DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 1-9 are pending in the present application, and they are subjected to the following species restriction.
Species Election/Restriction
A. This application contains claims directed to the following patentably distinct species of a transgene.
(i) transgene is a target antigen for immunization; and (ii) transgene is a therapeutic antibody.
The species are independent or distinct because each of the above species is structurally distinct one from the other, and having different properties one from the other.
Applicant is required under 35 U.S.C. 121 to elect a single disclosed species, or a single grouping of patentably indistinct species, for prosecution on the merits to which the claims shall be restricted if no generic claim is finally held to be allowable. Currently, at least claim 1 is generic.
B. This application contains claims directed to the following patentably distinct species of a delivery vehicle for a eukaryotic replicative pUC-free minicircle expression vector.
(i) a liposome; and (ii) a nanoparticle.
The species are independent or distinct because each of the above species is structurally distinct one from the other, and having different properties one from the other.
Applicant is required under 35 U.S.C. 121 to elect a single disclosed species, or a single grouping of patentably indistinct species, for prosecution on the merits to which the claims shall be restricted if no generic claim is finally held to be allowable. Currently, at least claim 1 is generic.
There is a serious search and/or examination burden for the patentably distinct species as set forth above because at least the following reason(s) apply:
Each of the recited species is different one from the others because each is structurally and functionally different one from the others, as well as having different properties one from the others. The species require a different field of search (e.g., searching different CPC classes or electronic resources, or employing different search queries); and/or the prior art applicable to one species would not likely be applicable to another species; and/or the species are likely to raise different non-prior art issues under 35 U.S.C. 101 and/or 35 U.S.C. 112, first paragraph.
Applicant is advised that the reply to this requirement to be complete must include (i) an election of a species to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected species or grouping of patentably indistinct species, including any claims subsequently added. An argument that a claim is allowable or that all claims are generic is considered nonresponsive unless accompanied by an election.
The election may be made with or without traverse. To preserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the election of species requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable on the elected species or grouping of patentably indistinct species.
Should applicant traverse on the ground that the species, or groupings of patentably indistinct species from which election is required, are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing them to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the species unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other species.
Upon the allowance of a generic claim, applicant will be entitled to consideration of claims to additional species which depend from or otherwise require all the limitations of an allowable generic claim as provided by 37 CFR 1.141.
During a telephone conversation with attorney Lane Womack’s associate on 02/17/2026 a provisional election was made without traverse to prosecute the following species: (i) the transgene is a target antigen for immunization; and (ii) the eukaryotic replicative pUC-free minicircle expression vector is introduced into the eukaryotic organism in a nanoparticle. Affirmation of this election must be made by applicant in replying to this Office action.
Claims 3, 5-6 and 7 were withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected species. It is noted that withdrawn claim 6 is dependent on the non-elected, and withdrawn claim 5.
Accordingly, claims 1-2, 4 and 8-9 are examined on the merits herein with the above elected species.
Claim Objections
Claim 1 is objected to because of the phrase “a eukaryotic region encoding the transgene”. This is because it is technically incorrect for a eukaryotic region in a eukaryotic replicative pUC-free minicircle expression vector (a DNA) to encode the transgene (a DNA), rather the eukaryotic region comprises the transgene. Claim 1 is also objected to because of the lack of a closing bracket for the term “ii)”. Please be consistent since the claim already recites “(i)”.
Claim 2 is objected to because of the phrase “the transgene is a target antigen for immunization”. This is because a transgene is usually comprised of nucleotides whereas a target antigen is composed of amino acids. The examiner suggests to modify the above phrase with - - the transgene encodes a target antigen for immunization - - to overcome this objection.
Claim Rejections - 35 USC § 112
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.
Claims 1-2, 4 and 8-9 are 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.
In independent claim 1, it is unclear what is encompassed by the limitation “a target eukaryotic cell”. This is because it is unclear which particular cell type and/or in which particular tissue in a eukaryotic organism is the intended target eukaryotic cell. Clarification is requested because the metes and bounds of the claim are not clearly determined. For the purpose of a compact prosecution, the examiner interprets the limitation to include any eukaryotic cell that permits transfection of a eukaryotic replicative pUC-free minicircle expression vector with a transgene and expresses the transgene in a eukaryotic organism.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2, 4 and 8-9 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Williams (US 2010/0303859) in view of Lu et al (Mol. Ther. 20:2111-2119, Epub May 8, 2012) and Hyde et al (US 8,871,503).
