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 .
Claim(s) 241-260 are pending and under consideration.
Preliminary Amendments
Applicant’s preliminary amendment filed on 11/01/2024 is acknowledged. The claim(s) were amended to cancel 1-240.
Priority
Acknowledgement is made that this application is a 371 of PCT/US2022/077108 filed 09/27/2022 and claims priority based on provisional application(s) filed as 63/248,801 on 09/27/2021.
All claims are given the priority date of 09/27/2021.
Information Disclosure Statement
Receipt of the information disclosure statement(s) on 03/26/2024 and 05/16/2025 are acknowledged. The signed and initialed PTO-1449 form(s) has/have been mailed with this action.
Drawings
Minor Objections
The drawings are objected to because of the following:
In Figs. 2B, 2D, 2E, 2F, 7B, there are words that are illegible;
In Fig. 28B and 29, the conditions are indistinguishable from one another.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency #1: This application fails to comply with the requirements of 37 CFR 1.831-1.834 because it does not contain a “Sequence Listing XML” as a separate part of the disclosure. A “Sequence Listing XML” is required because there are >10 specifically defined nucleotides in multiple locations in the drawings) and pages 121 to 141 contain specifically defined nucleotide sequences.
Required response - Applicant must provide:
• A “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2.; together with
o A statement that indicates the basis for the amendment, with specific references to particular parts of the application as originally filed, as required by 37 CFR 1.835(a)(3);
o A statement that the “Sequence Listing XML” includes no new matter as required by 37 CFR 1.835(a)(4)
AND
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(a)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
Specific deficiency #2 - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. See the following locations:
Fig. 2B;
Fig. 2F;
Fig. 7B;
Fig. 31; and
Fig. 32.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
Minor informalities
The disclosure is objected to because of the following informalities:
Page 105 of the specification refers to SEQ ID NOs: 1-4 (lines 15-19), however, there is no corresponding separate sequence listing with the application (see above section on Nucleotide disclosures).
Appropriate correction is required.
Trademarks and/or Tradenames
The use of the following term(s), which is/are a trade name or a mark used in commerce, has been noted in this application.
Plasmid-Safe (p.46, line 20; p.50, line 12; p.87, line 6; p.88, line 17);
Triton (p.60, line 11; p.92, lines 2, 4);
Qiagen (p.60, line 12,13; p.92, line 4);
Ribogreen (p.75, line 21);
Oligofectamine (p.80, lines 2 and 13);
NEON (p.85, line 20);
rCutsmart (p.91, line 14 and 19); and
New England Biolabs (p.90, line 29; p.91, lines 4, 8-9, 14, p.94, line 25)
The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 253 is objected to because of the following informalities: claim 253 further limits claim 241 (not claim 252), which contains sections (a) through (d), by adding section (f). It would be remedial to amend claim 253 to recite section (e) for consistency.
Claim 258 is objected to because of the following informalities: the recitation of “less than” before “<” in the phrase “. . . less than <1.0% RNA content by mass, and less than <5 EU/mg endotoxin.”, is redundant. It would be remedial to remove “less than” for consistency with the first listed item, “. . . wherein the pharmaceutical composition comprises <1.0% protein content by mass, . . .”
Appropriate correction is required.
Claim Interpretation
Claim 241, section (d), the phrase “. . . to produce a circular backbone and a therapeutic circular DNA vector lacking a type IIs restriction site.”, is being interpreted as only the therapeutic circular DNA vector is lacking the type IIs restriction site, not the circular backbone. The basis for this interpretation can be found in Figure 1 and 3.
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.
Claim(s) 241-243, 246-247, 250, and 253-256 are rejected under 35 U.S.C. 103 as being unpatentable over Schnepp et al (WO 2019/178500 A1; published September 19th, 2019) in view of De Bettingnies et al (US 2019/0040397 A1; published February 7th, 2019).
