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 .
Application Status
This action is written in response to applicant’s correspondence received on 10/03/2024. Claims 1-3, 5-6, 8, 10-12, 14-17, 19, 22-26, and 29 are currently pending and under examination.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application 2028321 filed in Netherlands on May 28, 2021.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, 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.
Claim Objections
Claims 1, 11, and 22 are objected to because of the following informalities:
In claims 1, 11, and 22, the numerical value is written as “5,5 kilo base-pairs”. Consistent with U.S. punctuation practice, the decimal separator should be a period rather than a comma.
In claims 11 and 22, the acronym “kbp” is defined as being “kilo base-pairs”. However, the acronym has previously been defined in claim 1. An acronym should only be defined the first time it appears in an independent claim or in the group of claims under an independent claim.
Appropriate correction is required.
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 1-3, 5-6, 8, 10-12, 14-17, 19, and 29 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. Those claims included in the statement of rejection but not otherwise discussed are rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim 1 recites a method of delivering a nucleic acid into a cell in vitro with a single step “providing a saponin”. Claim 1 does not recite any additional steps. Thus, it is unclear whether the method requires delivering a nucleic acid into a cell in vitro or not. It is unclear whether the method simply requires providing a saponin as the active step suggests or the method requires delivering a nucleic acid into a cell, which the body of the claim fails to recite the steps necessary to accomplish the delivery.
Claim 11 recites a method for delivering a nucleic acid into a cell in vitro with 3 steps: providing a nucleic acid, providing a saponin, and incubating the cell with the nucleic acid in the presence of the saponin. The claimed method only requires that the cell, nucleic acid, and saponin are incubated together, and does not require that the nucleic acid to be delivered into the cell. Therefore, it is unclear whether the claimed method requires the nucleic acid to be delivered into the cell or not. It is unclear whether the incubation step alone results in delivery or additional steps are required.
Claim 29 recites “wherein the nucleic acid comprises more than at least 6 kbp” (emphasis added). This recitation renders the determination of the scope of the claim difficult as the claim recites two different ranges of lengths. It is unclear whether the claim requires a nucleic acid having a length greater than 6 kbp (>6 kbp) or at least 6 kbp (≥6 kbp). The metes and bounds of the claim cannot be determined with reasonable certainty.
Claim Interpretation
Claim 1 recites a method “of delivering a nucleic acid into a cell in vitro” without reciting active step directed to delivery of a nucleic acid into a cell. Thus, this recitation is interpreted as an intended use of the method. Further, the claim recites “wherein the nucleic acid comprises more than 5.5 kbp”, which elaborates on the intended use of the method. Under the broadest reasonable interpretation, the length of the nucleic acid does not impose a positive limitation on the method. Therefore, claim 1 is interpreted as a method comprising providing a saponin, wherein the saponin is a bisdesmosidic triterpenoid 12, 13-dehydrooleanane-type saponin.
Claim 11 recites a method “for delivering a nucleic acid comprising more than 5.5 kbp into a cell in vitro” without reciting active steps directed to the delivery of the nucleic acid into a cell. Thus, it is interpreted as reciting an intended use of the method.
Claim 22 recites “suitable for in vitro delivery of a nucleic acid into a cell”. It is interpreted as an intended use of the nanoparticle.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-3, 5-6, 8, 10-12, 14-17, and 19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., law of nature, natural phenomenon, or product of nature) without significantly more. The inventor discloses and claims naturally occurring saponins. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter?
Claims 1 and 11 are directed to a method or process, which is one of the statutory categories of invention.
Step 2A, Prong 1: Do the claims recite an abstract idea, law of nature, or natural product?
Claim 1 recites a method “of delivering a nucleic acid into a cell in vitro”, which is merely reciting an intended use of the method, rather than an active step (see Claim Interpretation discussion above). Claim 1 recites one single step, “providing a saponin, wherein the saponin is a bisdesmosidic triterpenoid 12, 13-dehydrooleanane-type saponin”. The specification defines this type of saponin as a specific group of triterpenoid saponins, such as SO1861 and GE1741 (pg. 2, line 19). Weng (J. Control Release, 2015, 206:75-90; IDS received on 11/28/2023, Cite No. C16) discloses saponin SO1861 is natural, plant derived glycoside from Saponaria officinalis L. (abstract, para. 2). Further, the step of “providing” merely identifies the naturally occurring saponin that is made available and does not require manipulation, transformation, or use of the saponin beyond its mere presence. Claim 1 does not recite additional active steps of contacting, administering, incubating, or delivering the natural product to achieve a particular result. Accordingly, claim 1 as a whole, is not distinguishable from a claim directed to the natural product itself because the only limitation is the saponin being provided. Therefore, the eligibility analysis in Step 2A, Prong 1 focuses on whether the claimed saponin is markedly different than its naturally occurring counterpart. The instantly claimed saponin lacks any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart, SO1861, as taught by Weng. Thus, claim 1 is directed to a judicial exception.
