DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communication filed 5-8-26.
Claims 1, 3-6, 12-17, 33-35, 38, 39, 48-51, 62, 63, 99, 100, and 104 are pending in the instant application.
Election/Restrictions
Claims 6, 12, 13-15, 17, 33, 34, 39, 99, 100 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5-8-26.
Applicant’s election without traverse of Group I, an antigen as the target protein, a picornavirus leader (L) protein as the enhancer protein comprising SEO ID NO: 2 as the second polynucleotide encoding the enhancer protein, claims 1, 3, 4, 5, 15, 16, 35, 38, 48-51, 62, 63, 66 and 104, SEQ ID No. 2, in the reply filed on 5-8-26 is acknowledged.
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, 5, 15, 16, 35, 38, 48-51, 62, 63, 66 and 104 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for the expression in mice of the pGBA-NanoLuc_STD plasmid and the enhancer protein GBA-NanoLuc_EG plasmid formulated into lipid nanoparticles (LNPs), and enabling for the expression of adalimumab in mice serum following intramuscular and subcutaneous administration of AAV_Adalimumab_STD or AAV_Adalimumab_EG, does not reasonably enable methods for predictably increasing the activity of the target protein in the subject, or predictably lowering the expression level of the target protein in the subject, or predictably increasing the uniformity of expression of the target protein at the injection site of the subject, or predictably increasing the duration of active target protein in a cell of the subject, or predictably increasing the expression level of the target protein in the subject comprising the administration of a first polynucleotide encoding any target protein and a second polynucleotide encoding any enhancer protein that is an inhibitor of nucleocytoplasmic transport (NCT).
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The following factors have been considered in determining that the specification does not enable the skilled artisan to make and/or use the invention over the broad scope claimed.
The breadth of the claims:
The claims are drawn to methods of expressing any target protein in a subject comprising administering to the subject a system comprising: a) a first polynucleotide encoding the target protein; and b) a second polynucleotide encoding an enhancer protein comprising an inhibitor of nucleocytoplasmic transport (NCT), which NCT inhibitor is optionally a viral protein optionally comprising a picornavirus leader (L) protein which optionally is the L protein of Encephalomyocarditis virus (EMCV) or a functional variant thereof, which L protein shares at least 90% identity to SEQ ID NO: 2, which target protein is optionally an antigen, which enhancer protein increases the activity of the target protein in the subject, or lowers the expression level of the target protein in the subject, or increases the uniformity of expression of the target protein at the injection site of the subject, or which enhancer protein increases the duration of active target protein in a cell of the subject, or increases the expression level of the target protein in the subject.
Teachings in the specification:
The specification teaches the optimization of AAV vectors encoding Adalimumab in the presence and absence of enhancer protein L, and their ability to enhance or prolong expression of reporter genes. The construction, optimization and expression of various vectors were tested in HEK293T cells in vitro.
The specification also teaches the following in vivo results:
FIGS. 26A and 26B show the concentration of adalimumab in mouse sera after treating mice with recombinant AAV vectors encoding adalimumab alone, AAV_Adalimumab_STD, and with the enhancer protein L,AAV_Adalimumab_EG.
FIG. 26A shows the results of AAV vectors AAV_Adalimumab_STD or AAV_Adalimumab_EG administered via intramuscular injections. FIG. 26B shows the results of AAV vectors administered via subcutaneous injections.
FIGS. 32A-32C show bioluminescence imaging results of Balb/c mice treated with pGBA-NanoLuc_STD plasmid and the enhancer protein GBA-NanoLuc_EG plasmid, formulated into lipid nanoparticles (LNPs).
The examples provided in the instant specification, of the expression in mice of
the pGBA-NanoLuc_STD plasmid and the enhancer protein GBA-NanoLuc_EG plasmid formulated into lipid nanoparticles (LNPs), and the expression of adalimumab in mice serum following intramuscular and subcutaneous administration of AAV_Adalimumab_STD or AAV_Adalimumab_EG, are not representative or correlative of the ability to express any target protein in a subject comprising administering to the subject a system comprising: a first polynucleotide encoding the target protein; and a second polynucleotide encoding any enhancer protein comprising an inhibitor of nucleocytoplasmic transport (NCT), which NCT inhibitor is optionally a viral protein optionally comprising a picornavirus leader (L) protein which optionally is the L protein of Encephalomyocarditis virus (EMCV) or a functional variant thereof, which target protein is optionally any antigen, which enhancer protein increases the expression level and/or activity of the target protein in the subject, or lowers the expression level of the target protein in the subject, or increases the uniformity of expression of the target protein at the injection site of the subject, or which enhancer protein increases the duration of active target protein in a cell of the subject, as instantly claimed.
In light of the teachings in the specification, one skilled in the art would not accept on its face the examples provided in the instant disclosure as being correlative or representative of the ability to increase the expression level and/or activity of a target gene, increase uniformity of expression of the target protein or increase the duration of the active target protein in any subject. Since the specification fails to provide the requisite guidance for these expression changes in a subject, and since determination of the factors required for accomplishing these phenotypes in any subject is highly unpredictable, it would require undue experimentation to practice the invention over the broad scope claimed.
For these reasons, the instant rejection for lacking enablement over the full scope claimed is proper.
Claim Rejections - 35 USC § 102
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 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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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.
Claim(s) 1, 3-5, 16, 35 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Porter et al (US 2007/0243169).
