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 15-18 and 22-37, of record 11/3/2025, are pending and subject to prosecution. Claim 15 is amended. Claim 37 is newly added.
The amendment to the claims filed on 11/3/2025, does not comply with the requirements of 37 CFR 1.121(c) because claim 15 is not properly marked up to reflect the changes to the claim text. Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states (emphasis added):
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
(1) Claim listing. All of the claims presented in a claim listing shall be presented in ascending numerical order. Consecutive claims having the same status of “canceled” or “not entered” may be aggregated into one statement (e.g., Claims 1–5 (canceled)). The claim listing shall commence on a separate sheet of the amendment document and the sheet(s) that contain the text of any part of the claims shall not contain any other part of the amendment.
(2) When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of “currently amended,” and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of “currently amended,” or “withdrawn” if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as “withdrawn—currently amended.”
(3) When claim text in clean version is required. The text of all pending claims not being currently amended shall be presented in the claim listing in clean version, i.e., without any markings in the presentation of text. The presentation of a clean version of any claim having the status of “original,” “withdrawn” or “previously presented” will constitute an assertion that it has not been changed relative to the immediate prior version, except to omit markings that may have been present in the immediate prior version of the claims of the status of “withdrawn” or “previously presented.” Any claim added by amendment must be indicated with the status of “new” and presented in clean version, i.e., without any underlining.
(4) When claim text shall not be presented; canceling a claim.
(i) No claim text shall be presented for any claim in the claim listing with the status of “canceled” or “not entered.”
(ii) Cancellation of a claim shall be effected by an instruction to cancel a particular claim number. Identifying the status of a claim in the claim listing as “canceled” will constitute an instruction to cancel the claim.
(5) Reinstatement of previously canceled claim. A claim which was previously canceled may be reinstated only by adding the claim as a “new” claim with a new claim number.
As noted above, the amendment under consideration herein fails to comply with 37 CFR 1.121 because claim 15 lacks all of the previously presented text and the new text with the required mark-ups. The amendment could be therefore considered non-compliant. In the interest of compact prosecution, the amendment at issue will not be considered non-compliant, however, any future responses failing to comply with 37 CFR 1.121 will be held non-compliant and will not be considered.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 15-17 and 22-36 under 35 U.S.C. 103 over Schüler et al. (US 20140073007 A1) as evidenced by Szymczak et al. (Expert Opinion on Biological Therapy, 2005), in view of Kim et al. (Journal of Virology, 1998):
RE: Rejection of claims 15-18 and 22-36 under 35 U.S.C. 103 over Schüler et al. (US 20140073007 A1), as evidenced by Szymczak et al. (Expert Opinion on Biological Therapy, 2005), in view of Kim et al. (Journal of Virology, 1998), further in view of Merino et al. (Cancer Research, 2006):
The applicant asserts that neither Schüler et al. nor Kim et al. teach or suggest the claimed system comprising a multiplex of lentiviral vectors for modular protein expression in eukaryotic cells (Applicant Remarks, page 7-9). The applicant asserts that one of ordinary skill in the art would not have “converted a standard plasmid vector… into a functional lentiviral vector that expresses the same components” (Applicant Remarks, page 8). The applicant asserts that the claimed system confers advantages in that more cDNAs can be incorporated because alternate promoters are dispensable and in that lentivirus can be generated without the standard multi-step, multi-plasmid process (Applicant Remarks, page 9-10).
These arguments are not found persuasive. The teachings of Schüler et al. are not limited to a single plasmid encoding multiple cDNAs, contrary to the applicant’s assertions. Schüler et al. disclose a two-vector system, each with a polylinker, a visible marker gene, a 2A site and a selectable marker gene (¶0118). Schüler et al. disclose the vectors can be viral, including lentiviral (¶0061 and 0074). Kim et al. provide specific motivation for the use of an HIV-1-based viral vector by teaching that they are attractive for gene transfer into nondividing cells (See page 811, col. 1, ¶1).
