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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/14/26 has been entered.
A decision by the Patent Trial And Appeal Board was rendered on 12/05/25, affirming the rejections in part.
Receipt is acknowledged of Amendments, Remarks and an IDS filed on 05/14/26. Claims 97, 110-113, 119-121, 123-124 and 148-154 have been amended, no claims have been cancelled and new claims 152-160 have been added. Claims 97-104, 106-134 and 148-160 are pending. Claims 119, 123 and 129-134 are withdrawn. Accordingly, claims 97-104, 106-118, 120-122, 124-128 and 148-160 are under examination on the merits.
Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 153 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 153 is rejected for failing to comply with the written description requirement because the Specification does not provide any evidence that Applicants envisioned or tested any formulation comprising a polymethacrylate based polymer having positively charged tertiary amine group that is not poly(dimethylaminoethyl methylacrylate) (pDMAEMA). As evidenced by Van de Wetering et al and Sprouse et al (Attached) the commonly known and used polymethacrylate based polymer having positively charged tertiary amine group is poly(dimethylaminoethyl methylacrylate) (pDMAEMA). Thus, it is not well known in the art and the specification fails to disclose what polymers are within the scope of a “polymethacrylate based polymer having positively charged tertiary amine group that is not poly(dimethylaminoethyl methylacrylate) (pDMAEMA)”.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 152-160 are rejected under 35 U.S.C. 103 as being unpatentable over Almarsson et al (US 20160243259) in combination with Patra et al (Pharmaceutical significance of Eudragit: A review) and as evidenced by Brito et al (US 20110077284).
Almarsson et al ‘259 teach compositions and methods for the preparation, manufacture and therapeutic use of polynucleotides formulations containing amino acids (See Title and Abstract).
Regarding claims 152-155, in part, Almarsson et al teach that the said formulations may be in the form of a dry powder for oral and pulmonary administration (See [0847], [0867] and [0898]). The said polynucleotides may be formulated in a lipid nanoparticle (See [0442] and [0443]). The formulation may be a powder which may be made by the way of lyophilization or spray drying (See 1012). The formulations may contain cholesterol and one or more cationic lipid including 1,2-distearloxy-N,N-dimethylaminopropane (DSDMA), DODMA, DLin-DMA, or 1,2-dilinolenyloxy-3-dimethylaminopropane (DLenDMA) (See [0421]).
Almarsson et al teach polynucleotide formulations containing at least one amino acid wherein the said polynucleotides may take the form or function as modified mRNA molecules which encode at least one polypeptide of interest (See [0008]-[0009], [0060] and [0070]). The polymer may encapsulate the nanospecies or partially encapsulate the nanospecies. The immunogen may be a recombinant protein, a modified RNA and/or the said polynucleotide (See [0486]).
It is disclosed that the said polynucleotides can be formulated using one or more excipients to: (1) increase stability; (2) increase cell transfection; (3) permit the sustained or delayed release; (4) alter the biodistribution (e.g., target the polynucleotide to specific tissues or cell types); (5) increase the translation of encoded protein in vivo; and/or (6) alter the release profile of encoded protein in vivo. The formulations can include, liposomes, lipid nanoparticles, polymers, etc (See [0395], [0403] and [0417]).
Regarding claim 152, it is disclosed that the cationic lipid having formula (I) in US Patent Publication No. US20140039032 may be used in a lipid nanoparticle to deliver nucleic acid molecules (e.g., polynucleotides described herein) (See [0452]).
(The cationic lipid having formula (I) in US Patent Publication No. US20140039032, is
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which is not the cationic lipid excluded in claim 152).
It is disclosed that the polymers which may be used in the formulation and/or delivery of said polynucleotides may be, poly(ethylene)glycol (PEG), poly(N-2-hydroxypropylmethacrylamide) (pHPMA), poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA), etc, (See [0454]). It is disclosed that the lipid nanoparticle engineered to penetrate mucus may comprise a polymeric material (i.e. a polymeric core) including polyacrylates, polymethacrylates, etc (See [0488], [0521]-[0522]).
Regarding claim 155, it is further disclosed that bulking agents are included in lyophilized polynucleotide formulations to yield a “pharmaceutically elegant” cake, stabilizing the lyophilized polynucleotides during long term (e.g. 36 month) storage. (See [0841]).
Regarding claim 156, it is disclosed that a solid lipid nanoparticle (SLN) may be spherical with an average diameter between 10 to 1000 nm. (See [0501] and [0562]).
In one disclosed example, formulations with certain lipidoids, may contain 42% lipidoid, 48% cholesterol and 10% PEG (C14 alkyl chain length) (See [0411]).
