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 .
Status of Claims
Claims 1-2, 4-10, 12-13, 16, 18, 20, 22, 24-26, 28, and 31 are pending.
Priority
Claims 1-2, 4-10, 12-13, 16, 18, 20, 22, 24-26, 28, and 31 are a 371 of PCT/US 2022/016580 filed on February 16, 2022, which has priority to PRO 63/149,985 filed on February 16, 2021.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on May 28, 2024, and on November 1, 2024, were filed before the mailing of the First Office Action on February 21, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Drawings
The drawings are objected to because for the following reasons:
Fig. 1 parts A, B, C, D, E, and F are not legible.
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 disclosure is objected to because of the following informalities: The specification contains “vertexing” where it appears on pg. 2 Line 27, pg. 9 Line 15, and pg. 20 Line 17. The term appears to be a typographical error and that the intended term is “vortexing” which is a well-known laboratory mixing technique. For examination purposes, the term has been interpreted as “vortexing”.
Appropriate correction is required.
Claim Objections
Claim 1 is objected for the following reasons:
Claim 1 recites “reducing a polarity of the first solution”. It should read as “reducing [[a]] the polarity of the first solution”.
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 7 and10 is 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.
Claim 7 recites “adding a varying concentration of the water-miscible organic solvent…to control the particle-size growth”. “adding a varying concentration” as written is ambiguous. The specification does not provide sufficient guidance as to what concentrations are encompassed or how variation correlates to particle size. Because of this, a person of ordinary skill would not be able to ascertain the metes and bounds of the claimed subject matter.
Claim 10 recites “or by manual pipette mixing and vertexing method”. “vertexing” is unclear. The term “vertexing” is not a recognized term of art, and although stated in the specification, that creates ambiguity as to the scope making it difficult for a person of ordinary skill to ascertain what process steps would work for preparing the nucleic acid/lipid nanoparticle composition.
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.
Claims 1-2, 4-10, 12-13, 16, 18, 20, 22, 24-26, 28, and 31are rejected under 35 U.S.C. §103 as being unpatentable over Smith et al. [WO 2017 218704 A1], in view of Liu et al. [Understanding the solvent molecules induced spontaneous growth of uncapped tellurium nanoparticles, Nature, 2016], in view of Hoshyar et al. [The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction, Nanomedicine, 2016], in view of Hong et al. [Effects of mono- and di-valent metal cations on the morphology of lipid vesicles, Chemistry and Physics of Lipids, 2018], in view of Anderson et al. [Static Dielectric constants for liquid water from 300 K to 350 K at pressures to 13 MPa using a new radio-frequency resonator, Journal of Chemical Engineering Data, 2000], in view of Tang [Flash nanocomplexation (FNC) as a scalable and tunable platform for anti-cancer drug/gene delivery, Johns Hopkins University Master of Science Biotechnology thesis, 2018], in view of Mauro et al. [US Patent No 7,456,273], in view of Wikipedia [HEK293 Cells, Wayback Machine, Jan. 2021].
Regarding claim 1, Smith et al. teaches a method for preparing a plurality of nucleic acid/lipid nanoparticles having an average size ranging from 210 nm to 1200 nm and a polydispersity index from 0.05 to 0.5, the method comprising [¶ 00101, 00420, 00421]: a) preparing or providing a first solution comprising a plurality of nucleic acid/lipid nanoparticles having a first particle size ranging from 20 to 200 nm [¶ 00420].
However, Smith et al. does not teach reducing the first solution from a dielectric constant of about 80 to about 45 to 60 in order to induce particle-size growth where a second solution also forms a second plurality size of nucleic acid/lipid nanoparticles where the size is in the range between 210 nm and 1200 nm.
Smith et al also does not teach reversing the polarity of the second solution with a dielectric constant of about 65 to 80 in order to halt growth of the plurality of nucleic acid/lipid nanoparticles.