The examiner does agree that a person of ordinary skill in the art at the time of the invention (i.e., someone who is able to design, construct, and use expression vectors) would have understood that each system requires particular consideration. However, the transfer of a given expression cassette from a plasmid vector to a viral vector was not onerous in 2018, contrary to the applicant’s arguments. Rather than requiring the “re-engineering” of a plasmid vector, commonly-used cloning systems enabled the relatively simple transfer of an expression cassette to a shuttle plasmid for generating a viral vector comprising the expression cassette. For example, Gruh et al. (2005) teach the LentiShuttle platform for the fast and convenient cloning of expression cassettes from plasmids into lentiviral vectors (See page 530, col. 3, ¶1). Because Schüler et al. teach nonviral and viral vectors as being equally preferential (See ¶0061), one of ordinary skill would readily recognize and successfully achieve transgene expression strategies that were originally plasmid-based using viral vectors. Thus, modification of a two-plasmid system to a two-viral vector system would have been successful at the time of the invention. Kim et al. provide specific motivation for the use of an HIV-1-based lentiviral vector by teaching that they are attractive for gene transfer into nondividing cells (See page 811, col. 1, ¶1).
Regarding the asserted advantages of the claimed invention, it is known in the art that lentiviral vectors comprising an intact LTR do not require an additional promoter for transgene expression; additional promoters can be used is stronger or constitutive expression is desired (See Kim et al., page 812, col. 2, ¶1-2). Therefore, this “space-conserving” aspect is obvious. Additionally, in arguing that the instant claims enable the production of a lentiviral vector without the need for accessory plasmids, the applicant is referring to a specific system and method that are not claimed.
The rejections are maintained in modified form to address amended limitations.
Maintained Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 15-17 and 22-37 are rejected under 35 U.S.C. 103 as being unpatentable over Schüler et al. (US 20140073007 A1), of record, as evidenced by Szymczak et al. (Expert Opinion on Biological Therapy, 2005), of record, in view of Kim et al. (Journal of Virology, 1998).
Regarding claims 15-16, 23-24, and 37: Schüler et al. teach an expression vector that can be retroviral (which reads on “retroviral backbone”) or lentiviral (which reads on “retroviral backbone” and “derived from a lentivirus”) for gene expression in eukaryotic cells such as HEK (which reads on “human cells”) and HeLa (which reads on “human cells” and “cell lines established from cancers”) (See ¶0061 and 0074). The vector comprises a promoter (which reads on “regulatory elements”), a gene of interest, a reporter gene (which reads on “visible marker gene”), a selection marker gene (which reads on “selectable marker gene”), and a 2A sequence (which reads on “nucleic acid molecule encoding a proteolytic cleavage site”) (See ¶0015). The vector can comprise additional enhancer elements (which read on “regulatory elements”) (See ¶0061). The transgenes are integrated into multiple cloning sites (which reads on “polylinker for the insertion of a nucleic acid molecule”) (See ¶0124). The transgenes are under transcriptional control of the same promoter in a single expression cassette (which reads on “regulatory elements are operably linked to said polylinker, said visible marker gene and said selectable marker gene”) (See ¶0016). The reporter gene can be operably linked to the selection marker gene via a 2A sequence (which reads on “the nucleic acid molecule encoding a proteolytic cleavage site links the visible marker gene to the selectable marker gene”) (See ¶0015). An IRES site is located 3’ to the gene of interest and can be followed immediately by the reporter gene (which reads on “a standard internal ribosomal entry site… nucleic acid sequence located 3’ to the polylinker site and 5’ to the visible marker gene”) (See ¶0015). In an embodiment, Schüler et al. teach a two-vector strategy for protein expression wherein one vector comprises RFP (which reads on “visible marker gene”) and a zeocin resistance gene (which reads on “selectable marker gene”) and the other vector comprises GFP (which reads on “visible marker gene”) and P5CS (which reads on “selectable marker gene”) (See ¶0118). The vectors read on “a plurality of… expression vectors”, “comprising a separately identifiable visible marker gene or a different selectable marker gene”, and “comprises a unique selectable marker gene as well as a separately identifiable visible marker gene”. Schüler et al. do not expressly teach the vector as comprising an HIV-1 backbone.
Kim et al. teach an HIV-1-derived expression vector (pH5Z) that comprises the intrinsic 5’ and 3’ LTRs (U3, R, and U5) (which reads on “an HIV-1 lentiviral backbone comprising regulatory elements wherein the regulatory elements comprise a long terminal repeat”) (See fig. 1). Lentiviruses such as HIV-1 can be used for gene therapy in nondividing cells (See page 811, col. 1, ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the vector system of Schüler et al. to comprise an HIV-1 packaging backbone, such as is taught by Kim et al. One would be motivated to make this modification because Kim et al. teach that lentiviruses such as HIV-1 are attractive for gene transfer into nondividing cells (See page 811, col. 1, ¶1). There would be a reasonable expectation of success in making this modification because Schüler et al. teach that the expression vector can be lentiviral (See ¶0061).
