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 .
Restriction/Election
Applicant’s election without traverse of Group I, drawn to a pseudotyped virus or virus-like particle comprising a fusion protein comprising a VSVG ECD or a fragment or analog capable of fusing with a cellular membrane linked to a polypeptide comprising an antigen binding domain specific for CD3 and corresponding to claims 1, 3-4, 11-12, 17-18, 20, 30, 32-33, 40-41, 45-46, and 49-50 in the reply filed 01/12/2026 is acknowledged.
Claim Status
Claims 1, 3-4, 11-12, 17-18, 20, 30, 32-33, 40-41, 45-46, 49-50, 52-53, and 57 are pending. Claims 52-53, 57 are withdrawn for being directed to a non-elected invention.
Claims 1, 3-4, 11-12, 17-18, 20, 30, 32-33, 40-41, 45-46, and 49-50 are under examination.
Claim Objections
Claim 12 and 41 are objected to for missing sequence identifiers. The claims disclose the sequences GGGGS and GCGCS without properly identifying the corresponding SEQ ID NO.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-4, 12, 17, 20, 30, 32-33, 41, 45, and 49-50 are 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
The teachings of the specification and the claimed invention
The claims are directed to a pseudotyped virus or virus-like particle comprising a fusion protein comprising a VSVG ECD or a fragment or an analog thereof “capable of fusing with a cellular membrane”. The independent claims 1 and 30 do not define what structure or sequences from the native VSVG must be maintained in the fragments or analogs in order for them to maintain the capability of fusing with a cellular membrane.
The pseudotyped virus of claim 11 and the fusion protein of claim 40 define the VSVG analogs and fragment as SEQ ID NO: 1, 18, 33, 35, 37, 59, and 60. The specification “Sequence Table” starting on Pg. 48 teaches the same sequences, thereby providing structure required for the VSVG to fuse with a cellular membrane.
The state of the relevant art
It is well established in the art that upon initial binding on the cell surface, VSV is internalized by receptor-mediated endocytosis and the virus is transported into endosomal compartments, where the virus fuses and releases its genome into the cytosol to initiate replication (Sun et al. Future Virol. 2010;5(1):85-96, Pg. 4, Full paragraph 2). Early studies identified key regions of the of the VSVG protein responsible for fusion to membranes, including amino acids 118–139 which is located in the trimer interface and is responsible for stabilization of the fusion domain the low pH form and residues 181-212 in the hinge region between domain III and fusion domain IV which is involved in repositioning the fusion domain to the top of the molecule during conformational changes of the G protein from pre- to post-fusion states (Pg. 7, Full paragraph 1).
Nikolic (Nat Commun. 2018 Mar 12;9(1):1029) teaches the LDL receptor is the major entry port of VSV and lentiviruses pseudotyped by VSVG and teaches the basis of binding of VSVG to the LDL receptor (Pg. 9, Discussion, Paragraph 1). The CR domain recognition by VSVG involves basic residues H8 and K47, pointing toward the calcium-coordinating acidic residues, and R354 which interacts with C=O groups of the main chain (Pg. 9, Discussion, Paragraph 2).
Thus, the VSVG has known residues and polypeptide stretches that are required for stability, conformation and binding to the LDL receptor. These residues are necessary for imparting the ability of the pseudotyped virus to fuse with the cellular membrane of a target cell.
Accordingly, one skilled in the art would be unable to predict or envision a genus of VSVG fragments and analogs that maintain membrane fusion capability as recited in the instant claims.
Claim analysis
Based on the teachings of the specification and the state of the relevant art, the claims have the following written description issues:
Claims 1 and 30 disclose a fusion protein comprising a VSVG ECD or a fragment or an analog thereof capable of fusing with a cellular membrane. However, the terms “fragment” and “analog” of VSVG ECD is defined by functional language only, that is, being capable of fusing with a cellular membrane. The term “fragment” reads on as little as two amino acids of the original structure. The claims constitute an indefinite, unbounded functional limitation that covers all ways of performing a function and the inventor has not provided sufficient disclosure to show possession of the invention.