With respect to the first solution being reduced in polarity where the dielectric constant is reduced from about 80 to 45 to 60, Lui et al. teaches that nanoparticle size and aggregation behavior are strongly influenced by the dielectric constant of the surrounding medium [Abstract]. Lui et al. goes on to explain that reducing the dielectric constant of a solution decreases electrostatic stabilization forces and increases interparticle attraction. This leads to promotion of nanoparticle growth and/or aggregation [Distinct growth kinetics of uncapped Te NPs in different solvents ¶ 4 & 5]. Lui et al. further discloses that the dielectric constant of aqueous systems can be predictably reduced by introducing organic solvents, e.g. ethanol, in order to lower polarity and results in lowering the overall polarity of the medium/solution [Results ¶ 6].
With respect to the different nanoparticle size, Hoshyar et al. teaches that nanoparticle size is a result-effective variable that can significantly impact in vivo pharmacokinetics, biodistribution, cellular uptake, and biological interaction [Abstract]. Hoshyar et al. further discloses that varying nanoparticle size is a recognized design parameter used for modulating biological behavior and targeting characteristics [Blood circulation half-life], and that determining particle size is a routine objective in nanoparticle formulation [Biodistribution ¶ 2].
It would have been prima facie obvious to a person of ordinary skill in the art to modify the systems and methods of Smith et al. where lipid nanoparticles with nucleic acids were used for delivery of prophylactics and/or polypeptides with the combined teachings of both Liu et al. and Hoshyar et al. where Liu et al. discussed the role of reducing the dielectric constant/polarity in order to facilitate nanoparticle growth/aggregation and Hoshyar et al. taught that nanoparticle size is known parameter that helps to determine biodistribution. Based on this, there is a reasonable expectation of success that a person of ordinary skill using the teachings of Smith et al. combined with the teachings of Liu et al. and Hoshyar et al. to modify a solvent environment of a nanoparticle containing solution by reducing the polarity and dielectric constant in order to induce nanoparticle growth and/or aggregation leading to particles of different size where first and second solutions containing different sized nanoparticles could be obtained via routine dielectric constant adjustment.
For claim 2 where the first nanoparticle size has a range between about 40 nm to about 120 nm, Smith et al. discloses nanoparticle sizes ranging from about 40 nm to 150 nm [¶ 00420].
For claim 4 where the second particle size is selected from the group consisting of about 210 nm to 1200 nm, Smith et al. discloses particle sizes up to 500 nm [¶ 00217]. Additionally, as stated above, Lui et al. and Hoshyar et al. teach that obtaining different nanoparticle size based on the dielectric constant can be obtained through modifications to a solution, and given that Hoshyar teaches that nanoparticle size directly affects biodistribution and cellular interactions, a person of ordinary skill in the art would recognize varying particle size would optimize delivery and targeting based on biological need.
For claim 5 where the first solution further contains one or more multivalent cations, Hong et al., discussing effects of mono- and di-valent metal cations on lipid vesicles, teaches that binding of divalent cations, i.e. Ca2+ or Mg2+, can induce aggregation and fusion of lipid vesicles by increasing the net surface potential (zeta potential). Therefore, this demonstrates that multivalent cations in a lipid containing solution can influence colloidal behavior [Introduction ¶ 4 and 2].
For claim 6 where the polarity of the first solution is reduced by adding a water-miscible organic solvent, Liu et al. discloses the addition of ethanol [Fig. 5].
For claim 7 where the water-miscible organic solvent is added to the first solution to control particle size, Liu et al. discloses that the solvent with the lower dielectric constant and lower polarity allow for repulsive forces to diminish thereby facilitating more aggregation, i.e. growth [Abstact, Distinct growth kinetics of uncapped Te NPs in different solvents ¶ 5]. Based on this, there is a reasonable expectation of success that a person of ordinary skill would recognize the teachings of Liu et al. combined with the teachings of both Smith et al. and Hong et al. that a reduced dielectric constant, e.g. adding a water miscible organic solvent to an aqeous solution like water which has a dielectric constant of about 80, would lead to a lower dielectric constant thereby facilitating expanded growth and/or aggregation for a lipid nanoparticle solution.
For claim 8 where the water-miscible organic solution can be ethanol, methanol, butanol, etc., Liu et al. discloses the use of both methanol and ethanol [Fig. 5, Introduction ¶ 4].