Regarding claim 241, Schnepp et al teaches, “In another aspect, the invention features methods of producing an isolated circular DNA vector (e.g., any of the circular DNA vectors described herein). The method includes:
(i) providing a sample including a circular DNA molecule including an AAV genome (e.g., a recombinant AAV (rAAV) genome, e.g., an AAV episome), wherein the AAV genome includes a heterologous gene and a terminal repeat sequence (e.g., one or more terminal repeat sequences (e.g., one or more inverted terminal repeat (ITR) sequences (e.g., two ITR sequences) or long terminal repeat (LTR) sequences (e.g., two LTR sequences)));
(ii) amplifying the AAV genome using polymerase (e.g., phage-polymerase)-mediated rolling-circle amplification (e.g., an isothermal polymerase (e.g., phage polymerase)-mediated rolling circle amplification) to generate a linear concatemer;
(iii) digesting the concatemer using a restriction enzyme to generate an AAV genome; and
(iv) allowing the AAV genome to self-ligate to produce an isolated DNA vector including the heterologous gene and the terminal repeat sequence.”, (p.5, lines 21-31; and figure 5 and figure 17).
Further, regarding part (c) of Claim 241, claim 242-243, and 247, Schnepp et al teaches Type IIP restriction enzyme (i.e., SwaI) that cuts a first and second site per unit and a Type IIH restriction enzyme (i.e., AhdI) that cuts away from the insert but still once a monomeric unit (see Fig. 9). Schnepp et al also teaches, “FIG. 10 is a photograph of an agarose gel showing the results of a SwaI digestion of amplified DNA. DNA amplified from either 1 ng or 6 ng of the TG-18 plasmid template was digested with SwaI to produce a 244-bp fragment (Lanes 2 and 3, arrow). This is the same size fragment released from the original TG-18 plasmid vector (Lane 1). Also included is DNA amplified from a plasmid template lacking the DD element (TG-dDD) that was produced by removing the DD element from TG-18 using a SwaI digest (Lanes 4 and 5).”, (p. 12, lines 25-30).
Regarding claim 253, Schnepp et al teaches, “In some embodiments, linear DNA is specifically degraded, e.g., using plasmid-safe DNase, to purify the circular DNA.”, (p. 29, lines 31-32, and Fig. 12B).
Regarding claim 254, Schnepp et al teaches a heterologous gene encodes a therapeutic protein configured to treat retinal dystrophy, wherein the gene includes one or more of the following: ABCA4, CEP290, ABCC6… (p.5, line 35 to p.6 line 2).
Regarding claim 255 and 256, Schnepp et al teaches, “In some embodiments, a heterologous gene includes a therapeutic nucleic acid, such as a therapeutic RNA (e.g., microRNA).”, (p. 16, lines 9-10).
Schnepp et al does not explicitly teach (a) a type IIs restriction enzyme digestion, (b) a T4 ligase, and (c) wherein the therapeutic circular vector lacks a type IIs restriction site.
De Bettingnies et al teaches, “The insertion or extraction of DNA fragments corresponding to functional elements (antibiotic resistance genes, cloning sites, molecular labels, promoters, origins of replication in other organisms, selection cassettes, etc.) in/from plasmids (circular DNA molecules naturally present in some bacteria) has enabled the development of a multitude of different vectors, suitable for various uses, each vector being developed for an especial and specific application. The end user therefore selects a vector adapted to his needs and introduces into it his own DNA fragment of interest by DNA cloning methods. These methods are traditionally based on the use of, on the one hand, restriction enzymes, most often of type IIp (that is to say enzymes which recognise and cleave DNA at short palindromic sequences) and, on the other hand, DNA ligases, which are capable of putting back together DNA fragments produced by the restriction enzymes. These methods require multiple steps, of which the number increases the risk of exposure to exogenous contaminants that could degrade the DNA, and also the risk of self-pairing or incorrect pairings. Similarly, these methods require the use of multiple enzymes, which are effective to a greater or lesser extent, which constitutes a disadvantage that is difficult to overcome. Difficulties can also be encountered depending on the compatibility of the donor and acceptor plasmids.”, (para [0002]).