In general, absent at least the conserved structure required for VSVG fragment or analog to be capable of fusing with a cellular membrane, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what polypeptide with a particular set of functional properties would look like structurally. One of skill in the art would neither expect nor predict the appropriate functioning of the VSVG ECG fragments and analogs as broadly as is claimed. There is no disclosure of a correlation between structure and function that would allow those of skill in the art to recognize other members of the claimed genus from the disclosure.
Claims 3-4, 12, 17, 20, 32-33, 41, 45, and 49-50 are rejected for being dependent on claims 1 and 30 and do not provide limitations that overcome the written description rejection.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3-4, 11-12, 17, 20, 30, 32-33, 40-41, 45, and 49-50 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by “Frost 2021" (US 2021/0107949 A1, published 04/15/2021, effectively filed at least 09/17/2018).
The disclosure of Frost 2021 is directed to methods of modifying lymphocytes by contacting the cells with recombinant retroviral particles (see Abstract). Frost 2021 discloses a replication incompetent retroviral particle comprising one or more pseudotyping elements on the surface of the retroviral particle and a membrane bound T cell activation element that binds CD3 (Pg. 305, claim 1).
Regarding claim 1, 4 and 12, pertaining to a pseudotyped virus or virus-like particle comprising a fusion protein comprising a VSVG ECD linked to a polypeptide comprising an antigen binding domain specific to CD3 (claim 1) and wherein said polypeptide is an scFv of an antibody that specifically binds CD3 (claim 4a.), and wherein said polypeptide is linked to an N-terminus of said VSVG ECD (claim 12a.), Frost discloses the pseudotyping plasmid encoding “UCHT1-(G4S)3-VSVG” set forth in SEQ ID NO:455, wherein the anti-CD3 scFv from UCTH1 fused to the amino terminus of the VSVG ([0533], Lines 11-14, SEQ ID NO:455 shown on Pg. 296).
Regarding claim 3, wherein the antigen binding domain specific to CD3 is OKT3, Frost teaches the fusion polypeptide can comprise OKT3-scFv fused to the envelope protein ([0361], Lines 12-15).
Regarding claim 11, wherein said VSVG ECD comprises or consists of an amino acid sequence selected from the listed sequences, Frost discloses the VSVG sequence SEQ ID NO:336 identical to instant SEQ ID NO:1 which corresponds to VSVG with the signal sequence. Additionally, the fusion “UCHT1-(G4S)3-VSVG” set forth in SEQ ID NO:455 comprises the VSVG without a signal sequence identical to instant SEQ ID NO:60.
Instant SEQ ID NO:1 and Frost 2021 SEQ ID NO: 336:
PNG
media_image1.png
760
642
media_image1.png
Greyscale
Regarding claim 17, wherein said VSVG and the polypeptide are linked via a linker and the linker comprises or consists of an amino acid sequence selected from the listed sequences, the UCHT1-(G4S)3-VSVG linker (G4S)3 is identical to instant SEQ ID NO:28.
Regarding claim 20, wherein the virus is selected from the disclosed list (claim 20a.), teaches the the pseudotyped viruses were lentiviral particles ([0532], Lines 1-5).
Regarding the fusion protein of claims 30, 32-33, 40-41, and 45, the fusion protein is anticipated by the pseudotyped virus described above, which expresses the fusion protein comprising a VSVG extracellular domain linked to a polypeptide comprising an antigen binding domain specific to CD3.
Regarding claim 49, pertaining to a nucleic acid molecule encoding a fusion protein of claim 30, Frost teaches plasmids encoding the VSVG pseudotyping element ([0525], Lines 1-3).
Regarding claim 50, pertaining to a pharmaceutical composition comprising a pseudotyped virus and a pharmaceutically acceptable carrier, excipient or adjuvant, Frost discloses a pharmaceutical composition comprising a replication incompetent retroviral particle as an active ingredient ([0416], Lines 1-4).
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.
