DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communication filed 12-17-26.
Claims 1-11, 13-15 are pending in the instant application.
Election/Restrictions
Claims 11, 13-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12-17-26.
Applicant’s election without traverse of Group I, claims 1-10, in the reply filed on 12-17-26 is acknowledged.
Claim Objections
Claims 1-10 are objected to because of the following informalities: The claims begin with the word “Method.” The claims should recite – A method – in claim 1 and – the method – in claims 2-10.
Arbitrary punctuation appears in the claims. See, e.g., claim 5, line 1, which recites an unnecessary comma “characterized in that, lactose”; claim 7, line 2, recites “drying step, in which”; claim 8, line 1, recites “characterized in that, the additional.”
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 1-10 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.
Regarding claims 1-10, the phrases “preferably”, " in particular”, “especially”, “characterized in that”, “in the vincinity”, render the claims indefinite because it is unclear whether the limitations following the phrases are part of the claimed invention. See MPEP § 2173.05(d).
Claim 1 (lines 7 and 11) and claim 6 (line 3) contain the trademark/trade names “Onpattro”, “Buchi B-290” and “Pumpsil” respectively. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a formulation, a spray drying apparatus and tubing material and, accordingly, the identification/description is indefinite.
35 U.S.C. 112(f)
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
CLAIM INTERPRETATION
The terms “accumulation means” and “temperature controlling means” have been adequately described in the specification at pages 15, 27, 29, 34, 35, Figures 6-8, 15, and Table 3.
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.
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.
Claim(s) 1-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al (Molecular Pharmaceutics, Vol. 13, pages 134-143 (2016)), Schulze et al (Nucleic Acid Based Therapies, Small, Vol. 14, 1701870, pages 1-8 (2018)), Xie et al (J. of Controlled Release, Vol. 229, pages 120-129 (2016)), Okuda et al (J. Controlled Release, Vol. 279, pages 99-113 (2018)), the combination in view of Wu et al (International J. Pharmaceutics, Vol. 566, pages 33-39 (2019)) and Cal et al, J. Pharmaceutical Sciences, Vol. 99, No. 2, pages 575-585 (2010)), the combination further in view of Sung et al (US 2016/0120855).
The claims are drawn to methods for producing high yield nano-in-micro (NIM) encapsulated bioactive siRNA dry powder comprising :providing an aqueous suspension comprising polyplexes formed from a polyamine optionally comprising polyethyleneimine-graft-polycaprolactone-block-polyethylene glycol (PEI-g-PCL-b-PEG or PPP) and/or a bioconjugate of polyethylenimine optionally comprising Transferrin conjugated polyethylenimine (Tf-PEI), and/or polyspermine is used as polyamine, and/or polyamide and/or polyester and siRNA, wherein the polyplexes are provided with and/or encapsulated into water soluble excipients optionally comprising highly purified water and/or sugar alcohol and/or sugar, or providing an aqueous suspension comprising lipid nanoparticles formed from an ionizable cationic lipid, a helper lipid, a pegylated lipid, cholesterol and siRNA, wherein the lipid nanoparticles are provided with and/or encapsulated into water soluble excipients optionally comprising highly purified water and/or sugar alcohol and/or sugar, and the mass ratio of siRNA to a sugar and/or sugar alcohol is between 0.001% and 0.02% for aqueous suspension comprising lipid nanoparticles and optionally lactose is used as sugar or used with a sugar alcohol for an aqueous suspension comprising lipid nanoparticles,
The claims are further drawn to spray drying the aqueous suspension using a spray drying apparatus optionally comprising Buchi B-290 by feeding the aqueous suspension to a spray drying atomizing nozzle and subjecting the atomized droplets to a heated gas stream of a carrier gas optionally comprising dried and cleaned air through a multicomponent atomizing nozzle for the suspension and an atomizing gas; collecting a spray dried powder in an accumulation means of the spray drying apparatus characterized with a temperature controlling means to be limited to an upper threshold temperature which is equal to or below a melting temperature of the respective naked siRNA, or which upper threshold temperature is set to 90oC or 80oC for aqueous suspension comprising polyplexes, and/or the upper threshold temperature is 63oC for aqueous suspensions comprising lipid nanoparticles, which aqueous suspension is fed to the nozzle and optionally comprising an additional drying step in which a carrier gas is fed through the spray drying apparatus and the atomizing nozzle without being mixed with aqueous suspension, and which spray dried powder has already been transferred to the accumulation means, which spray dry nozzle comprises an upper threshold temperature of 90°C for aqueous suspension comprising polyplexes and/or 63°C for aqueous suspension comprising lipid nanoparticles, and which additional drying step is carried out until a residual moisture of the spray dried powder of less than 3% or 2% is reached.
Liu et al (Molecular Pharmaceutics, Vol. 13, pages 134-143 (2016)) teach tumor targeted siRNA delivery using polyethylenimine polycaprolactone poly-ethylene glycol folate (PEI_PCL-PEG-Fol) (See esp. the Abstract and Introduction on page 134). Liu teaches the strategy of using copolymers of PEI-PCL-PEG-Fol, where PEI acts as a polycation to condense nucleic acids, hydrophobic PCL provides biodegradability and/or encapsulation of drugs, hydrophilic PEG offers excellent biocompatibility and prolonged circulation, and folate targeted Folate receptor positive tumor cells. PEI-PCL-PEG based siRNA delivery systems have been shown to have enhanced in vivo circulation times and improved cytoplasmatic delivery of siRNA (see Fig. 1 and text on page 135, text in right hand col. on page 137, text on page 138).