Step 2A, Prong 2: Claim 1 does NOT recite additional elements, and therefore, claim 1 does not include additional elements that integrate the judicial exception into a practical application.
Step 2B: Claim 1 does NOT recite any additional elements, and therefore, claim 1 does not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Claims 2 and 3 recite specific structure of the saponin, and wherein the saponin is GE1741. Freie Universitat Berlin (WO 2019/011914 A1; Published Date January 17, 2019; IDS received on 11/28/2023, Cited No. B6) (hereinafter as Freie) discloses natural product SO1861 comprises instantly recited formula (I) (pg. 2, lines 5-12), and GE1741 is also a naturally occurring saponin from Gyposphila elegans M. Bieb (pg. 13, line 25). Accordingly, the instantly claimed saponin lacks any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart. Thus, claims 2 and 3 are directed to a judicial exception (Step 2, Prong 1), and claims do not recite additional elements (Step 2, Prong 2, and Step 2B).
Claims 5-6, and 8 recite limitations of the nucleic acid, but the claims do not require any active steps of forming the nanoparticle with the saponin, combining the nucleic acid with the saponin, or delivering the nucleic acid. The claims are describing the nucleic acid which is recited as an intended use in the claims. Similarly, claim 10 recites wherein the cell is a eukaryotic cell, but the claim does not require any active steps of combining the saponin with the eukaryotic cell. The claim is describing the cell that is recited as intended use in claim 1. Accordingly, the saponin recited in these dependent claims still lacks any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart. Thus, claims 5-6, 8, and 10 are directed to a judicial exception (Step 2, Prong 1), and claims do not recite additional elements (Step 2, Prong 2, and Step 2B).
Claim 11 recites additional active steps that are not included in claim 1, but these steps merely require providing the nucleic acid and incubating the cell with the nucleic acid in the presence of the natural product. The claim does not require interaction between the nucleic acid and the natural product, interaction between the cell and the natural product, or delivering the nucleic acid into the cell by the properties of the natural product. Accordingly, the incubation step merely places the natural product in an ordinary laboratory environment without requiring any technological application or transformation of the natural product. Therefore, these additional elements are considered insignificant extra-solution activity. The term “extra-solution activity” can be understood as activities incidental to the primary process or product that are merely a nominal or tangential addition to the claim. The addition of insignificant extra-solution activity does not amount to an inventive concept, particularly when the activity is well-understood or conventional (see MPEP § 2106.05(g)). Therefore, this additional element does not integrate the judicial exception into a practical application (Step 2, Prong 2). Further, the incubation step is a well-understood, routine, and conventional activity in the biology field. Therefore, claim 11 does not include additional elements that are sufficient to amount to significantly more than the judicial exception (Step 2B).
Claim 12, 14-16, 17, and 19 recite limitations of the nucleic acid and concentration of the saponin. The eligibility analysis is discussed above as applied to claims 2-3, 5-6, and 8. Therefore, claims 12, 14-16, 17, and 19 are also directed to a judicial exception.
Subject Matter Eligibility Analysis
Claim 22 is directed to a composition (e.g., product) that comprises a nanoparticle comprising (i) a nucleic acid comprising more than 5.5 kbp, (ii) a poly-lysine peptide, and (iii) a saponin being a bisdesmosidic triterpenoid 12, 13-dehyrooleanane-type saponin. Although the composition comprises a natural product, the saponin, the nanoparticle or composition is produced by combining multiple components, nature-based and non-nature-based products (see MPEP 2106.04(c)(I)(A)). Accordingly, the markedly different characteristic analysis is applied to the resultant combination, rather than its component parts. There is no naturally occurring counterpart of a nanoparticle or composition that comprises the natural product saponin. Thus, claim 22 and its dependent claims 23-26, and 29 are not directed to a judicial exception.
