DETAILED ACTION
Applicant's election with traverse of Claims o Group II (claims 19-23) with species election of Eudragit E100 in the reply filed on February 03 2026 is acknowledged. The traversal is on the ground(s) Applicants desire to preserve the issue for subsequent petition. This is not found persuasive because as set forth in MPEP 818.01, applicant has not distinctly and specifically pointed out the supposed errors upon which the applicant relies for concluding that the requirement is in error. The requirement is still deemed proper and is therefore made FINAL.
Claims 1, 8-26 are pending in the application. Claims 1, 8-18, and 24-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected group or species, there being no allowable generic or linking claim. Applicant timely traversed the restriction/election requirement in the reply filed on February 3 2026. Accordingly, claims 19-23 are being examined on the merits herein.
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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. This application is a 371 of PCT/EP2021/000047 (04/14/2021) which claims priority to FOR GERMANY 10 2020 002 360.6 (04/18/2020) as reflected in the filing receipt issued April 4 2023.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
No IDS has been filed.
Drawings
The drawings are objected to because Figures 1A, 1B, and 13A- 13B are objected to because “st”, “x”, “y”, “z” are not defined in the specification or the drawings.
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.
Specification
The following guidelines illustrate the preferred layout for the specification of a utility application. These guidelines are suggested for the applicant’s use.
Arrangement of the Specification
As provided in 37 CFR 1.77(b), the specification of a utility application should include the following sections in order. Each of the lettered items should appear in upper case, without underlining or bold type, as a section heading. If no text follows the section heading, the phrase “Not Applicable” should follow the section heading:
(a) TITLE OF THE INVENTION.
(b) CROSS-REFERENCE TO RELATED APPLICATIONS.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT.
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A READ-ONLY OPTICAL DISC, AS A TEXT FILE OR AN XML FILE VIA THE PATENT ELECTRONIC SYSTEM.
(f) STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINT INVENTOR.
(g) BACKGROUND OF THE INVENTION.
(1) Field of the Invention.
(2) Description of Related Art including information disclosed under 37 CFR 1.97 and 1.98.
(h) BRIEF SUMMARY OF THE INVENTION.
(i) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S).
(j) DETAILED DESCRIPTION OF THE INVENTION.
(k) CLAIM OR CLAIMS (commencing on a separate sheet).
(l) ABSTRACT OF THE DISCLOSURE (commencing on a separate sheet).
(m) SEQUENCE LISTING. (See MPEP § 2422.03 and 37 CFR 1.821 - 1.825). A “Sequence Listing” is required on paper if the application discloses a nucleotide or amino acid sequence as defined in 37 CFR 1.821(a) and if the required “Sequence Listing” is not submitted as an electronic document either on read-only optical disc or as a text file via the patent electronic system.
The specification is objected to because 1) there is not a brief description of the drawings and 2) the specification does not clearly define “st”, “x”, “y”, “z” in figures 1A-1B and 13A-13B.
Abstract
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure is objected to because the abstract is longer than 150 words. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claim 19 objected to because of the following informalities: it is dependent on claim 1, which has been withdrawn. 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.
Claim 21 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 21 recites the broad recitation " contains a buffer", and the claim also recites "in particular an acetate buffer, citrate buffer, lactate buffer, phosphate buffer, phosphate-citrate buffer or mixtures of the buffers" which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 19-23 are rejected under 35 U.S.C. 103 as being unpatentable over Jain et al. (Med. Chem. Commun., 2015) in view of Kolbe et al. (EP0987029) and Scott et al. (USPGPUB No. 20030059474).
Applicant Claims
The scope of Claim 19 is interpreted as the following:
A method for the production of nanoparticles comprising the following measures:
production of an aqueous solution of a cationic copolymer containing the recurring structural units of the formulae (Ia) and (Ib)
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692
702
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44
290
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having a pH between 3 and 6.5,
ii) production of an aqueous solution of a nucleic acid,
iii) mixing of the two solutions produced in steps i) and ii) in a selected quantity ratio of nucleic acid and copolymer to give a desired molar N/P ratio of nitrogen atoms in the copolymer to phosphate groups in the nucleic acid between 1 and 200, and iv) agitation of the resulting mixture.