For claim 9 where the polarity of the second solution is reversed by diluting with water, Anderson et al., discussing the dielectric properties of water, discloses that water has a dielectric constant of about 80 near room temperature [Results for Water ¶ 1]. Given this, a person of ordinary skill would have understood from the teachings in Anderson et al. that water provides a high polarity environment compared to other organic solvents, e.g. ethanol, and that increasing the water content of the second solution would raise the dielectric constant further inhibiting lipid nanoparticle growth resulting in an increased dielectric constant leading to stabilizing colloidal nanoparticles.
For claim 10 where the solution is prepared by using continuous flash nanocomplexation or manual pipette mixing and vortex method, Tang, discussing flash nanocomplexation as a scalable and tunable platform for forming nanoparticles, discloses the use of flash nanocomplexation (FNC) as a viable method for preparing nanoparticle solutions [Abstract].
For claim 12 where the nucleic acid concentration is determined to be about 100µg/mL, determining and adjusting a nucleic acid concentration to a desired level, such as 100µg/mL, is routine in the art using standard techniques and can be easily adjusted by a person of ordinary skill in the art through routine dilution or concentrating the solution using standard methods.
For claim 13 where the nucleic acid is selected from a group consisting of genomic DNA, plasmid DNA, mRNA, miRNA, shRNA, and siRNA, Smith et al. discloses that plasmid DNA, siRNA, shRNA, miRNA, mRNA, and others can be combined with a pharmaceutically acceptable salt [¶ 0005, 00228, 00104].
For claim 16 where the lipid is selected from the group that includes cationic lipids and ionizable lipids, Smith et al. discloses the use of both cationic and ionizable lipids [¶ 00191].
For claim 18 where the cationic lipid is used, Smith et al. discloses that lipids may be zwitterionic, or other known synthetic cationic lipids. Additionally, the cationic lipids listed are members of well-known class of synthetic cationic lipids and that choosing any particular member, e.g. DODMA or DOEPC, from the class for nucleic acid delivery would be considered routine optimization. This is because cationic lipids such as DODMA, DOTMA, DOTAP, and DOEPC are well known in the art for forming complexes with nucleic acids and for preparing lipid nanoparticles. Because of this, it would be prima facie obvious to a person of ordinary skill in the art to select any of lipid from these classes of lipids for inclusion in a nucleic acid/lipid nanoparticle since the cationic nature and ability to encapsulate nucleic acids are well documented.
For claim 20 where a nucleic acid/lipid nanoparticle is prepared by the method of claim 1, Smith et al. teaches a method for preparing a plurality of nucleic acid/lipid nanoparticles having an average size ranging from 210 nm to 1200 nm and a polydispersity index from 0.05 to 0., the method comprising [¶ 00101, 00420, 00421]: a) preparing or providing a first solution comprising a plurality of nucleic acid/lipid nanoparticles having a first particle size ranging from 20 to 200 nm [¶ 00420].
However, Smith et al. does not teach reducing the first solution from a dielectric constant of about 80 to about 45 to 60 in order to induce particle-size growth where a second solution also forms a second plurality size of nucleic acid/lipid nanoparticles where the size is in the range between 210 nm and 1200 nm.
Smith et al also does not teach reversing the polarity of the second solution with a dielectric constant of about 65 to 80 in order to halt growth of the plurality of nucleic acid/lipid nanoparticles.
With respect to the first solution being reduced in polarity where the dielectric constant is reduced from about 80 to 45 to 60, Lui et al. teaches that nanoparticle size and aggregation behavior are strongly influenced by the dielectric constant of the surrounding medium [Abstract]. Lui et al. goes on to explain that reducing the dielectric constant of a solution decreases ¶electrostatic stabilization forces and increases interparticle attraction. This leads to promotion of nanoparticle growth and/or aggregation [Distinct growth kinetics of uncapped Te NPs in different solvents ¶ 4 & 5]. Lui et al. further discloses that the dielectric constant of aqueous systems can be predictably reduced by introducing organic solvents, e.g. ethanol, in order to lower polarity and results in lowering the overall polarity of the medium/solution [Results ¶ 6].
