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 . Claims included in the prosecution are claims 1, 21, 22, 24, 36, 45-47, 54, 61-63 and 65-69.
Applicants' arguments, filed 09/18/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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.
Claims 1, 21, 22, 24, 36, 45-47, 54, 61-63 and 65-69 are rejected under 35, U.S.C. 103 as being unpatentable over Mangeot et al. (US 2012/0322147, Dec. 20, 2012) (hereinafter Mangeot) in view of Selaru (US 2018/0028687, Feb. 1, 2018) (hereinafter Selaru), Cheng et al. (US 2015/0133420, May 14, 2015) (hereinafter Cheng), Walfish et al. (US 2016/0011197, Jan. 14, 2016) (hereinafter Walfish), and Khvorova et al. (US 2017/0183686, Jun. 29, 2017) (hereinafter Khvorova).
Mangeot discloses a microvesicle secreted by a eukaryotic cell, wherein the microvesicle comprises a viral membrane fusion protein and a protein of interest (i.e., cargo) (i.e. polypeptide) (i.e., therapeutic agent) (¶ [0012]). The viral membrane fusion protein is overexpressed (¶ [0011]). The protein of interest may be an exogenous protein (¶ [0166]). The microvesicle secreted by the eukaryotic cell does not comprise any viral structural protein (¶ [0016]). The term “viral structural protein” refers to viral proteins that contribute to the overall structure of a capsid protein (¶ [0017]). The microvesicle may not contain any nucleic acid encoding for the protein of interest (¶ [0019]). Typically, the eukaryotic cell is a mammalian cell. Examples of suitable mammalian cells include HEK-293 cells (¶ [0020]). The microvesicles are considered to be exosome-like and have a size between 40 and 150 nm (¶ [0063]). The viral membrane fusion protein enables the microvesicles to efficiently deliver the material contained in said microvesicles to a target cell (¶ [0068]). The microvesicles can be used for vaccination purposes (¶ [0106]).
Mangeot differs from the instant claims insofar as not disclosing wherein microvesicles have a lipid bilayer and a lumen comprising cytosol from the source cell.
However, Selaru discloses wherein exosomes refers to a small membrane extracellular vesicle of ~30-300 nm diameter that is secreted from producing cells into the extracellular environment. The surface of an exosome comprises a lipid bilayer from the membrane of the donor cell and the lumen of the exosome is topologically the same as the cytosol from the cell that produces the exosome. The exosome contains proteins (¶ [0042]).
Mangeot discloses wherein the microvesicles are exosome-like. Accordingly, it would have been prima facie obvious to one of ordinary skill in the art that the microvesicles of Mangeot comprises a lipid bilayer and a lumen comprising cytosol since exosomes comprises these components as taught by Selaru.
The combined teachings of Mangeot and Selaru do not disclose wherein the viral membrane fusion protein is Nipah virus protein F or G.
However, Cheng discloses wherein expression of Nipah fusion (F) and attachment (G) proteins by themselves induces pH-independent cell membrane fusion and 25HC inhibits virus-cell membrane fusion (¶ [0114]).
Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. The microvesicles of Mangeot comprises a viral membrane fusion protein. Accordingly, it would have been obvious to one of ordinary skill in the art to have incorporated Nipah F or Nipah G into the microvesicles of Mangeot since they are known and effective viral membrane fusion proteins as taught by Cheng.
The combined teachings of Mangeot, Selaru, and Cheng do not disclose wherein the microvesicles do not comprise a nucleus.
However, Walfish discloses wherein removing nuclei removes bulk of cellular DNA (¶ [0115]).
Mangeot discloses wherein the microvesicles do not contain any nucleic acid. Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to have removed the nucleus since this is a known method for not having nucleic acids as taught by Walfish,
The combined teachings of Mangeot, Selaru, Cheng, and Walfish do not teach wherein the microvesicles comprise a targeting moiety.