The examiner is interpreting -COOR9, -COO-R10- and -CONH-R10- as directed to an ester or amide:
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200
400
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.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Jain et al. is directed to dimethylaminoethyl methacrylate copolymer-siRNA nanoparticles for silencing a therapeutically relevant gene in macrophages.
Taught is targeting anti-Bfl1/A1 siRNA to macrophages employing nanoparticles of the cationic polymethacrylate polymer Eudragit® E100 (Dimethylaminoethyl Methacrylate Copolymer; DMC). The cationic nanoparticles were hypothesized to overcome the problems associated with intracellular siRNA delivery, such as rapid degradation by nucleases, low intracellular uptake, and limited blood stability. The choice of polymer was supported by literature reports confirming the ability of Eudragit polymers to induce autophagy in macrophages, a primary defense mechanism of the immune system against infectious diseases like tuberculosis, thereby affecting host–bacterial interactions. Also, Eudragit polymers are reportedly more benign to the cells as compared to standard cationic transfection polymers like polyethylenimine (PEI) and poly(L-lysine) (PLL), which are known to possess both in vitro and in vivo toxicity (page 692, left column, 4th paragraph).
DMC belongs to a polymethacrylate class of polymers, which contain tertiary amine groups. As with other polymethacrylates, DMC contains tertiary amino groups, which were hypothesized to yield good transfection of nucleic acids. The importance of tertiary amino groups for imparting a good transfection capability has been already demonstrated in the case of branched PEI (polyethyleneimine) compared to linear PEI, through several transfection experiments in previous publications. However it is important to note that DMC, despite its similarity to PEI with regard to its tertiary amino groups, lacks the severe toxicity associated with the latter, which in turn enhances its applicability for transfecting mammalian cells. In addition, DMC is soluble up to pH 5.5 and swellable and permeable above pH 5.0. The polymer is protonated at this pH and is anticipated to provide a proton sponge effect to the endosome due to its cationic dimethylaminomethyl groups. Due to this effect, the siRNA loaded nanoparticles of Eudragit have been anticipated to enter the cytoplasm after breaking the endosomal compartment (page 692, nanoparticle preparation and characterization). The optimized DMC nanoparticles demonstrated a positive zeta potential which allowed them to efficiently bind to the negatively charged nucleic acids (page 692, last paragraph).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Jain et al. teaches complexes between positively charged DMA and negatively charged nucleic acids and that DMC is protonated at pH 5.0, Jain et al. does not expressly teach a solution of the cationic polymer with a buffer at a pH between 3 and 6.5 and mixing with an aqueous solution of a nucleic acid at a N/P ratio between 1 and 200. However, these deficiencies are cured by Kolbe et al. and Scott et al.
Scott et al. is directed to sustained release microspheres. Example 8 teaches the preparation of bovine serum albumin (negatively charged species) microspheres using Eudragit E100. Taught is dissolving the Eudragit E100 polymer in a 1:1 solution of 0.1M sodium acetate buffer (pH 5.0) and ethanol. The final pH of the solution was pH 6.5. Then an aliquot of a mg/ml solution of BSA was combined with the Eudragit E100 solution. A clear solution was formed. The BSA/polymer solution was incubated in a 70 °C water bath for 30 minutes. A milky white suspension was observed indicating microsphere formation (paragraph 0248-0249). Other example teach vortexing of the mixture (see Example 7, 9). Other macromolecules taught include nucleic acids (paragraph 0178).