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.
Claims 1, 5-6, 8, 10-11, and 14-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Weng (J. Control Release, 2015, 206:75-90; IDS received on 11/28/2023, Cite No. C16).
Regarding claim 1, the claimed method is interpreted as a method comprising providing a saponin, wherein the saponin is a bisdesmosidic triterpenoid 12, 13-dehydrooleanane-type saponin (see Claim Interpretation above). Weng teaches a method of delivering a nucleic acid into a cell in vitro, the method comprising providing a saponin, specifically SO1861 saponin which is a plant derived glycoside from Saponaria officianalis (abstract). Regarding the claim limitation “wherein the saponin is a bisdesmosidic triterpenoid 12, 13-dehydrooleanane-type saponin”, the specification defines this type of saponin as a specific group of triterpenoid saponins, such as SO1861 and GE1741 (pg. 2, line 19). Accordingly, the SO1861 saponin used in the method of Weng meets the instant claim limitation. Weng further teaches wherein the nucleic acid is a plasmid DNA, specifically pEGFP-N3 (pg. 77, col. 1, para. 2)
Regarding claim 5, Weng further teaches wherein the plasmid DNA forms part of a liposome/peptide/DNA mixture (i.e., nanoparticle), which comprises a polylysine peptide, specifically 16 lysine residues (i.e., nanoparticle-forming compound) (pg. 77, col. 1, para. 2).
Regarding claim 6, Weng further teaches the lysine peptide (i.e., nanoparticle-forming compound) and the DNA is in a mass ratio of 4:1 (pg. 77, col. 1, para. 2).
Regarding claim 10, Weng further teaches wherein the cell is a neuro-2A cell (i.e., eukaryotic cell) (pg. 77, col. 2, para. 2).
Regarding claim 11, see claim interpretation above regarding the length of the nucleic acid as intended use of the method. Weng further teaches the method comprises the steps of: (i) providing the nucleic acid (e.g., plasmid pEGFP-N3 was cloned and propagated in bacteria cells, nanoplexes comprising the cationic lipoplex and plasmid DNA was formulated) (pg. 77, col. 1, para. 2); (ii) providing a saponin of recited type (e.g., SO1861 was added) (pg. 77, col. 2, para. 2); (iii) incubating the cell with the nucleic acid in the presence of the saponin (e.g., the transfection medium was replaced by 1 mL normal growth medium + SO1861) (pg. 77, col. 2, para. 2).
Regarding claims 14 and 15, the teachings of Weng regarding the nucleic acid forms part of a nanoparticle, wherein the nanoparticle comprises nanoparticle-forming compounds that is in recited mass ratio with the nucleic acid are discussed above as applied to claims 5 and 6, respectively.
Regarding claim 16, Weng further teaches wherein the saponin concentration is 1.25 or 2.25 µg/mL (pg. 77, col. 2, para. 2).
Claims 1-3, 5-6, 8, 10-12, and 14-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Freie Universitat Berlin (WO 2019/011914 A1; Published Date January 17, 2019; IDS received on 11/28/2023, Cited No. B6) (hereinafter as Freie).
Regarding claims 1-3, the specification defines this type of saponin as a specific group of triterpenoid saponins, such as SO1861 and GE1741 (pg. 2, line 19). Freie teaches a method of delivering a plasmid DNA, particularly pEGFP-N3, into a cell in vitro, wherein the plasmid DNA is delivered in the form of a cationic lipoplex comprising poly-lysine peptide with an integrin receptor targeting amino acid (pg. 4, lines 1-10; pg. 16, line 15). Freie further teaches the method comprises a saponin GE1741 isolated from Gypsophila elegans that exhibits superior effect with respect to intracellular delivery of peptides and nucleic acids than the saponin SO1861, and wherein the saponin’s structure corresponds to instantly recited formula (I) with all the recited limitations for R groups (pg. 2, lines 5-12) or formula (IX) which is identical to instantly recited formula (II) (pg. 8).
Regarding claim 5, Freie further teaches wherein the plasmid DNA is formulated as nanoplexes (i.e., nanoparticle) comprising a poly-lysine peptide (i.e., nanoparticle-forming compound) (pg. 16, lines 20-22).
Regarding claim 6, Freie further teaches the lysine peptide and the DNA is in a mass ratio of 4:1 (pg. 16, line 23).