The instant claims encompass a method of expressing a transgene (e.g., a transgene encodes a target antigen for immunization, elected species) with a eukaryotic replicative pUC-free minicircle expression vector, the method comprising: introducing (e.g., via intramuscular or intradermal delivery) the eukaryotic replicative pUC-free minicircle expression vector into a eukaryotic organism comprising a target eukaryotic cell under conditions sufficient to permit transfection of the eukaryotic replicative pUC-free minicircle expression vector into the target cell and expression of the transgene, wherein eukaryotic replicative pUC-free minicircle expression vector comprises: (i) a eukaryotic region encoding the transgene having the transgene and having 5’ and 3’ ends, ii) a spacer region that links the 5’ and 3’ of the eukaryotic region, said spacer region comprising a R6K bacterial replication origin and a RNA-OUT selectable marker; the same method wherein the eukaryotic replicative pUC-free minicircle expression vector is introduced into the eukaryotic organism in a nanoparticle (elected species).
With respect to the elected species, Williams disclosed a family of improved eukaryotic expression plasmids useful for gene therapy, genetic immunization and/or interferon therapy in humans, other mammals, birds or fish, wherein the expression plasmids have reduced size, sequence content and antibiotic free selection (see at least the Abstract; Disclosure of the Invention; Brief Summary of the Invention; and paragraph 24). An exemplary immunostimulatory influenza H5 HA “bird flu” pDNAVACCultra plasmid (NTC8382-41H-HA) comprises a synthetic HA (vietnam1203) gene, an RNA-OUT selectable maker and an immunostimulatory RNA element (41H) cloned between the Eukaryotic terminator and the prokaryotic replication pUC origin (paragraphs 61, 95; and Figure 1). Williams also stated “In another preferred embodiment for therapy or vaccination, the RNA based selectable marker of the invention is incorporated into other DNA vaccine or therapeutic plasmid backbones, a non-limiting list includes VR1012, pVAX1, pVC0396, pCMVkm2, pITR, pCOR, pPJV7563, pWG4303 and derivatives” (last sentence of paragraph 96). It is noting that pCOR vector contains R6K gamma replication origin as evidenced at least by lines 13-14 at page 55 of the present application. An exemplary RNA-OUT selectable marker has the sequence of SEQ ID NO: 15 (139 bp) (paragraphs 184-185; and Fig. 21). Williams further disclosed the vector to be delivered to a cell in vivo, in vitro or ex vivo, utilizing one or more of the plurality of delivery methods known in the art that includes nanoparticles, microparticles, lipofection and others (paragraph 100). Williams also stated explicitly “For delivery to an organism, delivery may be by oral, buccal, nasal, inhalation, topical, vaginal, rectal, intravenous, intramuscular, intradermal, epidermal, systemic, or by other routes of administration known in the art” (last sentence in paragraph 100).
Williams did not teach specifically a method of expressing a transgene with a eukaryotic replicative pUC-free minicircle expression vector into a eukaryotic organism, wherein the eukaryotic replicative pUC-free minicircle expression vector comprises: (i) a eukaryotic region encoding the transgene and having 5’ and 3’ ends, (ii) a spacer region that links the 5’ and 3’ ends of the eukaryotic region, said spacer region comprising a R6K bacterial replication origin and a RNA-OUT selectable marker.
At the effective filing date of the present application (11/19/2012), Lu et al already taught that the length and not the sequence or the origin of the extragenic DNA flanking the expression cassette is responsible for plasmid-mediated transgene silencing, with shorter spacers ≤500 bp exhibited similar transgene expression patterns to conventional minicircle DNA vectors whereas DNA sequences of ≥1 kb in length resulted in transgene silencing (see at least the Abstract; section titled “Short plasmid BB sequences inserted as spacers are incapable of silencing transgene expression in vivo while longer plasmid BB sequences silence the transgene” and Figures 1-5). Lu et al stated “Previously, we have substituted various prokaryotic antibiotic resistance genes and/or various plasmid origins of replication, and eliminated non-essential plasmid BB sequences but transgene silencing still occurred regardless of the specific substitutions. In all cases, the plasmid BB was well over 1Kb" (bridging sentence between right col. on page 2113 to left col. on page 2114); and “[w]e constructed minicircles containing a 500 bp pUC-derived bacterial plasmid origin of replication in either the hFIX or hAAT expression cassette (Figures 3 and 4). As shown in Figures 3 and 4, 500 bp BB spacer failed to silence either the hAAT or hFIX transgene expression cassette in vivo. This result confirmed that generic plasmid origin sequence is not sufficient for transgene silencing in DNA plasmid vectors. On the other hand, when a fragment of a BB-a 1.5kb BB containing pUC origin and kanamycin resistance gene was placed in between the 5’ and 3’ ends of the hFIX expression cassette (MC.EF1α-hFIX-hGHpA-pUC-Kan (1.5kb)), transgene expression was silenced (Figure 5)” (connecting paragraph between right col. on page 2114 to left col on page 2115).