Moreover, De Bettingnies et al teaches, “The invention also makes it possible to restrict the content of the vectors solely to the sequences of interest selected by the user. There is no residual plasmid sequence or nucleotide scar resulting from the use of conventional restriction enzymes and the need to use multiple cloning sites. The invention thus allows users to exert total control over the components of the vector produced.”, (para [0037]).
Regarding claim(s) 241-242, and 250, De Bettingnies et al teaches Type IIs restriction enzyme digestion with BsaI at two sites around a sequence of interest, a ligase, and the loss of a recognition site (see figure 1). De Bettingnies et al teaches, “The method according to the invention requires the use of just a single restriction enzyme, which is a type IIs restriction enzyme.”, (para [0030]).
Regarding claim 246, De Bettingnies et al teaches, “The assemblies were performed with the aid of the enzyme BsaI (NEB) and the ligase T4 HC (Promega) in the buffer of the ligase T4 HC, in accordance with the protocol described above.”, (para [0553]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the Type IIP (i.e., SwaI) and Type IIH restriction enzyme/sites per monomeric unit in Schnepp et al with the Type IIs restriction enzyme/sites (i.e., BsaI) of De Bettingnies et al, to yield the predictable result of digesting the linear concatemer with a Type IIs restriction enzyme that cuts a first, second, and third site per unit of linear concatemer. Type IIP/H and Type IIs restriction enzyme structures/sites and functions were both known in the art before the effective filing date of the claimed invention. One of skill in the art would be motivated to substitute the Type IIP/H for the Type IIs restriction enzyme/site because De Bettingnies et al teaches that conventional restriction (namely Type IIP) enzymes (a) require multiple steps, (b) risk self-pairing or incorrect pairings, and (c) require the use of multiple enzymes. De Bettingnies et al teaches only using Type IIs restriction enzymes. Type IIs restriction enzymes make it possible to (a) restrict the content of the vectors to solely the sequences of interest selected by the user, (b) that there is no residual plasmid sequence, (c) no nucleotide scarring which is typically of convention e.g., Type IIP restriction enzymes, and (d) the use of a Type IIs restriction enzyme allows for the loss of the recognition site post-ligation. One of skill could have looked to the teachings of Schnepp et al and De Bettingnies et al and substituted each restriction enzyme/site for a BsaI Type IIs restriction enzyme/site and arrived at the claimed invention with a high likelihood of success.
Regarding claim(s) 243 and 247, De Bettingnies et al teaches, “The product of the reaction is a DNA molecule, preferably circular and containing the desired number of molecular building blocks, these being assembled in an ordered fashion, based on the complementarities of the sutures.”, (para [0123]). Moreover, De Bettingnies et al teaches, “An adapter contains at least: a sequence of 5, 6, 7 or more nucleotides corresponding to the binding site of the used enzyme with type IIs activity for the assembly according to the invention, a sequence of 1 to 8 and more nucleotides corresponding to the spacing between the binding site and the cleavage site of the enzyme used. The length of this sequence is dependent on the intrinsic characteristics of the type IIs enzyme used, a sequence of 2 to 5 or more nucleotides corresponding to the single-stranded end produced by the action of the type IIs enzyme used. Since this sequence enables the pairing of fragments that are to be assembled, it corresponds de facto to the definition of a suture.”, (see para [0106] to [0109]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of De Bettingnies et al, i.e., manipulation of the adaptor sequences, with the combined teaches of Schepp et al in view of De Bettingnies et al, i.e., a linear concatemer digested by BsaI (a type IIs restriction enzyme) in three sites per monomeric unit, to yield the predictable results of the third BsaI site forming an overhang that is non-complementary to the first or second site. One of skill in the art would be motivated to do so because Schnepp in view of De Bettingnies et al teaches that the therapeutic region ligates, i.e., contains complementarity, and that the third cut site is away from the therapeutic region (i.e., gene of interest). De Bettingnies et al teaches adaptor design which contains 5-7 or more nucleotides corresponding to the binding site and 1 to 9 or more nucleotides corresponding to a spacing between the binding site and cleavage site, and a 2 to 5 or more nucleotides corresponding to the end for complementarity purposes. De Bettingnies further teaches that the invention also makes it possible to restrict the content of the vectors solely to the sequences of interest selected by the user and allows users to exert total control over the components of the vector produced. Thus, one of skill in the art could look to the teachings of Schnepp et al in view of De Bettingnies et al and the rest of the teachings of Bettingnies et al, and arrived at the claimed invention with a high likelihood of success.