Regarding claim 10, Freie further teaches wherein the cell is eukaryotic cell (pg. 27, line 15).
Regarding claim 11, see claim interpretation above regarding the length of the nucleic acid as intended use of the method. Freie further teaches the method comprises the steps of: (i) providing the nucleic acid, (ii) providing a saponin of recited type, and (iii) incubating the cell with the nucleic acid in the presence of the saponin (e.g., incubating Neuro2a cells with particles comprising a peptide bound to DNA, a saponin is added to the solution) (pg. 22, lines 25-29).
Regarding claims 12 and 17, the teachings of Freie regarding a saponin of instantly recited formula (I) and (II) are discussed above as applied to claims 2 and 3.
Regarding claims 14 and 15, the teachings of Freie regarding the nucleic acid forms part of a nanoparticle, wherein the nanoparticle comprises nanoparticle-forming compounds that is in recited mass ratio with the nucleic acid are discussed above as applied to claims 5 and 6, respectively.
Regarding claim 16, Freie further teaches wherein the saponin concentration is 1 µg/mL to 25 µg/mL (pg. 30; claim 13).
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 5-6, 8, 10-11, 14-16, 19, 22, 25-26, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Weng (J. Control Release, 2015, 206:75-90; IDS received on 11/28/2023, Cite No. C16) in view of Hart (Gene Therapy, 1997, 4:1225-1230) as evidenced by Promega (pGL2 Luciferase Reporter Vectors, Technical Manual; Revised on March 2007).
Regarding claim 1, Weng teaches a method of delivering a nucleic acid into a cell in vitro, the method comprising providing a saponin, specifically SO1861 saponin which is a plant derived glycoside from Saponaria officianalis (abstract). Regarding the claim limitation “wherein the saponin is a bisdesmosidic triterpenoid 12, 13-dehydrooleanane-type saponin”, the specification defines this type of saponin as a specific group of triterpenoid saponins, such as SO1861 and GE1741 (pg. 2, line 19). Accordingly, the SO1861 saponin used in the method of Weng meets the instant claim limitation. Weng further teaches wherein the nucleic acid is a plasmid DNA, specifically pEGFP-N3 (pg. 77, col. 1, para. 2), which is carried in cationic lipoplexes modified with (i) a 16-fold lysine domain to bind and condense the DNA, and (ii) integrin binding motifs such as arginine-glycine-aspartic acid (RGD) to exploit the integrin-mediated endocytosis for cell entry (paragraph bridging columns on pg. 76). Weng further teaches an ideal sequence of events is a) binding of the lipoplex or nanocarrier containing the DNA to the cell surface, b) endocytosis of the carrier and delivery of the DNA into intracellular compartments such as endosomes and lysosomes, and c) release of the DNA into the cytosol for subsequent transport into the nucleus. Thus, it is critical that DNA escape from the endosomes/lysosomes into the cytosol to avoid degradation by nucleases (pg. 75, col. 2, para. 2). Weng further teaches saponin SO1861 is a transfection multiplier that triggers endo-/lysosomal escape of the DNA into the cytosol and augments delivery of the DNA into target cells (pg. 76, col. 2, para. 3).
However, Weng does not teach wherein the nucleic acid comprises more than 5.5 kilo base-pairs (kbp).
Hart teaches a method of delivering a plasmid DNA into epithelial cells in vitro via integrin-mediated endocytosis, wherein the method comprising cationic lipoplexes modified with (i) a short polylysine tail of 16 lysine residues for binding to and condensing plasmid DNA, and (ii) an integrin binding motif containing the conserved RGD residues (pg. 1225, col. 2, para. 1). Hart further teaches the plasmid DNA is pGL2-control vector containing the firefly luciferase reporter gene regulated by the SV40 promoter (pg. 1229, col. 1, para. 4), which is 6,047 base pairs as evidenced by Promega (pg. 7). Hart further teaches the cationic lipoplexes is a nonviral vector system that offers important advantages over viral vectors, especially “the lack of any strict DNA size packaging limit” (pg. 1225, col. 2, para. 2).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the plasmid DNA of Weng to be at least 5.5 kbp as taught by Hart because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. Each of the substituted component (Weng’s plasmid DNA carrying a fluorescent protein gene to Hart’s plasmid DNA carrying a luciferase gene) and its function (provide detection signal) were known in the art. Further, it would have been obvious to one to have substituted the plasmid DNA of Weng to any plasmid DNA of at least 5.5 kbp encoding desirable sequences as taught by Hart. One would have been motivated to have done so for the advantage of delivering plasmid DNA encoding for therapeutic proteins that are large in size. One would have had a reasonable expectation of success in doing so because Weng teaches that saponin plays an important role in triggering endo-/lysosomal escape of the DNA into the cytosol, whereas the plasmid DNA is condensed via binding with polylysine in the cationic lipoplex. Further, Hart demonstrates cationic lipoplex is capable of condensing plasmid DNA greater than 5.5 kbp and delivering into cells via integrin-mediated endocytosis as this nonviral vector delivery system is not limited by any strict DNA size (pg. 1225, col. 2, para. 2). In addition, successful expression of Hart’s plasmid DNA indicates that the cationic lipoplex successfully escaped cytosolic endosomes/lysosomes.