Porter et al (US 2007/0243169) teach methods of expressing a target protein in a subject comprising administering to the subject a polynucleotide encoding the target protein and a polynucleotide encoding an enhancer protein comprising SEQ ID No. 2. Porter teaches that the addition of EMCV L protein (of SEQ ID No. 2) disrupts nucleocytoplasmic trafficking and rapidly inhibits accumulation of cargo in HELA nuclei in a Ran dependent manner. Porter teaches the arrest of cargo at the nuclear periphery of NPCs in L treated samples and the restoration of import activity upon addition of wildtype Ran (see esp. pages 1-5, ¶ 0054, Example 2 on page 9, ¶¶ 0068, 0084, claims 13-17; see also the alignment set forth below between SEQ ID No. 1 of Porter and instantly claimed SEQ ID No. 2).
Align w/ SEQ ID No. 2
RESULT 1
US-11-654-848-1
(NOTE: this sequence has 12 duplicates in the database searched.
See complete list at the end of this report)
Sequence 1, US/11654848
Publication No. US20070243169A1
GENERAL INFORMATION
APPLICANT: PORTER, FREDERICK WILLIAM
TITLE OF INVENTION: PROTEIN INHIBITOR OF RAN ACTIVITY AND METHODS OF USE THEREOF
FILE REFERENCE: 960296.00358
CURRENT APPLICATION NUMBER: US/11/654,848
CURRENT FILING DATE: 2007-05-25
PRIOR APPLICATION NUMBER: 11/654,848
PRIOR FILING DATE: 2007-01-18
NUMBER OF SEQ ID NOS: 17
SEQ ID NO 1
LENGTH: 67
TYPE: PRT
ORGANISM: Encephalomyocarditis virus
Query Match 100.0%; Score 367; Length 67;
Best Local Similarity 100.0%;
Matches 67; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MATTMEQETCAHSLTFEECPKCSALQYRNGFYLLKYDEEWYPEELLTDGEDDVFDPELDM 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MATTMEQETCAHSLTFEECPKCSALQYRNGFYLLKYDEEWYPEELLTDGEDDVFDPELDM 60
Qy 61 EVVFELQ 67
|||||||
Db 61 EVVFELQ 67
RESULT 1
AOD41393
(NOTE: this sequence has 13 duplicates in the database searched.
See complete list at the end of this report)
ID AOD41393 standard; protein; 67 AA.
XX
AC AOD41393;
XX
DT 24-JAN-2008 (first entry)
XX
DE Encephalomyocarditis virus (EMCV) leader protein, SEQ ID 1.
XX
KW protein deactivation; signal peptide; protein purification;
KW recombinant protein.
XX
OS Encephalomyocarditis virus.
XX
FH Key Location/Qualifiers
FT Region 10..23
FT /label= Zinc_finger_motif
FT Domain 37..61
FT /label= Acidic_domain
XX
CC PN US2007243169-A1.
XX
CC PD 18-OCT-2007.
XX
CC PF 18-JAN-2007; 2007US-00654848.
XX
PR 18-JAN-2006; 2006US-0743139P.
PR 20-JAN-2006; 2006US-0760248P.
XX
CC PA (PORT/) PORTER F W.
CC PA (PALM/) PALMENBERG A C.
CC PA (WIES/) WIESE C.
CC PA (BOCH/) BOCHKOV Y A.
XX
CC PI Porter FW, Palmenberg AC, Wiese C, Bochkov YA;
XX
DR WPI; 2007-892274/82.
XX
CC PT Inhibiting Ran protein activity in a eukaryotic cell or cell-free extract
CC PT by exposing a portion of purified encephalomyocarditis virus or Theiler's
CC PT murine encephalomyelitis virus leader protein to a cell to inhibit Ran
CC PT activity.
XX
CC PS Claim 3; SEQ ID NO 1; 32pp; English.
XX
CC The present invention relates to a novel method of inhibiting Ran protein
CC activity in at least one eukaryotic cell or cell-free extract. The method
CC comprises: (a) exposing an amino acid sequence comprising at least a
CC portion of purified encephalomyocarditis virus (EMCV) or Theiler's murine
CC encephalomyelitis virus (TMEV) leader protein to at least one cell in an
CC amount to inhibit Ran activity in the cell; and (b) evaluating Ran
CC protein activity in the cell or cell-free extract. Evaluating Ran protein
CC activity in a cell or cell-free extract comprises measuring the change in
CC localization of cellular transport-specific proteins or RNA and the
CC ability of a cell-free extract to undergo Ran-dependent tubulin
CC condensation into visible cellular spindle assemblies. Ran functions as a
CC gatekeeper for nuclear pores, regulating the interactions between nuclear
CC transporter molecules and transport of proteins or nucleic acids into
CC and/or out of a cell's nucleus. Ran hydrolyzes the GTP to guanosine
CC diphosphate (GDP) and the resulting gradient of Ran-GTP and Ran-GDP
CC across the nuclear envelope drives nuclear transport. By inhibiting Ran-
CC GTP hydrolysis or inhibiting Ran exchange of GTP for GDP, nuclear
CC transport may be stopped or manipulated for therapeutic effect. EMCV
CC leader protein binds to the Ran protein, thus inhibiting Ran activity in
CC eukaryotic cells. Also described is, a composition comprising an amino
CC acid segment and a pharmaceutical carrier, where the amino acid segment
CC contains at least a portion of EMCV or TMCV L protein. The present
CC sequence is EMCV leader protein.
XX
SQ Sequence 67 AA;
Query Match 100.0%; Score 367; Length 67;
Best Local Similarity 100.0%;
Matches 67; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MATTMEQETCAHSLTFEECPKCSALQYRNGFYLLKYDEEWYPEELLTDGEDDVFDPELDM 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MATTMEQETCAHSLTFEECPKCSALQYRNGFYLLKYDEEWYPEELLTDGEDDVFDPELDM 60
Qy 61 EVVFELQ 67
|||||||
Db 61 EVVFELQ 67
Conclusion
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Jane Zara
6-10-26
/JANE J ZARA/Primary Examiner, Art Unit 1637
Prosecution Insights