Accordingly, claim(s) 241-243, 246-247, 250, and 253-256 are unpatentable over Schnepp et al in view of De Bettingnies et al.
Claim(s) 244 and 245 are rejected under 35 U.S.C. 103 as being unpatentable over Schnepp et al (supra) in view of De Bettingnies et al (supra) as applied to claim(s) 241-243, 246-247, 250, and 253-256 above, and further in view of Chen et al (WO 2007/018744 A2; published February 15th, 2007).
Schnepp et al in view of De Bettingnies et al does not teach (a) diluting the DNA between digestion and ligation, or (b) wherein the DNA concentration at the beginning of the ligation is greater than or equal to 20ug/mL but less than 160ug/mL.
Chen et al teaches making high quality DNA in a cell-free system, free of bacteria contaminants, and optimally free of flanking bacterial gene coding sequences which can minimize or silence gene expression when used for expression inside a target cell.
Regarding claim 244, Chen et al teaches, “Diluting the reaction volume prior to ligation favors the formation of monomeric circular product.”, (para [0032] and Figure 4).
Regarding claim 245, Chen et al teaches, “a) T4 DNA ligase. Following restriction enzyme digestion of cell free amplified DNA, heat inactivation of the restriction enzyme and ethanol/salt precipitation of the DNA, the intramolecular ligation (self-ligation) of linear DU was performed in 138 μl and 690 μl reactions respectively containing 700 fmol of DNA in 1x ligation buffer.”, (para [0130]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to combine the teachings of Chen et al, i.e., diluting the DNA prior to ligation with the teachings of Schnepp et al in view of De Bettingnies, i.e., producing a therapeutic circular DNA vector (as taught by the combined teachings above) to yield the predictable results of diluting the digested DNA of (c) prior to the ligation step in (d). One would be motivated to do so because Chen et al teaches that diluting the reaction volume prior to ligation favors the formation of a monomeric circular product. One of skill in the art could look to the teachings of Chen et al and Schnepp et al in view of De Bettingnies et al and arrive at the claimed invention with a high likelihood of success.
Furthermore, although some claimed concentrations differ from those of cited reference, section 2144.05 II of the MPEP states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.")”
Accordingly, claims 244 and 245 are unpatentable over Schnepp et al in view of De Bettingnies in further view of Chen et al.
Claim(s) 257-260 are rejected under 35 U.S.C. 103 as being unpatentable over Schnepp et al (supra) in view of De Bettingnies et al (supra) as applied to claim(s) 241-243, 246-247, 250, and 253-256 above, and further in view of FDA (Guidance for Industry: Considerations for Plasmid DNA Vaccines for Infectious Disease Indications; pages 1-13, published November 2007).
Regarding claim 257, Schnepp et al teaches, “The pharmaceutical compositions described herein may be assessed for contamination by conventional methods and formulated into a pharmaceutical composition intended for a suitable route of administration.”, (p. 30, line 25-27).
Regarding claim 259, Schnepp et al teaches, “. . . provided herein is a pharmaceutical composition including any one or more of the aforementioned circular DNA vectors and a pharmaceutically acceptable carrier.”, (p.7, lines 3-4).
Regarding claim 260, Schnepp et al teaches, “In another aspect, the invention features a method of inducing expression (e.g., episomal expression) of a heterologous gene in a subject in need thereof, the method including administering to the subject a pharmaceutical composition including any of the aforementioned circular DNA vectors and a pharmaceutically acceptable carrier (e.g., a non-immunogenic pharmaceutical composition).”, (p.7, lines 8-11).