Additionally, Hyde et al already disclosed the plasmid pGM160 (SEQ ID NO: 1) into which sequences can be cloned for expression from the hCEFI promoter for therapeutic application, along with the pGM151 (SEQ ID NO:2) and pGM144 (SEQ ID NO: 4) plasmids containing the coding sequences for the CFTR polypeptide and luciferase reporter polypeptide, respectively; with all of these plasmids contain an R6K origin of replication of about 300 basepairs (see Abstract; Summary of the Invention; particularly col. 11, line 62 continues to line 25 on col. 12; issued claims 1-8; and Figures 1-3). Hyde et al stated explicitly “The R6K origin is activated by the R6K specific initiator protein B encoded by the pir gene and hence constructs of the invention comprising the R6K origin will typically be grown in strains expressing the pir gene. Any suitable strain expressing the pir gene may be employed. In a preferred instance, constructs of the invention employing the R6K origin are grown in the E. coli strain GT115, EC100 Dpir-116 or DH10 Bpir116”, and “In a particularly preferred instance, the origin of replication may comprise the sequence of nucleotides 2599 to 2870 of SEQ ID No: 4, a functional fragment thereof, or a functional variant of either. The fragment and variants may be any of the lengths and possess any of the level of sequence identity specified herein” (col. 12, lines 3-17).
Accordingly, it would have been obvious for an ordinary skilled artisan to modify the teachings of Williams by also expressing a transgene (e.g., a synthetic HA (vietnam1203) gene) in a mammal with an improved eukaryotic expression plasmid with reduced size, sequence content and antibiotic free selection that has an extragenic DNA spacer that is equal or less than 500 bp in length and comprising a non-pUC origin of replication such as the R6K replication origin and a RNA-OUT selectable marker; and wherein the spacer links the 5’ and 3’ end of a eukaryotic region comprising the transgene, in light of the teachings of Lu et al and Hyde et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modifications because Lu et al already taught at least that the length and not the sequence or the origin of the extragenic DNA flanking the expression cassette is responsible for plasmid-mediated transgene silencing, with shorter spacers ≤500 bp exhibited similar transgene expression patterns to conventional minicircle DNA vectors whereas DNA sequences of ≥1 kb in length resulted in transgene silencing. Lu et al also taught that generic plasmid origin sequence is not sufficient for transgene silencing in DNA plasmid vectors; and demonstrated that minicircles containing a 500 bp pUC-derived bacterial plasmid origin of replication in either the hFIX or hAAT expression cassette failed to silence either the hAAT or hFIX transgene expression cassette in vivo. Moreover, Hyde et al also disclosed successfully the use of plasmid constructs containing an R6K origin for therapeutic application. Furthermore, Williams teaches explicitly that other DNA vaccine or therapeutic plasmid backbones may be used not necessarily limited to a plasmid backbone with pUC ori, such as the pCOR vector containing the R6K gamma replication origin; and that intramuscular or intradermal administration can be used for vector delivery into an organism and the vector can also be in the form of nanoparticles for in vivo delivery.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Williams, Lu et al and Hyde et al; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified method resulting from the combined teachings Williams, Lu et al and Hyde et al is indistinguishable and it is encompassed by the claimed method of the present application. Since the modified method has the same method step (e.g., intramuscular or intradermal administration) and same starting materials (pUC-free minicircle expression vector with the recited limitations), such modified method would necessarily result in a transfection and expression of a transgene in a targeted cell.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-2 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 10,047,365.