Regarding claim 5, Weng further teaches wherein the plasmid DNA forms part of a liposome/peptide/DNA mixture (i.e., nanoparticle), which comprises a polylysine peptide, specifically 16 lysine residues (i.e., nanoparticle-forming compound) (pg. 77, col. 1, para. 2).
Regarding claim 6, the teachings of Weng regarding the nanoparticle and nanoparticle-forming compound are discussed above as applied to claim 5. Weng further teaches the lysine peptide (i.e., nanoparticle-forming compound) and the DNA is in a mass ratio of 4:1 (pg. 77, col. 1, para. 2).
Regarding claim 8, the obviousness to substitute the plasmid DNA of Weng to Hart’s plasmid pGL2-control vector is discussed above as applied to claim 1. Hart discloses the plasmid DNA is pGL2-control vector contains the firefly luciferase reporter gene regulated by the SV40 promoter (pg. 1229, col. 1, para. 4), which is 6,047 base pairs as evidenced by Promega (pg. 7).
Regarding claim 10, Weng further teaches wherein the cell is a neuro-2A cell (i.e., eukaryotic cell) (pg. 77, col. 2, para. 2).
Regarding claim 11, the obviousness to modify Weng’s plasmid DNA to Hart’s plasmid is discussed above as applied to claim 1. Weng further teaches the method comprises the steps of:
(i) providing the nucleic acid (e.g., plasmid pEGFP-N3 was cloned and propagated in bacteria cells, nanoplexes comprising the cationic lipoplex and plasmid DNA was formulated) (pg. 77, col. 1, para. 2);
(ii) providing a saponin of recited type (e.g., SO1861 was added) (pg. 77, col. 2, para. 2);
(iii) incubating the cell with the nucleic acid in the presence of the saponin (e.g., the transfection medium was replaced by 1 mL normal growth medium + SO1861) (pg. 77, col. 2, para. 2).
Regarding claims 14 and 15, the teachings of Weng regarding the nucleic acid forms part of a nanoparticle, wherein the nanoparticle comprises nanoparticle-forming compounds that is in recited mass ratio with the nucleic acid are discussed above as applied to claims 5 and 6, respectively.
Regarding claim 16, Weng further teaches wherein the saponin concentration is 1.25 or 2.25 µg/mL (pg. 77, col. 2, para. 2).
Regarding claim 19, the obviousness to substitute the plasmid DNA of Weng to Hart’s plasmid pGL2-control vector is discussed above as applied to claim 1. The additional steps in the method of Weng are discussed above as applied to claim 11. Hart discloses the plasmid DNA is pGL2-control vector contains the firefly luciferase reporter gene regulated by the SV40 promoter (pg. 1229, col. 1, para. 4), which is 6,047 base pairs as evidenced by Promega (pg. 7).
Regarding claim 22, the obviousness to substitute the plasmid DNA of Weng to Hart’s plasmid is discussed above as applied to claim 1. Further, Weng teaches the plasmid DNA was formulated in a liposome/peptide mixture to form nanoplex suspensions (i.e., nanoparticle), followed by dilution with transfection medium and addition of SO1861 to be transfected into cells (pg. 77, col. 2, para. 2). Accordingly, Weng teaches a composition comprising a nanoparticle. Weng further teaches the peptide is a poly-lysine peptide (pg. 77, col. 1, para. 2).