Schnepp et al and De Bettingnies et al does not teach (a) at least 70% supercoiled monomer, (b) <1% protein content by mass, (c) <1% RNA content by mass, and (c) <5 EU/mg of endotoxin.
FDA teaches, “For the purposes of this guidance, DNA vaccines are defined as purified plasmid preparations containing one or more DNA sequences capable of inducing and/or promoting an immune response against a pathogen.”, (p. 1, para 2).
Regarding claim 257, FDA teaches, “We recommend that the fraction of plasmid in supercoiled conformation be included in the bulk release criteria, and that you establish a minimum specification for supercoiled plasmid content (preferably >80%).”, (p.3, para 5).
Regarding claim 258, FDA teaches, “You should evaluate bulk plasmid preparations for the presence of bacterial host cell macromolecules including DNA, RNA, and protein and set preliminary limits for the maximum level of each of these macromolecules (preferably <1%).”, (p. 3, para 6). FDA further teaches, “The amount of endotoxin in plasmid DNA vaccine preparations should not exceed 40 EU/mg plasmid.”, (p.4, para 1).
Therefore, it would have been obvious to try to one of skill in the art before the effective filing date of the claimed invention to combine the teachings of Schepp et al in view of De Bettingnies, i.e., producing a therapeutic circular DNA vector (as taught by the combined teachings above) with FDA, i.e., >80% super coiled, <1% of Macromolecules i.e., RNA and protein, and not exceeding 40 EU/mg to yield the predictable results of a circular DNA vector formulated for the production of a pharmaceutical composition. One of skill in the art could have looked to the teachings of FDA and be motivated to achieve those guidance criteria to allow the circular vector to be formulated for further pharmaceutical use i.e., plasmid DNA vaccines for infectious diseases. One could have combined the teachings of Schnepp et al in view of De Bettingnies et al with the guidance of the FDA and arrived at the claimed invention with a high likelihood of success.
Accordingly, claim(s) 257-260 are rejected over Schnepp et al in view of De Bettingnies et al in further view of FDA.
Claim(s) 248-249 and 252 is rejected under 35 U.S.C. 103 as being unpatentable Schnepp et al (supra) in view of De Bettingnies et al (supra) as applied to claim(s) 241-243, 246-247, 250, and 253-256 above, and further in view of Rehberger et al (US 2013/0203121 A1; published August 18, 2013).
Schnepp et al in view of De Bettingnies et al does not teach (a) wherein the one ore more restriction enzymes cut a fourth site of the linear concatemer per unit (in in the backbone sequence), (b) wherein the single restriction enzyme cuts a fourth site, and (c) the step (e) contacting the therapeutic circular DNA vector with a topoisomerase or a helicase.
Regarding claim(s) 248-249, Rehberger et al teaches, “Step (a) of the method according to the invention involves cleaving a parental plasmid with one or more restriction enzymes. This step is favourably carried out in vitro, i.e. on an isolated plasmid preparation. The parental plasmid is cleaved using restriction enzymes which permit the excision of a fragment which includes the sequence of the DNA vector (DNA vector fragment). This DNA vector fragment is obtained in linear form in addition to one or more further linear fragments corresponding to the additional heterologous sequences present in the parental plasmid. The region of the DNA vector is preferably not cut during restriction cleavage, while the remaining sequence, also known as miniplasmid (MP), is either left behind as a whole piece or is alternatively cleaved into smaller pieces. It is important here for no DNA fragments to be obtained which are similar in size to the DNA vector fragment. Restriction cleavage preferably proceeds quantitatively, such that no intact parental plasmid is any longer present after the enzymatic treatment of the DNA.”, (para [0043] to [0044]).
Rehberger et al teaches, “In order to prevent any linearised MP DNA, which may under certain circumstances have been entrained, from being circularised or a PP being reformed from linearised MC and linear MP, it is preferred when selecting the restriction enzymes for separating MC and MP to ensure that the MP is cut by means of an additional enzyme in such a manner that a complete MP fragment, which can be circularised with itself or with the MC, is not obtained.”, (para [0049]).