Regarding claim 158, it is disclosed that the said lipid nanoparticle may comprise one or more cationic lipids, one or more non-cationic lipids and one or more PEG-modified lipids. The lipid nanoparticle may comprise DLin-KC2-DMA, Cholesterol (CHOL), DOPE, DMGPEG-2000, C12-200, DMGPEG2K, etc (See 0585]).
Regarding claims 152, 153 and 159-160, Almarsson et al teach that in addition to traditional excipients such as any and all solvents, surface active agents, emulsifying agents, preservatives, etc, the formulation may comprise excipients including polymers, lipoplexes, polysorbates (20, 40 and 80), PVA, sorbitans, PEGs, peptides, proteins, and combinations thereof (See [0040], [0395] and claim 20). It is disclosed that the said lipid nanoparticle may comprise poloxamers coating PLGA nanoparticles without forming new chemical entities which are still able to rapidly penetrate human mucus (See [0489]-[0490], [0597] and [0606]).
Almarsson et al do not expressly disclose a polymethacrylate based polymer having a positively charged tertiary amine group that is no pDMAEMA, as stated in claim 153, or the specific amount of the polymethacrylate based polymer as stated in claim 157. These are well known in the art as disclosed by Patra et al. Almarsson et al disclose spray-drying as a method of preparing the said powders. Additionally, as evidenced by Brito et al spray drying is a commonly used method of making dry powders. Brito et al also provide further guidance on polymer coating, the concentration ranges, particle size, etc.
The Specification states that “In some embodiments, the one or more polymers include a polymethacrylate based polymer. In some embodiments, the one or more polymers include Eudragit EPO” (See [0022] of the published Spec).
Patra et al teach The Eudragit® range of polymers, like polymethacrylates are synthetic cationic and anionic polymers of dimethylaminoethyl methacrylates, methacrylic acid, and methacrylic acid esters in varying ratios. Several types are commercially available and may be obtained as the dry powder, and most commonly used as film-coating agents in tablet and capsule dosage forms (See page 33, 2nd col.).
It is disclosed that Eudragit™ EPO is a one agent that is soluble in acetone and alcohol (See Table 1). Eudragit™EPO is a cationic copolymer based on dimethylaminoethyl methacrylate, butylmethacrylate and methyl methacrylate. Chemically they are known as poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate. They are commonly used in film coating, odour and taste masking, moisture and light protection. Eudragit™ EPO is available in the form of powder with a characteristic amine like odor (See Page 34, 1st col.).
Patra et al further disclose that an extensive review on applications of Eudragit EPO revealed that it can be used in formulations such as solid dispersions, orally disintegrating tablets, nanoparticles, nanosuspensions, stabilization of liposomes, superior moisture protection for solid dosage forms, etc; (shown in Table 2) (See Page 35, 1st col.).
Disclosed are formulated nanostructured lipid carrier (NLC) surface modified with EudragitTM RS100 Model with drug genistein (See Page 41, Table 8 and Page 42, 1st para).
The drug containing core pellets were prepared by extrusion spheronisation technique and subsequently coated with 15% (w/w) polymer load of the combination of EudragitTM RL 30 D & EudragitTM RS 30 D (See Page 41, 2nd para).
As Evidenced by:
Brito et al teach a dry powder formulation for delivery to a mammal by inhalation, the formulation comprising particles comprising a lipid, a carrier, and one or more double-stranded siRNA molecules (See abstract and claim 1).
Brito et al disclose the following:
-dry powder formulations may be prepared by spray drying and that active agents can be sprayed dried from an aqueous solution (See [0020] and [0114]-[0116]).
- the active agent in the aqueous phase is combined with an organic solution optionally containing lipids and polymers such as poly(lactide-co-glycolide) or PLGA. This mixture can be spray dried (See [0021]).
-pharmaceutical excipients useful in the said composition include peptides, proteins, non-biological polymers, biological polymers, simple sugars, etc. Sugars include mannitol, monosaccharides such as fructose, maltose, etc, (See [0105], [0109]).
- polymeric excipients/additives include polyethylene glycols, pectin, poly(lactide-co-glycolide) (PLGA), polyethylene imine (PEI), poly-L-lysine (PLL) and other cationic polymers (See [0112]).
-these excipients are generally present in the composition in amounts ranging from about 0.01% to about 95% percent by weight, and more preferably from about 0.5 to about 80% (See [0101]).