Regarding claim 25, the teachings of Weng’s composition is discussed above as applied to claim 22. Weng teaches wherein the poly-lysine peptide consists of 16 lysine residues (e.g., K16) (pg. 77, col. 1, para. 2).
Regarding claim 26, the teachings of Weng regarding the nucleic acid forms part of a nanoparticle, wherein the nanoparticle comprises nanoparticle-forming compounds that is in recited mass ratio with the nucleic acid are discussed above as applied to claim 6.
Regarding claim 29, the teachings of Weng’s composition is discussed above as applied to claim 22 and the obviousness to substitute the plasmid DNA of Weng to Hart’s plasmid pGL2-control vector is discussed above as applied to claim 1. Hart discloses the plasmid DNA is pGL2-control vector contains the firefly luciferase reporter gene regulated by the SV40 promoter (pg. 1229, col. 1, para. 4), which is 6,047 base pairs as evidenced by Promega (pg. 7).
Claims 2-3, 12, 17, and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Weng (J. Control Release, 2015, 206:75-90; IDS received on 11/28/2023, Cite No. C16) in view of Hart (Gene Therapy, 1997, 4:1225-1230) as evidenced by Promega (pGL2 Luciferase Reporter Vectors, Technical Manual; Revised on March 2007) as applied to claim 1 above, and further in view of Freie Universitat Berlin (WO 2019/011914 A1; Published Date January 17, 2019; IDS received on 11/28/2023, Cited No. B6) (hereinafter as Freie).
Regarding claim 2, the obviousness to modify Weng’s plasmid DNA to Hart’s plasmid DNA comprising more than 5.5 kbp is discussed above as applied to claim 1. Weng teaches the method comprises a saponin SO1861 as a transfection multiplier to trigger endo-/lysosomal escape of the cationic lipoplex carrying the plasmid DNA into the cytosol (pg. 76, col. 2, para. 3). Weng further teaches the core structure of SO1861 consists of a hydrophobic triterpene backbone and branched carbohydrate chains (FIG. 1, reproduced below).
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However, Weng does not teach wherein the saponin is according to instantly recited formula (I).
Freie teaches a method of delivering a plasmid DNA, particularly pEGFP-N3, into a cell in vitro, wherein the plasmid DNA is delivered in the form of a cationic lipoplex comprising poly-lysine peptide with an integrin receptor targeting amino acid (pg. 4, lines 1-10; pg. 16, line 15). Freie further teaches the method comprises a saponin isolated from Gypsophila elegans that exhibits superior effect with respect to intracellular delivery of peptides and nucleic acids than the saponin SO1861, and wherein the saponin’s structure corresponds to instantly recited formula (I) with all the recited limitations for R groups (pg. 2, lines 5-12).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the saponin SO1861 of Weng to the saponin isolated from G. elegans M. Bieb as taught by Freie because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. Each of the substituted component (Weng and Hart’s saponin) and its function (transfection multiplier with properties to trigger endo-/lysosomal escape of the cationic lipoplex carrying the plasmid DNA) were known in the art. One would have been motivated to have done so for the advantage of using a saponin that exhibits “better properties” and “superior effects regarding the delivering of nucleic acids to cells” as taught by Freie (pg. 2, lines 5-12). One would have had a reasonable expectation of success in doing so because Freie demonstrates successful delivering of a plasmid DNA similar in size than Weng’s into a cell in vitro using the saponin of instantly recited structure.
Regarding claim 3, the obviousness to modify Weng’s saponin to a saponin according to formula (I) as taught by Freie is discussed above as applied to claim 2. Freie further teaches wherein the saponin is of formula (IX) which is identical to instantly recited formula (II) (pg. 8).
Regarding claims 12 and 17, the obviousness to modify Weng’s plasmid DNA to Hart’s plasmid DNA comprising more than 5.5 kbp is discussed above as applied to claim 1. Further, the obviousness to modify Weng’s saponin to a saponin according to formula (I) as taught by Freie is discussed above as applied to claim 2. Freie also teaches wherein the saponin is of formula (IX) which is identical to instantly recited formula (II) (pg. 8).
Regarding claims 23 and 24, the teachings of Weng’s composition is discussed above as applied to claim 22. Further, the obviousness to modify Weng’s saponin to a saponin according to formula (I) as taught by Freie is discussed above as applied to claim 2. Freie also teaches wherein the saponin is of formula (IX) which is identical to instantly recited formula (II) (pg. 8).
