comprises a paramyxoviral fusogen, in particular the fusion protein from the HVJ virus or Sendai virus for which the new references of Kaneda teaches as described above. It is noted that the new rejection does maintain in using the Tang reference, which describes using vectors comprising CAR for delivery to select cells, e.g. cancer cells. The new obviousness rejection describes above there being a reasonable expectation of including the CAR with the vectors described by Kaneda based on the work done by Tang in producing T-cell derived exosomes that comprise CARs for delivery to cancer cells. For these reasons, the arguments directed to the rejections made with the references of Yang et al., Tang et al., Franssen et al, and Mangeot et al. are moot since these rejection have been withdrawn.
Conclusion
Claims 1-2,4,11-12,14-20,22,30-37 and 40-42 are rejected. No claims are allowed.
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634