Although the claims at issue are not identical, they are not patentably distinct from each other because a method of constructing a eukaryotic replicative pUC-free minicircle expression vector and expressing a transgene of interest (e.g., a target antigen transgene for genetic immunization; dependent claim 4) therefrom into a target eukaryotic cell or a eukaryotic organism in claims 1-7 in U.S. Patent No. 10,047,365 anticipates a method of expressing a transgene with a eukaryotic replicative pUC-free minicircle expression vector in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 10,167,478.
Although the claim at issue is not identical, it is not patentably distinct from each other because a method of constructing a eukaryotic replicative pUC-free minicircle expression vector and expressing a transgene of interest therefrom into a target eukaryotic cell or a eukaryotic organism in claims 1-5 in U.S. Patent No. 10,167,478 anticipates a method of expressing a transgene with a eukaryotic replicative pUC-free minicircle expression vector in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus.
Claims 1-2, 4 and 8-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 10,047,365 or claims 1-5 of U.S. Patent No. 10,167,478 in view of Williams (US 2010/0303859).
The instant claims of the present application differ from claims 1-7 of U.S. Patent No. 10,047,365 in reciting specifically that the eukaryotic replicative pUC-free minicircle expression vector is introduced into the eukaryotic organism via intradermal or intramuscular delivery and/or the eukaryotic replicative pUC-free minicircle expression vector is introduced into the eukaryotic organism in a nanoparticle.
The instant claims of the present application differ from claims 1-5 of U.S. Patent No. 10,167,478 in reciting specifically that the transgene is a target antigen for immunization; the eukaryotic replicative pUC-free minicircle expression vector is introduced into the eukaryotic organism via intradermal or intramuscular delivery and/or the eukaryotic replicative pUC-free minicircle expression vector is introduced into the eukaryotic organism in a nanoparticle.
Before the effective filing date of the present application (11/19/2012), Williams already disclosed a family of improved eukaryotic expression plasmids useful for gene therapy, genetic immunization and/or interferon therapy in humans, other mammals, birds or fish, wherein the expression plasmids have reduced size, sequence content and antibiotic free selection (see at least the Abstract; Disclosure of the Invention; Brief Summary of the Invention; and paragraph 24). An exemplary immunostimulatory influenza H5 HA “bird flu” pDNAVACCultra plasmid (NTC8382-41H-HA) comprises a synthetic HA (vietnam1203) gene, an RNA-OUT selectable maker and an immunostimulatory RNA element (41H) cloned between the Eukaryotic terminator and the prokaryotic replication pUC origin (paragraphs 61, 95; and Figure 1). Williams further disclosed the vector to be delivered to a cell in vivo, in vitro or ex vivo, utilizing one or more of the plurality of delivery methods known in the art that includes nanoparticles, microparticles, lipofection and others (paragraph 100). Williams also stated explicitly “For delivery to an organism, delivery may be by oral, buccal, nasal, inhalation, topical, vaginal, rectal, intravenous, intramuscular, intradermal, epidermal, systemic, or by other routes of administration known in the art” (last sentence in paragraph 100).
Accordingly, it would have been obvious for an ordinary skilled artisan to modify a method of constructing a eukaryotic replicative pUC-free minicircle expression vector and expressing a transgene of interest into a target eukaryotic cell or a eukaryotic organism in claims 1-7 of U.S. Patent No. 10,047,365, or claims 1-5 of U.S. Patent No. 10,167,478 by also delivering a eukaryotic replicative pUC-free minicircle expression vector in the form of nanoparticles and/or via intramuscular or intradermal delivery into a eukaryotic organism, and the transgene includes a transgene that encodes a target antigen for immunization (for claims of U.S. Patent No. 10,167,478); in light of the teachings of Williams as set forth above with a reasonable expectation of success.
An ordinary skilled artisan would have been motivated to carry out the above modifications because Williams teaches a family of improved eukaryotic expression plasmids useful for gene therapy, genetic immunization and/or interferon therapy in humans, other mammals, birds or fish, wherein the expression plasmids have reduced size, sequence content and antibiotic free selection; and that intramuscular or intradermal administration can be used for vector delivery into an organism and the vector can also be in the form of nanoparticles for in vivo delivery.
The modified method resulting from combining claims 1-7 of U.S. Patent No. 10,047,365 or claims 1-5 of U.S. Patent No. 10,167,478 along with the teachings of Williams as set forth above is indistinguishable and it is encompassed by the claimed method of the present application.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Conclusions
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1633; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/Primary Examiner, Art Unit 1631