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.
Claims 1-3, 5-6, 8, 10-12, 14-17, 19, 22-26, and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, and 10 of U.S. Patent No. 11,708,388 in view of Weng (J. Control Release, 2015, 206:75-90; IDS received on 11/28/2023, Cite No. C16) and Hart (Gene Therapy, 1997, 4:1225-1230) as evidenced by Promega (pGL2 Luciferase Reporter Vectors, Technical Manual; Revised on March 2007).
Regarding instant claims 1 and 11, the claims of ‘388 recite a method for delivering a nucleic acid into a cell in vitro, the method comprising incubating the cell in the presence of a saponin according to formula (I) that is identical to instantly recited formula (I) (claims 1 and 6).
However, ‘388 does not recite the size of the nucleic acid.
Weng teaches a method of delivering a nucleic acid into a cell in vitro, the method comprising providing a saponin, specifically SO1861 saponin which is a bisdesmosidic triterpenoid 12, 13-dehydrooleanane-type saponin (abstract). Weng further teaches wherein the nucleic acid is a plasmid DNA, specifically pEGFP-N3 (pg. 77, col. 1, para. 2), which is carried in cationic lipoplexes modified with (i) a 16-fold lysine domain to bind and condense the DNA, and (ii) integrin binding motifs such as arginine-glycine-aspartic acid (RGD) to exploit the integrin-mediated endocytosis for cell entry (paragraph bridging columns on pg. 76). Weng further teaches an ideal sequence of events is a) binding of the lipoplex or nanocarrier containing the DNA to the cell surface, b) endocytosis of the carrier and delivery of the DNA into intracellular compartments such as endosomes and lysosomes, and c) release of the DNA into the cytosol for subsequent transport into the nucleus. Thus, it is critical that DNA escape from the endosomes/lysosomes into the cytosol to avoid degradation by nucleases (pg. 75, col. 2, para. 2). Weng further teaches saponin serves as a transfection multiplier that triggers endo-/lysosomal escape of the DNA into the cytosol and augments delivery of the DNA into target cells (pg. 76, col. 2, para. 3).
However, Weng does not teach wherein the nucleic acid comprises more than 5.5 kilo base-pairs (kbp).
Hart teaches a method of delivering a plasmid DNA into epithelial cells in vitro via integrin-mediated endocytosis, wherein the method comprising cationic lipoplexes modified with (i) a short polylysine tail of 16 lysine residues for binding to and condensing plasmid DNA, and (ii) an integrin binding motif containing the conserved RGD residues (pg. 1225, col. 2, para. 1). Hart further teaches the plasmid DNA is pGL2-control vector containing the firefly luciferase reporter gene regulated by the SV40 promoter (pg. 1229, col. 1, para. 4), which is 6,047 base pairs as evidenced by Promega (pg. 7). Hart further teaches the cationic lipoplexes is a nonviral vector system that offers important advantages over viral vectors, especially “the lack of any strict DNA size packaging limit” (pg. 1225, col. 2, para. 2).
Thus, it would have been obvious to one of ordinary skill in the art to have modified the nucleic acid of ‘388 to be a plasmid DNA as taught by Weng because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. Each of the substituted component and its function were known in the art. Further, it would have been obvious to one to have substituted the plasmid DNA of Weng to any plasmid DNA of at least 5.5 kbp encoding desirable sequences as taught by Hart. One would have been motivated to have done so for the advantage of delivering plasmid DNA encoding for therapeutic proteins that are large in size. One would have had a reasonable expectation of success in doing so because Weng teaches the same type of saponin is capable of triggering endo-/lysosomal escape of the plasmid DNA into the cytosol, while the plasmid DNA is condensed via binding with polylysine in the cationic lipoplex. Further, Hart demonstrates cationic lipoplex is capable of condensing plasmid DNA greater than 5.5 kbp and delivering into cells via integrin-mediated endocytosis as this nonviral vector delivery system is not limited by any strict DNA size (pg. 1225, col. 2, para. 2). In addition, successful expression of Hart’s plasmid DNA indicates that the cationic lipoplex successfully escaped cytosolic endosomes/lysosomes.
Regarding instant claims 2-3, 12, and 17, ‘388 further recites wherein R2 is two acetyl residues, which matches instantly recited formula (II) (claims 1 and 6).