Moreover, Rehberger et al teaches, “The unreacted parental plasmid and the miniplasmid obtained as a by-product which was not required were linearised by overnight restriction digestion using a suitable restriction enzyme which only cuts in the miniplasmid region. The minicircle was left unchanged by this reaction and therefore remained in the ccc state.”, (para [0097]).
Therefore, it would have been obvious to try to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Rehberger et al, i.e., adding an additional one cut site into the backbone sequence (reading on mini plasmid) with the teachings of Schnepp et al in view of De Bettingnies, i.e., producing a therapeutic circular DNA vector (as taught by the combined teachings above) with three BsaI cut sites, two adjacent to the therapeutic portion and one in the backbone section. One of skill in the art would be motivated to do so because Rehberger et al teaches that to prevent any linearized backbone back from being reformed with the therapeutic section it is preferred to cleave it into smaller pieces, but not too much smaller such that the DNA fragments are smaller than the DNA vector (therapeutic construct) size. Thus, given the size of any vector, one of skill in the art could systematically place restriction sites in a way that allows the backbone plasmid to be cut more than once but less than a number which would result in fragments smaller than the therapeutic circular DNA vector. One of skill in the art could look to the teachings of Rehberger et al and Schnepp et al in view of De Bettingnies et al and arrived at the claimed invention, i.e., four cut sites, two in the backbone with non-complementary overhangs to the therapeutic cut site with a high likelihood of success.
Regarding claim 252, Rehberger et al teaches, “Since retaining the superhelical structure is essential to the subsequent use of the MCs [mini circles], correspondingly stringent requirements apply to the purification method for isolating the MCs in order not to destroy the desired structure of the MCs during purification.”, (para [0004]).
Moreover Rehberger et al teaches, “The present invention accordingly provides a method for producing a circular DNA vector in superhelical form, comprising the steps:. . . (e) coiling the circular DNA vector from step (d) with a gyrase in order to obtain a circular DNA vector in superhelical form. . .”, (para [009] to [0014]).
Rehberger et al teaches, “If the MC is to be used as a DNA vector, specifically where it is to be used as a stably episomally replicating vector, it is necessary for the annular DNA molecule to assume superhelical form. This superhelical status is not obtained once circularisation with ligase is complete and must therefore be produced subsequently by gyrase treatment of the circular MC. The gyrase, which is commercially obtainable in recombinant form, is a type II topoisomerase which, in the presence of ATP, introduces negative superhelical structures into DNA.”, (para [0051]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Schnepp et al in view of De Bettingnies, i.e., producing a therapeutic circular DNA vector (as taught by the combined teachings above) with Rehberger et al, i.e., adding a type II topoisomerase after the ligation, to yield the predictable results producing a superhelical therapeutic circular DNA vector. One would be motivated to do so because Rehberger et al teaches a superhelical structure is essential to the use of mini circles, i.e., minicircle gene vectors for use in gene therapy (para [0025]). Thus, one could have looked to the teachings of both Schnepp et al in view of De Bettingnies et al and Rehberger et al and arrived at the claimed invention with a high likelihood of success.
Accordingly, claim(s) 248-249 and 252 is unpatentable of Schnepp et al in view of De Bettingnies et al in further view of Rehberger et al.
Claim 251 is rejected under 35 U.S.C. 103 as being unpatentable Schnepp et al (supra) in view of De Bettingnies et al (supra) as applied to claim(s) 241-243, 246-247, 250, and 253-256 above, and further in view of Jarvius et al (US 2016/0257991 A1; published September 8th, 2016; cited on IDS filed 03/26/2026 as A2).
Schnepp et al in view of De Bettingnies et al does not teach wherein steps (c) digestion and (d) ligation, occur simultaneously.