Kolbe et al. is directed to the use of a cationic polymer for the preparation of a complex with nucleic acid and related compositions. It is taught that in order to form complexes with nucleic acids, polymers are in cationic form (paragraph 0019). The complexes of the invention, also named polyplexes, may also be characterized by their theoretical charge ratio (+/-), which is the ratio of the positive charges provided by the cationic polymer to the negative charges provided by the nucleic acid in the complex, assuming that all potentially cationic groups are in fact in the cationic state and all potentially anionic groups are in fact in the anionic state. In general, an excess of positive charges on the complex facilitates binding of the complex to the negatively-charged cell surface. To obtain such a ratio, the calculation shall take into account all negative charges in the nucleic acid and shall then adjust the quantity of cationic polymer necessary to obtain the desired theoretical charge ratio indicated above. The quantities and the concentrations of the other ingredients shall be adjusted in function of their respective molar masses and their number of positive charges. The ratio is not specifically limited: quantities are selected so that the ratio between the number of positive charges in the cationic polymer and the number of negative charges in the nucleic acid is between 0.05 and 20, notably between 2.5 and 15, and preferably around 2.5 to 10 (paragraph 0030). The polymer/DNA complexes were obtained as followed: 2 µg of plasmid and the desired amount of cationic polymer [from 10 mM (in term of protonated amine) stock solutions, in water at pH 7.4; 1 N/P equivalent corresponds to the amount of polymer necessary to have one amino group (N) per phosphate group (P) of nucleic acid (330 Da mean MM)] were each diluted in 50 µl 5% glucose solution and vortexed. The two solutions were then mixed and gently vortexed/ Transfection efficiency depends on the polymer/DNA ratio. Optimal expression is obtained with a negative/positive charge ratio between 2.5 and 5 (paragraph 0049).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
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 Jain et al., Scott et al. and Kolbe et al. and utilize an aqueous solution of Eudragit E100 and an aqueous solution of nucleic acids such as siRNA and mix the two solutions together by vortexing followed by incubation in order to obtain complexes of Eudragit E100 and nucleic acids as suggested by Jain et al., Scott et al. and Kolbe et al. All three references teach the use of cationic polymers such as Eudragit E100 with negatively charged nucleic acids to form complexes.
Regarding the claimed methods steps, Scott et al. teaches a complex between Eudragit E100 and a negatively charged species. Specifically taught is dissolving the Eudragit E100 polymer in a 1:1 solution of 0.1M sodium acetate buffer (pH 5.0) and ethanol. The final pH of the solution was pH 6.5. Then an aliquot of a mg/ml solution of BSA was combined with the Eudragit E100 solution. A clear solution was formed. The BSA/polymer solution was incubated in a 70 °C water bath for 30 minutes. Jain et al. teaches DMC is soluble up to pH 5.5 and swellable and permeable above pH 5.0. The polymer is protonated at this pH and is anticipated to provide a proton sponge effect to the endosome due to its cationic dimethylaminomethyl groups. The optimized DMC nanoparticles demonstrated a positive zeta potential which allowed them to efficiently bind to the negatively charged nucleic acids. Kolbe et al. teaches in general, an excess of positive charges on the complex facilitates binding of the complex to the negatively-charged cell surface. To obtain such a ratio, the calculation shall take into account all negative charges in the nucleic acid and shall then adjust the quantity of cationic polymer necessary to obtain the desired theoretical charge ratio indicated above.
Therefore, based on these teachings one skilled in the art would have been motivated to utilize a solution of Eudragit E100 with a pH around 5 as this is the pH the polymer is protonated as taught by Jain et al. One skilled in the art would have been motivated to utilize a sodium acetate buffer as this buffer achieves a pH of 5.0. One skilled in the art would have been motivated to utilize the nucleic acid in a solution with a buffer in order to achieve a final pH in which the quantity of cationic polymer, i.e. the charge density of the cationic polymer, is the highest to achieve complex to the negatively charged nucleic acid as taught by Kolbe et al. Clearly, the prior art suggests optimization of the charge in order to achieve the optimal amount of complexing. Since the charge is achieved based on the pH and pH is achieved by a buffer, one skilled in the art would manipulate the buffer and pH to achieve the optimal charge. As taught by Kolbe et al. the N/P ratio between 2.5 and 5 is optimal.
Regarding method steps iv and v, vortexing reads on agitation. Scott et al. suggests incubation in order to achieve the particles.
Regarding claim 21 an acetate buffer is taught for achieving a pH of 5.0.
Regarding claims 22-23, the prior art clearly suggests the use of a buffer to achieve a desired ph. Scott teaches a final pH of 6.5. As set forth above, one skilled in the art would manipulate the pH in order to have the positively charged polymer and negatively charged nucleic acids at the optimal ratio. Since increasing the pH would result in less protonation of the cationic polymer, one skilled in the art would have been motivated to not have the pH of the nucleic acid be too high such that when mixed with the cationic polymer a complex cannot form.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Jorge et al. is directed to DNA condensation by pH-responsive polymers. Specifically, polyelectrolyte complexes between polycations and DNA are discussed. Manganiello et al. (Biomaterials, 2012) discussed diblock copolymers with tunable pH transitions for gene delivery.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ABIGAIL VANHORN/ Primary Examiner, Art Unit 1636
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