Schulze et al (Nucleic Acid Based Therapies, Small, Vol. 14, 1701870, pages 1-8 (2018)) teach spray dried nanoparticles in microparticle delivery systems for gene delivery comprising polyethylenimine (PEI) based nanoparticles in a poly(vinyl alcohol) matrix. Schulze teaches that PEI based polyplexes and their combination with liposomes and lipopolyplexes are efficient DNA and siRNA delivery devices, which lipopolyplexes include poly vinyl alcohol microparticles. Schulze teaches the introduction of compressed air to form fine dust readily inhaled by mice (see esp. abstract on page 1, conclusion, experimental section on pages 6-7).
Xie et al (J. of Controlled Release, Vol. 229, pages 120-129 (2016)) teach polyplexes prepared with PEI, and Tf-PEI siRNA polyplexes which combinations yielded different and optimal amine to phosphate ratios (see Fig. 1, right column of page 123). Tf-PEI condensed siRNA to 80% at N/P 5 and complete condensation at N/P 7.5. The sizes of the polyplexes ranged from 72-197 nm, polydispersity indices ranged from 0.24 to 0.39. PEI formed larger particles of 1133 nm to 1595 nm in size. (see esp. §§ 2.2-2.4 on page 121, 3.2 and 3.3 on page 123, 3.4 on page 124). SiRNA condensation efficiency of PEI and Tf-PEI was measured at different N/P ratios (see Fig. 2 on page 124).
Okuda et al (J. Controlled Release, Vol. 279, pages 99-113 (2018)) teach novel dry small interfering RNA (siRNA) powder for inhalation, and containing polyethyleneimine (PEI) as a delivery vector, and produced by spray freeze drying. Integrity of the siRNA was maintained when the reconstituted siRNA/PEI complex was dissolved. The inhalable dry siRNA/PEI powders provide effective pulmonary gene silencing in the lungs and spray freeze drying is appropriately applied to producing the siRNA/PEI powders (see the Abstract and introduction on pages 99-100, Table 1 on page 101, Section 2.11 on page 102).
The primary references do not teach conditions of atomizing, controlling temperature or conditions of drying the polyplexes comprising siRNA, nor do they teach the spray drying apparatus Buchi B-290.
Wu et al (International J. Pharmaceutics, Vol. 566, pages 33-39 (2019)) provide an evaluation of thermal and shear stresses in the spray drying process on the stability of siRNA dry powders. The solid state properties, chemical integrity and bioactivity of spray dried siRNA powder for inhalation (see the abstract on page 32). Wu teaches that chemical integrity and biological activity of siRNA can be preserved during spray drying by using a careful selection of process parameters and optimal excipients. Wu teaches spray drying with the proper selection of carbohydrate excipients and mild processing conditions, including relatively low inlet air temperature and low atomization gas flow rate, helps preserve the physicochemical properties and biological activity of siRNA. Drying temperatures and atomizing gas flow rates also are critical for determining particulate properties, including size, morphology, and residual moisture. Relatively high process air temperature and high atomizing gas flow rates are often needed to optimize aerosol performance. siRNA in combination with mannitol was investigated (see Introduction on pages 32-33; Table 1 on page 34; Section 3.1 on pages 34-35).
Cal et al, J. Pharmaceutical Sciences, Vol. 99, No. 2, pages 575-585 (2010)) teach hardware and process parameters affecting the properties of spray drying. Cal teaches atomization devices, drying chambers, droplet contact systems, auxiliary devices and collection of the dried product. Cal teaches spray drying phases, various forms of atomizers, and a variety of nozzles and dryers (see entire document, esp. the Abstract on page 575, Table 1 on page 579, Figure 4 on page 581Table 2 on page 585).
Sung et al (US 2016/0120855) teach the routine use of the spray drying apparatus Buchi B-290 for generating dry particles comprising siRNA (para 0061, 0138, 0202, 0207, 0223).
It would have been obvious to produce high yield polyplexes comprising encapsulated bioactive siRNA in dry powder using the recited steps because the methods of generating siRNA dry powder from using a spray drying apparatus had been taught previously by Liu, Schulze, Xie and Okuda. These authors also taught the components of the aqueous suspensions. The conditions of spray drying, the temperature optimization and the effects of thermal and shear stresses in the spray drying process had been taught by Wu, and the hardware and process parameters of spray drying techniques were also previously taught by Cal. The instantly claimed method of generating spray dried siRNA compositions would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention, reasonably relying on the combined teachings of Liu, Schulze, Xie and Okuda, Wu , Cal and Sung. And one of ordinary skill in the art would have reasonably expected the method claimed would produce stable, bioactive siRNA encompassed in dry powder formulation for in vivo delivery.
Conclusion
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
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Jane Zara
2-18-26
/JANE J ZARA/Primary Examiner, Art Unit 1637