However, Khvorova discloses wherein exosomes can be specifically targeted to a desired cell type or tissue type by expression of a targeting peptide on the exosome surface. The targeting peptide can bind to a moiety present on the surface of the desired target cells (¶ [0138]). Targeting peptides can be selected to target particular tissue types such as brain. This can be achieved by using a targeting peptide that interacts with a neuronal cell surface marker (¶ [0140]). The targeting peptide can be localized to the surface of the exosome by expressing it as a fusion protein with an exosomal transmembrane protein (¶ [0141]).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to have incorporated a targeting peptide to the microvesicle of Mangeot motivated by the desire to have the microvesicle target a desired cell type such as brain cells as taught by Khvorova.
In regard to the functional limitations recited in instant claims 63 and 65-67, as noted in Example 135 of the instant specification, “often, entry of complex biological cargo into target cells is accomplished by endocytosis. Endocytosis requires the cargo to enter an endosome, which matures into an acidified lysosome. Disadvantageously, cargo that enters a cell through endocytosis may become trapped in an endosome or lysosome and be unable to reach the cytoplasm. The cargo may also be damaged by acidic conditions in the lysosome. Some viruses are capable of non-endocytic entry into target cells; however, this process is incompletely understood. This example demonstrates that a viral fusogen can be isolated from the rest of the virus and confer non-endocytic entry on a fusosome that lacks other viral proteins.” Example 135 further discloses that there was “a significant delivery of Cre cargo by NivG+F fusosomes even when recipient cells were co-treated with Baf to inhibit endocytosis-mediated uptake.” Thus, since it appears that the claimed property is through a fusosome comprising a viral fusogen and Mangeot discloses microvesicles comprising a viral membrane fusion protein, the microvesicles of Mangeot would necessarily have the claimed properties when contacted with a target cell population.
In regard to instant claim 45 reciting a pharmaceutical composition, Mangeot discloses wherein the microvesicles can be used for vaccination purposes. Therefore, a pharmaceutical composition comprising the microvesicles with a pharmaceutically acceptable carrier would have been obvious.
In regard to instant claims 68 and 69, since the composition of the prior art comprises a targeting moiety like the claimed invention, one of ordinary skill in the art would reasonably expect more cargo to be present in target cells compared to non-target cells like the claimed invention. Since the cargo (i.e., protein) of the prior art is meant to be delivered to a target cell and not to a non-target cell as taught by Mangeot, it would have been obvious to one of ordinary skill in the art to have optimized the amount of cargo to be delivered to a target cell to be as high as possible. One of ordinary skill in the art would have has a reasonably expectation of success by modifying the amount of targeting moiety, which directs the composition to a specific cell type as taught by Khvorova.
Response to Arguments
Applicant argues that there is no evidence that the Nipah virus F or G proteins have any such recognized suitability for use in delivering cargo with fusosome compositions, much less with fusosome compositions having the specific features recited in the pending claims,
The Examiner does not find Applicant’s argument to be persuasive. Obvious to try is one of the rationales that supports a conclusion of obviousness. See MPEP 2143(I). As discussed in the rejection, Mangeot discloses a microvesicle comprising a viral membrane fusion protein. Mangeot does not recite a specific viral membrane fusion protein in their claim 1 or disclose a specific viral membrane fusion protein in their summary of invention (¶ [0011]-[0013]). Therefore, it would have been obvious to one of ordinary skill in the art that the viral membrane fusion protein of Mangeot is not limited and to have tried other known viral membrane fusion proteins, such as Nipah virus F or G proteins. Applicant has not shown wherein Nipah virus F or G proteins would be unsuitable for the composition of Manegot. As such, Applicant’s argument is unpersuasive.
Applicant argues that Cheng provides no express teaching that would lead the skilled artisan to specifically choose the fusion proteins of Nipah virus out from the many viruses discussed therein. Cheng provides no teaching that Nipah virus F and G proteins provide any advantage or expected beneficial result over the fusion proteins of Mangeot.
The Examiner does not find Applicant’s argument to be persuasive. Choosing from a finite number of identified, predictable solutions support a conclusion of obviousness. See MPEP 2143(I). Applicant has not shown wherein selection of fusion proteins of Nipah virus is advantageous such that it would not have been obvious to select any fusion protein virus disclosed by Cheng. As such, Applicant’s argument is unpersuasive.