Regarding claims 17 and 22: Following the discussion of claims 15-16, 23-24, and 37, Schüler et al. teach that the expression cassettes can be used in a multi-vector strategy with more than two vectors (which reads on “3-10… expression vectors”) (See ¶0090 and 0103). Schüler et al. do not expressly teach the more than two expression vectors as viral, however, Schüler et al. teach that viral vectors, such as retroviral or lentiviral vectors, can be used for introducing the transgenes into cells (See ¶0061 and 0072). The additional vectors could therefore also be retroviral or lentiviral vectors. Combining prior art elements according to known methods to yield predictable results is considered to be prima facie obvious. See 2143(I)(A).
Regarding claims 25 and 32-36: Following the discussion of claims 15-17, 21-24, and 37, Schüler et al. teach that the gene of interest can be a fusion or tagged gene (which reads on “amino terminal epitope tag operably linked to the polylinker”) (See ¶0066). Schüler et al. also teach the expression of a membrane-bound GFP from a pDisplay vector, wherein the GFP sequence is inserted after a hemagglutinin A tag (which reads on “a nucleic acid molecule encoding an amino terminal epitope tag operably linked to the… selectable marker gene” and “protein fusion tag operably linked to the polylinker or the selectable or visible marker genes”) (See ¶0128).
Regarding claims 26 and 29: Following the discussion of claims 15-17, 21-24, and 37, Schüler et al. teach the specific use of RFP and GFP as markers or reporters for separate vectors (See ¶0118). However, Schüler et al. also teach that the reporter gene can encode a fluorescent protein such as firefly luciferase, GFP, EGFP, and proteins having enhanced brightness such as eXFP or TagXFP, where X can be any green, red, yellow, blue, or protein (which reads on “EBFPII”, “mTagBFPII”, and “EYFP”) (See ¶0067-0068). Substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the result of the substitution yields more than predictable results. See MPEP 2143(I)(B).
Regarding claims 27 and 30: Following the discussion of claims 15-17, 21-24, and 37, Schüler et al. teach the specific use of a Zeocin (which reads on “phleomycin D1”) resistance gene and P5CS as selectable markers (See ¶0118). However, Schüler et al. also teach that the selection marker gene can encode a resistance marker for additional antibiotic drugs including hygromycin B, puromycin, and G418 (which reads on “G418 sulfate”) (See ¶0086). Substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the result of the substitution yields more than predictable results. See MPEP 2143(I)(B).
Regarding claims 28 and 31: Following the discussion of claims 15-17, 21-24, and 37, Schüler et al. teach that the DNA sequence coding for the 2A peptide from the Thosea assigna virus as reported by Szymczak et al. was used (See ¶0124). Szymczak et al. teach the 2A sequence as EGRGSLLTCGDVEENPGP, which is identical to instant SEQ ID NO 25 (See table 2 and alignment below).
PNG
media_image1.png
114
574
media_image1.png
Greyscale
Claims 15-18 and 22-37 are rejected under 35 U.S.C. 103 as being unpatentable over Schüler et al. (US 20140073007 A1), of record, as evidenced by Szymczak et al. (Expert Opinion on Biological Therapy, 2005), of record, in view of Kim et al. (Journal of Virology, 1998), further in view of Merino et al. (Cancer Research, 2006).
The teachings of Schüler et al., Szymczak et al., and Kim et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 18: Following the discussion of claims 15-17 and 22-37, Schüler et al., as evidenced by Szymczak et al., modified by Kim et al., render obvious an HIV-1 derived system for multiplex protein expression but do not teach the expression vector as H163.
Merino et al. teach the expression of exogenous transcription factor ELF3 in cells using an H163 lentiviral vector (See fig. 5E).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to further modify the vector system rendered obvious by Schüler et al., as evidenced by Szymczak et al., modified by Kim et al., to substitute the H163 vector taught by Merino et al. Substitution of a known element for another known element is considered to be prima facie obvious, absent a showing that the result of the substitution yields more than predictable results. See MPEP 2143(I)(B).
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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, Christopher M Babic, can be reached at 571-272-8507. 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.
/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633