Regarding claim 251, Jarvius et al teaches the process of performing a rolling circle amplification (RCA) reaction comprising at least two rounds of RCA via (a) (a) providing a concatemeric first RCA product, (b) cleaving the first RCA product into monomer units, (c) circularising monomer units resulting from said cleavage. Particularly, Jarvius et al teaches, “Thus steps (a), (b), (c) and (d) may be performed sequentially or substantially simultaneously (i.e. as part of the same reaction, in the sense that that reagents for the various steps are added or are present together, although it will be recognised of course that monomerisation/cleavage needs to occur before the generated monomer units are circularised by ligation). In particular, steps (b) and (c) may occur in combination.” (see para [0017] to [0023]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of Jarvius, i.e., performing the cleaving and circularization at the same time, to the method of producing a therapeutic circular DNA vector (as taught by the combined teachings above of Schnepp et al in view of De Bettingnies et al) to yield the predictable results of performing the digestion and ligation simultaneously. Both Jarvius et al and Schnepp et al in view of De Bettingnies et al contain comparable methods, i.e., producing a circular DNA template via RCA. One of skill in the art could have applied the known improvement of Jarvius et al in the same way to the combined method of Schnepp et al in view of De Bettingnies et al and the results would have been predictable.
Accordingly, claim 251 is unpatentable over Schnepp et al in view of De Bettingnies et al in further view of Jarvius et al.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claim 259 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 42 of copending Application No. 18/993,971 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
The instant claim is drawn to a pharmaceutical composition that is produced by the process of instant claim 257. Accordingly, the claim is a “product-by-process” claim. Regarding Product-by-Process claims, it is noted that MPEP 2113 states:
"[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)…
"The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature" than when a product is claimed in the conventional fashion. In re Fessmann, 489 F.2d 742, 744, 180 USPQ 324, 326 (CCPA 1974). Once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing an nonobvious difference between the claimed product and the prior art product. In re Marosi, 710 F.2d 799, 803, 218 USPQ 289, 292-33 (Fed. Cir. 1983)…
See also Ex parte Gray, 10 USPQ2d 1922 (Bd. Pat. App. & Inter. 1989) (The prior art disclosed human nerve growth factor (b-NGF) isolated from human placental tissue. The claim was directed to b-NGF produced through genetic engineering techniques. The factor produced seemed to be substantially the same whether isolated from tissue or produced through genetic engineering. While the applicant questioned the purity of the prior art factor, no concrete evidence of an nonobvious difference was presented. The Board stated that the dispositive issue is whether the claimed factor exhibits any unexpected properties compared with the factor disclosed by the prior art. The Board further stated that the applicant should have made some comparison between the two factors to establish unexpected properties since the materials appeared to be identical or only slightly different.) (Emphasis added).
Claim 42 of ‘971 recites, “A pharmaceutical composition comprising a therapeutically effective amount of the circular DNA vector of claim 1, or the nucleic acid vector of claim 18, and a pharmaceutically acceptable carrier.”
Where claim 1 recites, “A circular DNA vector comprising a promoter, a transgene, and a scaffold matrix attachment region (S/MAR) sequence, wherein the transgene is a therapeutic protein- encoding sequence derived from a protein expressed in respiratory epithelium, and wherein the circular DNA vector lacks a drug resistance gene.”
The circular DNA vector of claim 1 in the ‘971 application, which is comprised in the pharmaceutical composition (in a therapeutically effective amount) of claim 42, appears to be essentially the same as the therapeutic circular DNA vector of instant claim 257, which is comprised in the pharmaceutical composition of examined claim 259.
Accordingly, instant claim 259 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 42 of ‘971.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 259 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 78 of copending Application No. 18/992,141 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
The instant claim is drawn to a pharmaceutical composition that is produced by the process of instant claim 257. Accordingly, the claim is a “product-by-process” claim. Regarding Product-by-Process claims, see MPEP 2113 section in the above ‘971 rejection:
Claim 78 of the ‘141 recites, “A nucleic acid vector comprising:(a) a promoter comprising any one of SEQ ID NOs: 3-5; and (b) a cDNA sequence encoding MYO7A.”, wherein the nucleic acid vector is a non-integrating DNA vector.”, wherein the nucleic acid vector is a circular DNA vector selected from a plasmid DNA vector, a minicircle DNA vector, a synthetic circular DNA vector, a closed-ended DNA vector, a doggybone DNA vector, or a ministring DNA vector.”, wherein the nucleic acid vector lacks a drug resistance gene.”