Applicant argues that the problem proffered by the Examiner is already solved by the primary reference.
The Examiner does not find Applicant’s argument to be persuasive. Mangeot discloses in paragraph [0069] wherein the microvesicles need to contact the target cell to deliver a protein of interest into a target cell. Khvorova discloses in claim 37 wherein the targeting peptide directs the exosomes to neuronal cells. Thus, Khvorova is not solving the same problem solved by the primary reference since the targeting peptide directs exosomes to a target cell, which is not taught by Mangeot, which required direct contact. Additionally, even if Khvorova solves the same problem solved by the primary reference, Applicant’s argument is still unpersuasive since substituting equivalents known for the same purpose is obvious. See MPEP 2144.06(II). As such, Applicant’s argument is unpersuasive.
Applicant argues that the skilled artisan, reading Cheng or Khvorova, would be provided no reason to consider modifying a Nipah virus F or G protein, which Cheng seeks to inhibit, to further comprise a targeting moiety to enhance cell targeting.
The Examiner does not find Applicant’s argument to be persuasive. Applicant is not considering the teachings of Mangeot, which is the primary reference. Mangeot discloses a microvesicle comprising a viral membrane fusion protein that delivers to a target cell. Thus, since Nipah virus F or G protein is a viral membrane fusion protein, it would have been obvious to have a microvesicle comprising Nipah virus F or G protein delivered to a target cell. Since a targeting peptide can enhance cell targeting, the combination of a Nipah virus F or G protein and a targeting peptide would have been obvious. As such, Applicant’s argument is unpersuasive.
Applicant argues that the skilled artisan is not provided with any reason to combine the exosome composition of Khvorova with the viral fusion proteins of Cheng, when the compositions of Khvorova appeared to be more than sufficient to solve the problem of delivering a cargo to cells.
The Examiner does not find Applicant’s argument to be persuasive. The rejection states wherein the microvesicle of Mangeot is being modified and not the composition of Khvorova. Applicant has not persuasively argued wherein it would not have been obvious to have modified the microvesicle of Mangeot from the teachings of Khvorova. As such, Applicant’s argument is unpersuasive.
Applicant argues that a generalized disclosure of a Nipah virus F and G protein, or a fusion protein comprising a targeting peptide, does not establish that a person of ordinary skill in the art would have expected a paramyxovirus fusogen comprising a targeting moiety, incorporated into the fusosome, together with the other required components of claim 1, would have a reasonable expectation of success.
The Examiner does not find Applicant’s argument to be persuasive. As discussed above, Mangeot discloses a microvesicle comprising a viral membrane fusion protein. Mangeot does not recite a specific viral membrane fusion protein in their claim 1 or disclose a specific viral membrane fusion protein in their summary of invention (¶ [0011]-[0013]). Therefore, one of ordinary skill in the art would have had a reasonable expectation of success in incorporating Nipah virus F or G proteins into the microvesicle of Mangeot since the viral membrane fusion protein of Mangeot is not limited and Nipah virus F or G proteins are known and effective viral membrane fusion proteins. Furthermore, Mangeot discloses in paragraph [0069] wherein the microvesicle needs to contact the target cell to deliver a protein of interest into a target cell. Khvorova discloses in claim 37 wherein a targeting peptide directs exosomes to neuronal cells. Therefore, it would have been obvious to one of ordinary skill in the art to have incorporated a targeting peptide to the microvesicle of Mangeot motivated by the desire to have the microvesicle target a desired cell type. One of ordinary skill in the art would have had a reasonable expectation of success since Khvorova discloses wherein the targeting peptide can be localized to the surface of the exosome by expressing it as a fusion protein with an exosomal transmembrane protein. Although the prior arts do not disclose the exact combination of a paramyxovirus fusogen comprising a targeting moiety, obviousness does not require absolute predictability. See MPEP 2143.02(II). As such, Applicant’s argument is unpersuasive.
Conclusion
Claims 1, 21, 22, 24, 36, 45-47, 54, 61-63 and 65-69 are rejected.
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/TRACY LIU/Primary Examiner, Art Unit 1614