-the compositions can have good stability, with respect to both chemical stability and physical stability, i.e., aerosol performance, over time. With respect to chemical stability, the active agent contained in the formulation may degrade by no more than about 10% over a time course of 18 months. With respect to aerosol performance, compositions may exhibit a drop in emitted dose of no more than about 10%, or no more than about 5%, when stored under ambient conditions for a period of three months (See [0144]-[0145]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to combine the teachings of Patra et al with that of Almarsson et al as evidenced by Brito et al to arrive at the claimed invention. It would have been obvious to do so because Almarsson et al teach dry powder formulations comprising nanoparticles comprising mRNA, one or more lipids and one or more polymers for inhalation. Almarsson et al teach that the said mRNA may be encoding a peptide and/or a therapeutically active protein. Almarsson et al also teach that the polymer may be polymethacrylate and that the particles may be spray-dried. Patra et al teach the benefits and characteristics of polymethacrylate polymers in pharmaceutical compositions including Eudragit TM EPO and EudragitTM RS100, EudragitTM RL 30D & EudragitTM RS 30D commonly used as coating particles and tablets. Thus, it would have been obvious to one of ordinary skill in the art to incorporate other polymethacrylate polymers into the lipid nanoparticles of Almarsson et al with a reasonable expectation of success in preparing dry powder formulations comprising lipid nanoparticles comprising one or more lipids, mRNA and one or more polymers including polymethacrylate based polymers.
Thus, it would have been obvious to one of ordinary skill in the art to have looked in the art for specific polymethacrylate polymers for the disclosed nanoparticles of Almarsson et al as taught by Patra et al with a reasonable expectation of success.
Almarsson et al teach that it is known in the art that spray-drying is suitable and commonly used process for making dry powders. This is also taught by Brito et al. Almarsson et al teach a formulation that comprises about 10% polymer, which is PEG. Patra et al also teach a composition wherein the polymethacrylate polymer comprises about 15% of the composition and Brito et al teach that the polymer can be included in the composition in any suitable concentrations such as from 0.5 to 80%. With guidance from Almarsson et al, Patra et and Brito et al, one of ordinary skill in the art is more than capable of optimizing the concentrations as necessary.
The prior art contains all the claimed limitations, with the only difference being the lack of actual combination in a single prior art reference. One of ordinary skill could have combined the elements by known methods, and that in combination, each element performs the same function as it does separately.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Claims 153-160 are rejected under 35 U.S.C. 103 as being unpatentable over Almarsson et al (WO 2016118725 or US 20180085474) (citations from the US document) in combination with Brito et al (US 20110077284) and Van de Wetering et al (Structure-Activity Relationships of Water-Soluble CationicMethacrylate/Methacrylamide Polymers for Nonviral Gene Delivery).
Almarsson et al ‘474’s Application is titled lipid nanoparticle compositions and relates to nanoparticle compositions including an mRNA and a lipid component and methods of using the same (See Title and Abstract).
Almarsson et al disclose the following:
-nanoparticle composition including (i) a lipid component including a phospholipid, a PEG lipid, a structural lipid, and a compound of formula (I) and (ii) an mRNA encoding a polypeptide (See [0006]).
-a PEG lipid of a nanoparticle composition selected from the group consisting of a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, etc, (See [0015]).
- a phospholipid moiety including, phosphatidyl glycerol, 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), or a cationic and/or ionizable lipid such as 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLin-DMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA), etc (See [0017], [0019] and claim 31).
-Lipid component: that component of a nanoparticle composition that includes one or more lipids, which includes one or more cationic/ionizable, PEGylated, structural, or other lipids, such as phospholipids (See [0140]).
-a structural lipid of a nanoparticle composition selected from the group consisting of cholesterol, ergosterol, etc, and preferably cholesterol (See [0016]).
-a nanoparticle composition including a lipid component with a neutral or near neutral charge which may subsequently deliver mRNA to hepatocytes including LDLRs in a targeted manner (See [0113]).
- a pharmaceutical composition suitable for pulmonary administration comprising dry particles which comprise the active ingredient and wherein the particles have a diameter in the range from about 0.5 nm to about 7 nm or from about 1 nm to about 6 nm. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form (See [0095]).
- a nanoparticle composition including one or more mRNAs administered by inhalation; as an oral spray and/or powder, nasal spray, and/or aerosol (See [0118]).
-an mRNA included in a nanoparticle composition which may encode a therapeutic polypeptide and produce the therapeutic polypeptide upon contacting and/or entry into a cell. And, an mRNA included in a nanoparticle composition which may encode a polypeptide that may improve or increase the immunity of a subject (See [0104]).
-Diseases, disorders, and/or conditions characterized by dysfunctional or aberrant protein or polypeptide activity for which said compositions may be administered including genetic diseases (e.g., cystic fibrosis). A specific example of a dysfunctional protein is the missense mutation variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which produce a dysfunctional protein variant of CFTR protein, which causes cystic fibrosis (See [0115]).
-the encapsulation efficiency of an mRNA of a nanoparticle composition being at least 50%, at least 80% and preferably greater than 90% (See [0028], [0076] and [0133]).
-a nanoparticle composition administered by inhalation at a dose of about 0.001 mg/kg to about 10 mg/kg to a mammal (See [0029]).
- nanoparticle compositions which may include any substance useful in pharmaceutical compositions, including diluents, dispersion aids, binders, etc, such as lactose, sucrose, cellulose, mannitol, sorbitol, sodium chloride, powdered sugar, etc, (See [0060] and [0062]).
-a polymer included in and/or used to encapsulate or partially encapsulate a nanoparticle composition, which may be polyamines, polymethacrylates, polyamides, polyesters, sorbitan monostearate, TWEEN® 80, a poloxamer, etc (See [0056], [0058] and [0061]).
-the wt/wt ratio of the lipid component to the mRNA in the nanoparticle composition being from about 5:1 to about 50:1, such as from about 10:1 to about 40:1. The N:P ratio of the nanoparticle composition being from about 2:1 to about 8:1, from about 5.0:1, about 5.5:1, about 7.0:1 (See [0023]-[0024]).
Almarsson et al lack a specific disclosure on the powder being spray-dried or the amount of the polymer in the composition or the specific polymethacrylate based polymer. These are well known in the art as taught by Brito et al and van de Wetering et al.
Brito et al’s teachings are delineated above and incorporated herein.
Van de Wetering et al teach that almost all studied cationic methacrylate/methacrylamide polymers were able to condense the structure of plasmid DNA, yielding polymer/plasmid complexes (polyplexes) with a size of 0.1−0.3 μm and a slightly positive ζ-potential, which can be taken up by cells, e.g., via endocytosis. However, the transfection efficiency and the cytotoxicity of the polymers differed widely: the highest transfection efficiency and cytotoxicity were observed for poly[2-(dimethylamino)ethyl methacrylate], p(DMAEMA). It is concluded that “We therefore hypothesized that the superior transfection efficiency of p(DMAEMA) containing polyplexes can be ascribed to an intrinsic property of p(DMAEMA) to destabilize endosomes combined with an easy dissociation of the polyplex once present in the cytosol and/or the nucleus” (See abstract).
Van de Wetering et al disclose that “Figure 1 Chemical structure of (a) poly(2-(dimethylamino)ethyl methacrylate), p(DMAEMA); (b) poly(3-(dimethylamino)propyl methacrylate), p(DMAPMA); (c) poly(2-(dimethylamino)ethyl methacrylamide), p(DMAEMAm); (d) poly(3-(dimethylamino)propyl methacrylamide), p(DMAPMAm); (e) poly(2-(trimethylamino)ethyl methacrylate chloride), p(TMAEMA); (f) poly(2-(diethylamino)ethyl methacrylate), p(DEAEMA); and (g) poly(2-(dimethylamino)ethyl acrylate), p(DMAEA)” (See Page 590, 1st Col.).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to combine the teachings of Brito et al and van de Wetering et al with that of Almarsson et al to arrive at the claimed invention. It would have been obvious to do so because Almarsson et al teach dry powder formulations comprising nanoparticles comprising mRNA, one or more lipids and one or more polymers for inhalation. Almarsson et al teach that the said mRNA may be encoding a peptide and/or a therapeutically active protein such as CFTR. Almarsson et al also teach that the polymer may be polymethacrylate. While Almarsson et al do not expressly teach that the particles are spray-dried, it is known in the art that spray-drying is suitable and commonly used process for making dry powders. This is taught by Brito et al. Brito et al also teach that the polymer can be included in the composition is any suitable concentrations such as from 0.5 to 80%. With guidance from Brito et al, one of ordinary skill in the art is more than capable of optimizing the concentrations as necessary. Furthermore, van de Watering et al teach that polymethacrylate polymers including those with a positively charged tertiary amine are suitable for nanoparticles of lipids and DNA.
It would have been obvious to one of ordinary skill in the art to have looked in the art for specific polymethacrylate polymers for the disclosed nanoparticles of Almarsson et al as taught by van de Wetering et al with a reasonable expectation of success.
The prior art contains all the claimed limitations, with the only difference being the lack of actual combination in a single prior art reference. One of ordinary skill could have combined the elements by known methods, and that in combination, each element performs the same function as it does separately.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments
Applicant’s arguments with respect to claims 97-104, 105-118, 121, 122, 124-128 and 148-151 have been considered but are moot because the rejections have been withdrawn in light of the amendments.
Applicant made no comment or argument regarding the newly added claims 152-160, which are rejected as recited above.
Claims 97-104, 105-118, 121, 122, 124-128 and 148-151 are allowed.
Claims 152-160 are rejected and claims 119, 123 and 129-134 are withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mina Haghighatian whose telephone number is (571)272-0615. The examiner can normally be reached M-F, 7-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sue X. Liu can be reached on 571-272-5539. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616
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