Claims 1, 3-4, 11-12, 17-18, 20, 30, 32-33, 40-41, 45-46, and 49-50 are rejected under 35 U.S.C. 103 as being unpatentable over “Frost 2021" (US 2021/0107949 A1, published 04/15/2021, effectively filed at least 09/17/2018) as applied to claims 1, 3-4, 11-12, 17, 20, 30, 32-33, 40-41, 45, and 49-50 above, and further in view of "Frost 2017" (US 2017/0356010 A1, published 12/14/2017, effectively filed at least 04/19/2017, cited in IDS 09/26/2023) and Tan (US 2015/0232557 A1, published 08/20/2015, effectively filed 04/15/2013).
Frost 2021 teaches a replication incompetent retroviral particle comprising one or more pseudotyping elements on the surface of the retroviral particle and a membrane bound T cell activation element that binds CD3 (Pg. 305, claim 1). Frost teaches a fusion polypeptide “UCHT1-(G4S)3-VSVG” comprising anti-CD3 scFv UCHT1 linked with a (G4S)3 linker to a VSVG ECD. Frost 2021 also teaches OKT3 linked to the VSVG without providing the OKT3 sequence. Frost 2021 does not teach the fusion protein comprises or consists of an amino acid sequence selected from SEQ ID NO: 11, 12, 39-51 and 64-78.
This deficiency is taught by Frost 2017 and Tan.
Frost 2017:
The disclosure of Frost is directed to methods for genetically modifying lymphocytes using recombinant retroviral particles that express on their membrane a pseudotyping element that facilitates binding and fusing with the cell membrane and an activation element that binds CD3 ([0011], Lines 9-22, and Fig.1). Frost contemplates the use of anti-CD3 OKT3 scFv anchored to the membrane of the virus.
Frost 2017 teaches the virus comprises an anti-CD3 scFv from OKT3 and a GPI anchor attachment sequence ([0852], Lines 28-33). Frost 2017 teaches “OKT3scFvFc-GPI” encoding a peptide that includes a human IgK signal peptide fused to OKT3 scFv and human IgG1Fc fused to a GPI anchor attachment sequence ([0852], Lines 40-45). The sequence of OKT3 scFv with (GGGS)3 linker between the VH and VL are shown in Frost 2017 SEQ ID NO:285 (Pg. 216-217).
Tan:
The disclosure of Tan is directed to polypeptides that binds CD3 (Abstract).
Tan teaches secretory signal sequences are commonly positioned 5’ to the DNA sequence encoding the polypeptide of interest and in particular variations, a secretory signal used in the invention has the amino acid sequence MEAPAQLLFLLLLWLPDTTG (Tan, SEQ ID NO:79).
Regarding claims 18 and 46, wherein the fusion protein comprises or consists of an amino acid sequence selected from SEQ ID NO: 11, 12, 39-51 and 64-78., the combined teachings of Frost 2021, Frost 2017, and Sun teach each element of instant SEQ ID NO: 11.
The alignment of SEQ ID NO:11 (OKT3(VL-VH)-VSVG) and the reference components is shown below:
PNG
media_image2.png
910
1445
media_image2.png
Greyscale
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the fusion protein of the pseudotyped virus of Frost 2021 with the teachings of Frost 2017 and Tan to arrive at the instantly claimed fusion protein set forth in SEQ ID NO:11. One would have been motivated to do so because Frost 2021 teaches the VSVG polypeptide fusion with anti-CD3 scFv and contemplates the use of OKT3 in the fusion. However, Frost 2021 does not provide the sequence of the OKT3 scFv or the secretory signal sequence. Frost 2021 teaches the OKT3 scFv and Tan provides a signal sequence that directs the secretion of the recombinant protein. This modification constitutes combining prior art elements according to known methods to yield predictable results. There would be an expectation of success in modifying Frost 2021 with the teachings of Tan because Frost 2017 provides evidence of a successful VSVG/anti-CD3 scfv fusion, Frost 2017 provides the sequence for the widely-used anti-CD3 clone OKT3 and Tan provides the signal sequence required for secretion of this recombinant polypeptide. The technology for generating this recombinant peptide fusion was widely used at the time of filing as evidenced by the methods of Frost 2021, Frost 2017 and Tan.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROL ANN CHASE whose telephone number is (571)270-0934. The examiner can normally be reached Monday-Friday 9:00am-6:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646