With respect to the different nanoparticle size, Hoshyar et al. teaches that nanoparticle size is a result-effective variable that can significantly impact in vivo pharmacokinetics, biodistribution, cellular uptake, and biological interaction [Abstract]. Hoshyar et al. further discloses that varying nanoparticle size is a recognized design parameter used for modulating biological behavior and targeting characteristics [Blood circulation half-life], and that determining particle size is a routine objective in nanoparticle formulation [Biodistribution ¶ 2].
It would have been prima facie obvious to a person of ordinary skill in the art to modify the systems and methods of Smith et al. where lipid nanoparticles with nucleic acids were used for delivery of prophylactics and/or polypeptides with the combined teachings of both Liu et al. and Hoshyar et al. where Liu et al. discussed the role of reducing the dielectric constant/polarity in order to facilitate nanoparticle growth/aggregation and Hoshyar et al. taught that nanoparticle size is known parameter that helps to determine biodistribution. Based on this, there is a reasonable expectation of success that a person of ordinary skill using the teachings of Smith et al. combined with the teachings of Liu et al. and Hoshyar et al. to modify a solvent environment of a nanoparticle containing solution by reducing the polarity and dielectric constant in order to induce nanoparticle growth and/or aggregation leading to particles of different size where first and second solutions containing different sized nanoparticles could be obtained via routine dielectric constant adjustment resulting in the nucleic acid/lipid nanoparticle of claim 1.
For claim 22 for part a) that involves in vitro transfection for viral vector production where cells are transfected with the nucleic acid/lipid nanoparticle, Smith et al., referencing a vector [¶ 00324], incorporates US Patent No. 7, 456,273 disclosing the use of a viral vectors containing with a formulation, e.g. oligonucleotides and/or nucleic acid/lipid nanoparticles, where the vector is introduced into a cell [Para starting with “A method of the invention also can be performed by cloning a library”].
With respect to Claim 22 parts b) and part c), Smith et al. discloses contacting cells with external entities both in vivo and ex vivo with a lipid nanoparticle [¶ 00202].
With respect to claim 22 part d), Smith et al. discloses administering the lipid nanoparticle formulation [¶ 0082] in vivo using subcutaneous or intramuscular injection [¶ 00436], target tissues such as kidney, lung, spleen, and/or vascular endothelium in vessels where injections can intra-coronary, intra-femoral, or intratumoral [¶ 00235].
With respect to claim 22 part e), Smith et al. discloses liquid dosage forms for oral and parenteral administration [¶ 00433].
Here it is prima facie obvious prior to the filing of the claimed invention that a person of ordinary skill would modify the methods and systems of Smith et al. and Smith et al.’s incorporation of US Patent No. 7,456,273 where it discloses contacting cells both ex vivo and in vivo either through transfection into a viral vector or by contacting a cell. Additionally, it is also prima facie obvious to a person of ordinary skill to select injection sites, whether direct or indirect, e.g. administering into a target tissue or systemic administration, constitutes routine optimization well within the level of an ordinary skill in the art. Decisions determining injection site and method are commonly guided by such things as biodistribution, target accessibility, and therapeutic objective.
For claim 24 where the dosing the plurality of nucleic acid/lipid nanoparticles to a monolayer culture or a suspension culture, Smith et al., referencing the Mauro et al. patent, discloses the use of a petri dish [¶ 00208]. Furthermore, Mauro et al. specifically states the use of a monolayer culture where the mixture was used to infect Neuro2A cells in a monolayer culture [Para starting with “Three 100 mm dishes of COS 1 cells”].
For claims 25, 26, and 28 where the one or more cells are HEK293 cells, Wikipedia discloses that HEK293 cells in general are widely used for their reliable growth and propensity for transfection [Human embryonic kidney 293 cells]. Wikipedia further states these cells are also used in the biotechnology industry for production of therapeutic proteins and viruses for gene therapy [Id.]. Wikipedia then goes on to list each variant listed in claim 26 [Variants].
For claim 31 that comprises transfecting hepatocytes, progenitor cells, pluripotent stem cells, T cells, NK cells, and tumor cells, Smith et al. discloses that targeted cells for transfection include hepatocytes, stem cells, T cells, tumor cells, as well as other cell types ¶ 00501, 00502].
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims allowed.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638