The circular DNA vector. . . wherein the nucleic acid vector lacks a drug resistance gene of claim 78 in the ‘141 application does not indicate that the circular DNA vector is in a pharmaceutical composition, but the circular DNA vector appears to be essentially the same as the therapeutic circular DNA vector of instant claim 257, which is comprised in the pharmaceutical composition of examined claim 259. It would have been obvious to formulate the vector into a pharmaceutical composition to administer to a subject as is indicated in the method claims of the co-pending application.
Accordingly, instant claim 259 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 78 of ‘141.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 259 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/496,312 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
The instant claim is drawn to a pharmaceutical composition that is produced by the process of instant claim 257. Accordingly, the claim is a “product-by-process” claim. Regarding Product-by-Process claims, see MPEP 2113 section in the above ‘971 rejection:
Claim 1 of ‘312 recites, “A circular DNA vector or pharmaceutical composition thereof, wherein the circular DNA vector comprises a therapeutic sequence and a sequence comprising a bacterial replication origin, wherein the sequence comprising the bacterial replication origin is less than 50 bp in length, and wherein the circular DNA vector lacks a selectable marker.”
The circular DNA vector or a pharmaceutical composition thereof . . . wherein the circular DNA vector lacks a selectable marker of claim 1 in the ‘312 application, appears to be essentially the same as the therapeutic circular DNA vector of instant claim 257, which is comprised in the pharmaceutical composition of examined claim 259.
Accordingly, instant claims 259 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1of ‘312.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 259 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12 and 16 of copending Application No. 18/278,235 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
The instant claim is drawn to a pharmaceutical composition that is produced by the process of instant claim 257. Accordingly, the claim is a “product-by-process” claim. Regarding Product-by-Process claims, see MPEP 2113 section in the above ‘971 rejection:
Claim 12 of ‘235 recites, “A nucleic acid vector comprising a dendritic cell chemoattractant-encoding gene, a dendritic cell growth factor or activator-encoding gene, and a lymphocyte signaling protein-encoding gene.”, “which is a DNA vector.”, “which is a circular DNA vector.”, wherein the circular DNA vector is a synthetic circular DNA vector which lacks a bacterial origin of replication, a drug resistance gene, and a recombination site.”
Claim 16 of 235 recites, “A circular DNA vector comprising, in a 5' to 3' direction: (a) a promoter;(b) a self-replicating RNA molecule-encoding sequence comprising (i) a replicase-encoding sequence that transcribes RNA from the self-replicating RNA molecule and (ii) one or more heterologous protein- encoding sequences; and (c) a polyadenylation sequence, wherein the circular DNA vector lacks a bacterial origin of replication and/or a drug resistance gene.”
The circular DNA vector. . . wherein the synthetic circular DNA vector lacks a bacterial origin of replication, a drug resistance gene, and a recombination site of claim 12 in the ‘235 application; and the circular DNA vector. . . wherein the circular DNA vector lacks a bacterial origin of replication and/or a drug resistance gene of claim 16 in the ‘235 application do not indicate that the circular DNA vector is in a pharmaceutical composition, but the circular DNA vector appears to be essentially the same as the therapeutic circular DNA vector of instant claim 257, which is comprised in the pharmaceutical composition of examined claim 259. It would have been obvious to formulate the vector into a pharmaceutical composition to administer to a subject as is indicated in the method claims of the co-pending application.
Accordingly, instant claim 259 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12 and 16 of ‘235.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims allowed.
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/L.M.T./Examiner, Art Unit 1637
/J. E. ANGELL/Primary Examiner, Art Unit 1637