Regarding instant claims 5-6, and 14-15, the obviousness to modify the nucleic acid of ‘388 to a plasmid DNA of at least 5.5 kbp is discussed above as applied to instant claims 1 and 11. Weng further teaches wherein the plasmid DNA forms part of a liposome/peptide/DNA mixture (i.e., nanoparticle), which comprises a polylysine peptide, specifically 16 lysine residues (i.e., nanoparticle-forming compound) (pg. 77, col. 1, para. 2). Weng further teaches the lysine peptide (i.e., nanoparticle-forming compound) and the DNA is in a mass ratio of 4:1 (pg. 77, col. 1, para. 2).
Regarding instant claims 8 and 19, the obviousness to modify the nucleic acid of ‘388 to a plasmid DNA of at least 5.5 kbp is discussed above as applied to instant claims 1 and 11. Hart discloses the plasmid DNA is 6,047 base pairs, as evidenced by Promega (pg. 7).
Regarding instant claim 10, ‘388 recites wherein the cell is a eukaryotic cell (claim 2).
Regarding instant claim 16, Weng further teaches wherein the saponin concentration is 1.25 or 2.25 µg/mL (pg. 77, col. 2, para. 2).
Regarding instant claims 22-24, the obviousness to modify the nucleic acid of ‘388 to a plasmid DNA of at least 5.5 kbp is discussed above as applied to instant claims 1 and 11. ‘388 further recites a composition comprising a liposomal-based transfection reagent and a saponin according to formula (I) which is the same as instantly recited formula (I) (claim 3). ‘388 further recites wherein R2 is two acetyl residues, which matches instantly recited formula (II) (claim 3).
Regarding instant claims 25, 26 and 29, the teachings of Weng and Hart are discussed above as applied to instant claims5-6, and 8.
Claims 1-3, 5-6, 8, 10-12, 14-17, 19, 22-26, and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-11 of U.S. Patent No. 12,454,704 in view of Weng (J. Control Release, 2015, 206:75-90; IDS received on 11/28/2023, Cite No. C16) and Hart (Gene Therapy, 1997, 4:1225-1230) as evidenced by Promega (pGL2 Luciferase Reporter Vectors, Technical Manual; Revised on March 2007).
Regarding instant claims 1-3, 5-6, 8, 10-12, 14-17, 19, 22-26, and 29, the claims of ‘704 recite a method for delivering a nucleic acid into a cell in vitro, the method comprising incubating the cell in the presence of a saponin according to formula (I) that is identical to instantly recited formula (I) (claims 1 and 8). 704 further recites wherein the nucleic acid forms part of a nanoparticle (claim 10), wherein the cell is a eukaryotic cell (claim 9). ‘704 further recites wherein the saponin concentration is in instantly recited range (claim 11). The claims of ‘704 recite a composition comprising at least one liposomal-based transfection reagent and instantly recited saponin (claim 6). All instant limitations are addressed because they are either recited in patented claims or are render obvious by prior art in view of Weng and Hart, as evidenced by Promega to make the same modification based on the obviousness rationale as discussed above as applied to patented claims of U.S. Patent No. 11,708,388.
Claims 1-3, 5-6, 8, 10-12, 14-17, 19, 22-26, and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, and 12-13 of copending Application No. 19/108,042 in view of Weng (J. Control Release, 2015, 206:75-90; IDS received on 11/28/2023, Cite No. C16) and Hart (Gene Therapy, 1997, 4:1225-1230) as evidenced by Promega (pGL2 Luciferase Reporter Vectors, Technical Manual; Revised on March 2007).
Regarding instant claims 1-3, 5-6, 8, 10-12, 14-17, 19, 22-26, and 29, the claims of ‘042 recite a saponin-equipped polyplex (i.e., composition) comprising at least one nucleic acid, instantly recited saponin GE1741, and a polyplexing agent that comprises a polymeric scaffold that is 5 to 25 lysines (claims 1, 8, and 12-13). ‘042 further recites wherein the nucleic acid is a plasmid DNA (claim 17). All instant limitations are addressed because they are either recited in copending claims or are render obvious by prior art in view of Weng and Hart, as evidenced by Promega to make the same modification based on the obviousness rationale as discussed above as applied to patented claims of U.S. Patent No. 11,708,388.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowable.
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/QIWEN SU-TOBON/
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights