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 .
Receipt is acknowledged of Amendments, Remarks and an IDS filed on 08/11/26. Claims 1, 13-23 and 25-27 have been amended, no new claims have been added, and no claims have been canceled. Claims 1-29 are pending. Claims 21-29 are withdrawn from examination based on the Election of 08/11/26. Accordingly, claims 1-20 are under examination on the merits.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-23 in the reply filed on 08/11/26 is acknowledged.
Applicant has also elected the below Species:
The compound of 4A-SC7,
The core formula of
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’
The phospholipid, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE),
Cholesterol,
a PEG modified dimyristoyl-sn-glycerol.
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 1-17 are rejected under 35 U.S.C. 103 as being unpatentable over Lockhart et al (US 20190117796) in combination with Karve et al (WO 2020106946), Siegwart et al (US 20170121279) and Angel et al (WO 2016131052).
Lockhart et al teach polynucleotides encoding peptides, proteins, enzymes, and functional fragments thereof which can be effectively delivered to an organ, such as the lung, and expressed within cells of the organ. Disclosed are polyribonucleotides that can be used to treat a disease or condition associated with cilia maintenance and function, impaired function of the axoneme, such as DNAI1 or DNAH5 (See abstract).
Regarding claim 1, Lockhart et al teach that for administration by inhalation, the active compounds can be in the form of an aerosol, a mist, or a spray and may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer (See [0229], [0231] and [0245]).
Lockhart et al teach a method for treating a subject having or at risk of having primary ciliary dyskinesia, the method comprising administrating to the subject a composition that comprises a nucleic acid construct that encodes dynein axonemal intermediate chain 1 protein or a variant thereof, which nucleic acid construct includes codons that provide for heterologous or enhanced expression of the dynein axonemal intermediate chain 1 protein or a variant thereof within cells of the subject, thereby treating the subject having or at risk of having primary ciliary dyskinesia (See [0006]).
It is disclosed that at least 21 mutations in the DNAI1 gene have been found to cause primary ciliary dyskinesia. DNAI1 gene mutations result in an absent or abnormal intermediate chain 1 (See [0062]).
Lockhart et al teach and claim a pharmaceutical formulation comprising a polynucleotide that is at least 80% homologous to nucleic acids 1-1,000 of SEQ ID NO: 15, wherein said polynucleotide is an mRNA; wherein fewer than 15% of nucleotides within said polynucleotide are nucleotide analogues; and wherein said pharmaceutical formulation comprises a cationic lipid, a fusogenic lipid, a cholesterol and a polyethylene glycol (PEG) lipid (See [0156] and claims 1-4 and 7-9).
Lockhart et al teach that encapsulation of polynucleotides with formulations that can increase the endocytotic uptake can increase the effectiveness of the said composition. To overcome this challenge, in some cases, the composition comprises a nucleic acid construct, a vector, or an isolated nucleic acid encoding dynein axonemal intermediate chain 1 (DNAI1), wherein the nucleic acid construct comprises a complementary deoxyribonucleic acid encoding dynein axonemal intermediate chain 1, which composition is formulated for administration to a subject.
Lockhart et al teach a composition comprising an engineered polyribonucleotide which can be encapsulated or formulated with a pharmaceutical carrier. The formulation may be nanoparticles, PLGA microspheres, lipidoids, lipoplex, liposome, polymers, cationic lipids, etc, (See [0148] and [0150]).
It is also disclosed that the engineered polynucleotide in a composition may be at least 0.05%, 9%, or 10%. The encapsulation efficiency of the modified mRNA in the PLGA microsphere may be at least 96%, or at least 99% (See [0151] and [0209]).
The disclosure provides formulations that can be employed for effective delivery and translation of polyribonucleotide compositions to a subject (See [0157]).
Lockhart et al teach that the said lipidoid or lipid nanoparticle can comprise one or more lipids in various ratios. A nanoparticle can include at least 1, 2, 3, 4, 5, 9, 10 lipids or another suitable number of lipids. A composition can comprise a 40:30:25:5 ratio of C12-200:DOPE:Cholesterol:DMG-PEG2000 or a 40:20:35:5 ratio of HGT5001:DOPE:Cholesterol:DMG-PEG2000. A nanoparticle can be formed of any suitable ratio of lipids selected from the group consisting of DLin-K-DMA, DLin-KC2-DMA, PLGA, PEG, PEG-DMG (i.e. PEG modified dimyristoyl-sn-glycerol) (See [0155]-[0156]).
Lockhart et al further disclose that an engineered polyribonucleotide can be encapsulated in a lipidoid formulation. A lipidoid formulation can be a lipid, phospholipids, and others, such as cholesterol, DOPE, DOPC or DSPC and/or PEGylated lipids or any other lipid useful for preparing lipoplexes. The composition containing a lipidoid may contain about 40-60% lipidoid, about 40-60% cholesterol, and about 5-10% PEG-lipid. The composition containing a lipidoid may be about 50-75% lipidoid, about 20-40% cholesterol, and about 1-10% PEG-lipid (in percent by weight, based on the total weight of the composition) (See [0207]-[0208] and claim 7).
It is stated that the modified nucleotide compositions comprise less than 1 mg/mL of the polynucleotide (See Table 6).
The polydispersity index PDI of the nanoparticle formulation comprising the modified mRNA can be between 0.03 and 0.15 (See [0156]).
It is further disclosed that a nucleic acid construct encoding the DNAI1 gene sequence, is prepared and after diluting it in 5% glucose (final concentration), the RNA and jetPEI solutions are combined/mixed at a ratio of 1:1 with a final N/P ratio of 8. The mRNA is then administered by nebulizing (See [0245]).
Lockhart et al disclose that in some cases the composition, vector, or a nucleic acid construct comprising a nucleic acid construct encoding dynein axonemal intermediate chain 1 is provided, wherein fewer than 15%, or fewer than 2.5% of the nucleotides encoding DNAI1 are nucleotide analogues such as pseudouridine or 1-methyl pseudouridine (See [0103] and [0144]).
Regarding claim 5, Lockhart et al teach do not expressly state that the lipid composition is non-cytotoxic. However, since they teach the same lipid composition and teach the formulation for effective treatment of subjects, it is safe to assume that the said lipid composition is non-cytotoxic.
Lockhart et al lack specific disclosure on the average droplet sizes or the flow rate for nebulization. These are known in the art as taught by Karve et al. Lockhart et al is also silent regarding the core-repeating unit-terminating group (I-1) and lipid composition comprising 14:0 TAP. These are known in art as taught by Siegwart et al and Angel et al.
Karve et al teach an improved method of treating cystic fibrosis (CF) in a human subject, the method comprising administering a composition comprising an mRNA encoding a cystic fibrosis transmembrane conductance regulator (CFTR) protein at a concentration of 0.5 mg/mL or greater to a human subject via nebulization, at a suitable nebulization rate, e.g, at least 0.2 mL/minute (See abstract). The concentration of the mRNA encoding the CFTR protein ranges from 0.5 mg/mL to 0.8 mg/mL, optionally wherein the concentration is 0.6 mg/mL (See [0007], [0221] and claims 1-2).
Disclosed is a particularly effective method of administering liposome- encapsulated CFTR mRNA by nebulization to the lungs of a human subject for the treatment of cystic fibrosis (See [0006]). The said liposome comprises one or more cationic lipids, one or more non-cationic lipids, and one or more PEG-modified lipids including PEG-modified phospholipids. The non-cationic lipid may be a phospholipid such as DOPE (See [0015] and [0142]).
It is disclosed that the said cationic lipid may be DODAP, DOTAP, etc, (See [0134]-[0138]). The lipid delivery system may also comprise a cholesterol-based lipid (See [0130] and [0141]).
A suitable nebulizer produces droplets with an average size between 4 µm and 6 µm (See [0012]). Inhaled aerosol droplets of a particle size of 1-5 µm can penetrate the narrow branches of the lower airways. Aerosol droplets with a larger diameter are typically absorbed by the epithelia cells lining the oral cavity and are unlikely to reach the lower airway epithelium and the deep alveolar lung tissue (See [0208]).
In Table 9, Karve et al discloses MMAD, GSD, FPF, Mass Balance and Delivered Dose Results (VMT nebulizer 1)
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As can be seen, the MMAD and GSD values are well within the claimed values of examined claims 109 and 143-144.
Siegwart et al teach dendrimers with cationic groups and lipophilic groups formulated in compositions which contain a nucleic acid and one or more helper excipients (See abstract).
Disclosed is a dendrimer of the formula: Core-(Repeating Unit)n-Terminating Group (I)
wherein the core is linked to the repeating unit and wherein:
the core has the formula:
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wherein:
X3 is —NR6—, wherein R6 is hydrogen, alkyl(C≦8), or substituted alkyl(C≦8),
R3 and R4 are each independently amino, alkylamino(C≦12), dialkylamino(C≦12), or a substituted version of either of these groups; or a group of the formula: —(CH2CH2N)e(Rc)Rd;
wherein:
e is 1, 2, or 3;
Rc and Rd are each independently hydrogen, alkyl(C≦6), or substituted alkyl(C≦6);
c and d are each independently 1, 2, 3, 4, 5, or 6; or
wherein the repeating unit comprises a degradable diacyl and a linker;
the degradable diacyl group has the formula:
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wherein:
A1 and A2 are each independently —O—, wherein:
Y3 is alkanediyl(C≦12), alkenediyl(C≦12), arenediyl(C≦12),
R9 is alkyl(C≦8) or substituted alkyl(C≦8);
and
the terminating group has the formula:
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wherein:
Y4 is alkanediyl(C≦18) or an alkanediyl(C≦18),
and
R10 is hydrogen (See at least [0007], [0237-[0256] and claims).
The core may be defined as
(See [0194], [0206] and claim 32).
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Nucleic acid is a short interfering RNA, a messenger RNA (mRNA), etc, (See [0217]-[0219]).
Siegwart et al teach that the helper lipid is a PEG lipid or a phospholipid, such as 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). The phospholipid and the dendrimer are present in a molar ratio from about 10:1 to about 1:20 (See [0220]-[0230] and [0274]-[0275]). The PEG lipid is dimyristoyl-sn-glycerol (See [0226]).
Siegwart et al exemplify a formulation comprising dendrimer (lipid)+cholesterol+DOPE+PEG-DMG (formula 3) (See [0496])
It is stated that a pharmaceutically acceptable carrier is a solvent or solution and the composition is formulated for administration: orally, intraarterially, via inhalation, etc, (See [0234]).
In Example 10, Siegwart et al disclose evaluation of dendrimer nanoparticles for delivery of mRNA. It is disclosed that compositions containing either DSPC, DOPE, or no phospholipid and PEG-DHD as the PEG-lipid with the molar ratios of lipid (or dendrimer):cholesterol:phospholipid:PEG-lipid being 50:38.5:0(10):2 and a weight ratio of dendrimer to nucleic acid (mRNA) of 5, 10, 20, 30, or 40 to 1 and two different doses: a 50 ng dose and a 100 ng dose were tested. The delivery used a nanoparticle composition with 20:1 ratio N/P and DSPC as the phospholipid and PEG-DHD as the PEG-lipid (See [0499]).
Angel et al teach nucleic acid products and a method of their administration (See Title and Abstract).
The said composition contains one or more lipids that enhance uptake of RNA by cells; optionally, wherein the one or more lipids are selected from the lipids including:
1,2-dimyristoyl-3-trimethylammonium-propane (14:0 TAP),
1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (14:0 EthylPC),
1,2-dioleoyl-3-dimethylammonium-propane (DODAP),
or the liposome comprises dioleoylphosphatidylethanolamine (DOPE), etc, (See pages 16-17 and Table 1 and claims 20 and 30).
Routes of administration for the said formulation include inhalation and injection (See page 19, lines 15-18). The said formulations can be administered to treat respiratory conditions (See Page 52, lines 3-8).
It would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of Angel et al, Siegwart et al and Karve et al with that of Lockhart et al to arrive at the instant invention. It would have been obvious to do so because Lockhart et al and Karve et al teach methods of treating lung disorders including primary ciliary dyskenisia or cystic fibrosis by administering via a nebulizer a formulation comprising a lipid encapsulated polynucleotide such as mRNA for effective delivery and administration of the active agents to the subject. While Lockhart et al teach nebulization as an effective mode of delivery of the said formulations, they do not expressly disclose nebulization flow rates and droplet sizes. Thus, one of ordinary skill in the art wishing to follow Lockhart et al’s teachings would have been motivated to look in the art for suggestions on the said droplet sizes to optimize the said method. Karve et al teach a similar delivery system wherein the lipid encapsulated nucleic acids are delivered via a nebulizer and provide guidance on the suitable droplet sizes for an effective treatment and delivery to the pulmonary system.
Accordingly, the claims would have been obvious because a person of ordinary skill has good reasons to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
It also would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of Angel et al and Siegwart et al with the combined teachings of Karve et al and Lockhart et al to arrive at the instant invention. It would have been obvious to do so because Siegwart et al teach delivering nucleic acids including mRNA to target cells via liposomes of different lipids including those of the structural formula of core-repeating unit-terminating group and other phospholipids and helper lipids including PEG modified lipids. Angel et al teach that a nucleic acid drug is formulated with one or more lipids to enhance uptake of the nucleic acid drug by cells, and the lipids are selected from lipids including 14:0 TAP, 14:0 EPC, DOPE, etc. Thus, one of ordinary skill in the art would have been motivated to select one or more effective lipids listed by Angel et al because it is disclosed that the said lipids enhance delivery of nucleic acids to the cells or organs.
Accordingly, the claims would have been obvious because a person of ordinary skill has good reasons to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
In addition, all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Lockhart et al (US 20190117796) in view of Cheng et al (WO 2020051220) as evidenced by Zhou et al (Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model), Karve et al (WO 2020106946) and Angel et al (WO 2016131052).
Lockhart et al’s teachings are delineated above and incorporated herein.
Lockhart et al do not expressly disclose that the lipid composition comprises a compound having a core-repeating unit-Terminating Group I-1, or wherein the compound of formula I-1 is 4A3-SC7. These are remedied by the teachings in the art such as Cheng et al. Lockhart et al also teach administration of the said formulations to the lung by inhalation such as via a nebulizer or aerosol but is silent with regards to the droplet size. This is known in the art as taught by Karve et al. Lockhart et al also does not teach wherein the lipid is 14:0 TAP. This would have been obvious over the teachings of Angel et al.
Cheng et al ‘220 teach compositions which show preferential targeting or delivery of a nucleic acid composition to a particular organ, the composition comprising a steroid or sterol, an ionizable cationic lipid, a phospholipid, a PEG lipid, and a permanently cationic lipid which may be used to deliver a nucleic acid (See abstract and claim 1).
Cheng et al teach that “mDLNPs were formed with a third permanent cationic lipid with the headgroup l,2-dimyristoyl-sn-glycero-3-ethylphosphocholine chloride which has similar structure with DOTAP, but with shorter, 14 carbon, hydrophobic tails ((14:0) EPC) (FIG. 2B1). Similar to the DDAB strategy, (14:0) EPC5, (14:0) EPC15, (14:0) EPC40 and (14:0) EPC50 formulations were prepared, and the size distribution (FIG. 2B1) and in vivo Luc mRNA delivery were examined (FIG. 2B2). Like the mDLNPs analyzed above, the particle size was generally uniform (FIG. 2B1), and as expected, luminescence moved from liver to spleen, then to lung with increasing (14:0) EPC molar percentages”. The said steroid is preferably a cholesterol (See [0012] and [0031]).
It is disclosed that the said compositions may comprise cholesterol and DMG-PEG, DOPE, DSPC, etc. In some embodiments, the compositions further comprise 4A1-SC8, 4A3- SC8, 5A2-SC8, etc (See [0033]).
Cheng et al state that Ionizable cationic SORT lipids with tertiary amino groups (DODAP, C12- 200) enhanced liver delivery without any luciferase expression in the lungs (See [0084], Fig. 23A-23C).
Furthermore, Cheng et al teaches that the said ionizabie cationic lipid is a dendrimer further defined by the formula:
Core-Repeating Unit-Terminating Group (I) wherein the core is linked to the repeating unit by removing one or more hydrogen atoms from the core and replacing the atom with the repeating unit and wherein: the core has the formula:
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wherein:
X3 is -NR*-, wherein R& is hydrogen, alkyl<c<8), or substituted alkyl(c<8), —O , or alkylaminodiyl(c<8), alkoxydiykc s), arenediyl<c<8), heteroarenediyl(c<8>, heterocycloalkanediyl<c<8), or a substituted v ersion of any of these groups;
R3 and Ri are each independently amino, hydroxy, or mercapto, or alkylamino(c<i2), dialkylamino(c<i2), or a substituted version of either of these groups; or a group of the formula: N(Rf)f(CH2CH2N)e(Rc)Rd;
wherein: e and f are each independently 1, 2, or 3; provided that the sum of e and f is 3;
Rc, Rd, and Rf are each independently hydrogen, alkyi(c<6), or substituted alkyl<c<6);
c and d are each independently 1, 2, 3, 4, 5, or 6; or the core is alkylamine<c<i8), dialkylarnine<c<36), heterocycloalkane<c<i2), or a substituted version of any of these groups;
wherein the repeating unit comprises a degradable diacyl and a linker;
the degradable diacyl group has the formula:
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wherein: Ai and A2 are each independently 0 or -NRa-, wherein:
Ra is hydrogen, alkyi(c<6), or substituted alkyl<c<6);
Y3 is alkanediyl(c<i2), and
the terminating group has the formula:
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wherein: Y4 is alkanediykcus) or an alkanediyl(c<18), and R10 is hydrogen (See [0029] and claim 26).
Cheng et al teach a formulation wherein the core (i.e. formula I-I) is further defined as:
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(See [0029] and claim 31).
As evidenced by Zhou et al,
Zhou et al teach delivery of RNAs with the use of dendrimers including A3-SC8. Zhou et al also show that dendrimers SC7 and SC8 differ only in the length of tail and that they are very close in structure and both used for the same purpose (See page 520 and 522).
Karve et al and Angel et al’s teachings are delineated above and incorporated herein.
It would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of Angel et al, Karve et al and Cheng et al as evidenced by Zhou et al with that of Lockhart et al to arrive at the instant invention. It would have been obvious to combine Chang et al with Lockhart et al because Lockhart et al teach methods of treating a primary ciliary dyskinesia by administering via a nebulizer a formulation comprising a lipid encapsulated polynucleotide such as DNAI1 for effective delivery and administration of the active agents to the subject, especially lung and ciliary epithelial cells. Lockhart et al also disclose that the said composition comprises a cationic lipid and other lipids including SORT lipids. While Lockhart et al’s recommended cationic lipids include ionizable cationic lipids, they do not expressly disclose the claimed lipids. One of ordinary skill in the art, however, would have been motivated to select one or more ionizable cationic lipids of Cheng et al because Cheng et al teaches them used effectively in similar compositions and for delivery of nucleic acids. Cheng et al teach similar compositions and disclose that inclusion of an ionizable lipid was required for efficacy and that LNPs that contained SORT lipids, but no ionizable cationic lipid were inactive.
Thus, one of ordinary skill in the art would have been motivated to have combined Cheng et al and Lockhart et al’s teachings to prepare the claimed compositions comprising an ionizable cationic lipid, a SORT lipid with the polynucleotide active agent and administer it to a subject in need of treatment for primary ciliary dyskinesia with a reasonable expectation of success.
It further would have been obvious to include teachings of Karve et al because all references teach improved delivery of nucleic acids to the target cells with a lipid composition vehicle. Lockhart et al and Karve et al teach methods of treating primary ciliary dyskenisia or cystic fibrosis by administering via a nebulizer a formulation comprising a lipid encapsulated polynucleotide such as mRNA for effective delivery and administration of the active agents to the subject. While Lockhart et al teach nebulization as an effective mode of delivery of the said formulations, they do not expressly disclose droplet sizes, i.e. MMAD or GSD. Thus, one of ordinary skill in the art wishing to follow Lockhart et al’s guidance would have been motivated to look in the art for suggestions on the said droplet sizes to optimize the said method. Karve et al teach a similar delivery system wherein the lipid encapsulated nucleic acids are delivered via a nebulizer and provide guidance on the suitable flow rates and droplet sizes for an effective treatment and delivery to the pulmonary system. Angel et al teach that a nucleic acid drug is formulated with one or more lipids to enhance uptake of the nucleic acid drug by cells, and the lipids are selected from lipids including 14:0 TAP, 14:0 EPC, DOPE, etc. Thus, one of ordinary skill in the art would have been motivated to select one or more effective lipids listed by Angel et al because it is disclosed that the said lipids enhance delivery of nucleic acids to the cells or organs.
Accordingly, the claims would have been obvious because a person of ordinary skill has good reasons to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
In addition, all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10-28 of U.S. Patent No. 12,337,068 in view of Angel et al (WO 2016131052). Although the claims at issue are not identical, they are not patentably distinct from each other because the examined claims would have been obvious over the reference claims in view of Angel et al.
Examined claim 1 is drawn to an aerosol composition comprising aerosol droplets, wherein the aerosol droplets comprise an mRNA assembled with a lipid composition, wherein the mRNA expresses a DNAI1 protein, and wherein the lipid composition comprises:
(i) a compound that is a compound of Formula (I-1):
Core-Repeating Unit-Terminating Group (I-1),
or a pharmaceutically acceptable salt thereof,
wherein the core is linked to two to six repeating units; and
wherein:
the core has the formula:
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wherein:
X3 is —NR6— or heterocycloalkanediylC≤8, wherein R6 is hydrogen or alkylC≤8;
R3 and R4 are each independently amino, alkylaminoC≤12, or dialkylaminoC≤12; wherein the alkylamino or dialkylamino are each optionally substituted with amino;
each repeating unit comprises a degradable diacyl having the formula:
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wherein:
A1 and A2 are each independently —O—,
Y3 is —CH2CH2—, and
R9 is —CH3; and
the terminating group is selected from the group consisting of:
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(ii) 1,2-dimyristoyl-3-trimethylammonium-propane (14:0 TAP);
(iii) a phospholipid;
(iv) a cholesterol; and
(v) a polyethylene glycol-conjugated lipid (PEG-lipid).
Reference claim 10 is directed to the method of claim 1, wherein the ionizable lipid is a compound having the structural formula:Core−Repeating Unit−Terminating Group (D-I),
or a pharmaceutically acceptable salt thereof, wherein:
the core is linked to two to six repeating units by removing two to six hydrogen atoms from the core and replacing the hydrogen atoms with the repeating units; wherein:
the core has the formula:
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wherein, in Formula (D-IV):
X3 is —NR6—, —O—, or optionally substituted alkylaminodiyl(c≤8); wherein R6 is hydrogen, alkyl(c≤8), or substituted alkyl(c≤8),
R3 and R4 are each independently amino, optionally substituted alkylamino(c≤12), or optionally substituted dialkylamino(c≤12);
wherein:
c and d are each independently 1, 2, 3, 4, 5, or 6;
the repeating unit comprises a degradable diacyl group of the formula:
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229
783
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wherein, in Formula (D-VII):
A1 and A2 are each independently —O—;
Y3 is —CH2CH2—; and
R9 is —CH3; and
the terminating group has the formula:
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154
623
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wherein, in Formula (D-VIII):
Y4 is alkanediyl(c≤18) or an alkanediyl(c≤18); and
R10 is hydrogen.
Reference claim 1 is drawn to a method for selectively delivering an mRNA to the lungs of a subject, wherein the method comprises nebulizing a liquid pharmaceutical composition which comprises lipid nanoparticles (LNPs) comprising said mRNA to generate an aerosolized pharmaceutical composition, and administering the aerosolized pharmaceutical composition to the subject, wherein the LNPs comprise an ionizable lipid, a phospholipid, a PEG-lipid, and a sterol, wherein the LNPs have an mRNA integrity of between 75% and 99%, and wherein the aerosolized pharmaceutical composition comprises aerosol particles having: (a) a mass median aerodynamic diameter (MMAD) of from 1 μm to 10 μm,(b) a geometric standard deviation (GSD) of from 1 to 5, and (c) a fine particle fraction (FPF) percent of at least 50%, wherein administering the aerosolized pharmaceutical composition to the subject results in minimal amounts of mRNA in the blood, liver, and spleen of the subject.
One difference is that examined claims are directed to an aerosol composition while reference claims are directed to a method of selectively delivering the compositions to a subject’s lung and in the combination of compounds of the lipid composition.
The said difference is, however, obvious to one of ordinary skill in the art because the compositions of examined claims need to be delivered to a subject for it to have utility and function. Also, the method of reference claims delivers the examined composition.
The other difference is that reference claims disclose a cationic lipid, while the examined claims specify 14:0 TAP. This, however, would have been obvious over the teachings of Angel et al. Angel et al teach that a suitable cationic lipid for such formulations includes 14:0 TAP, 14:0 EPC or DODAP. Thus, one of ordinary skill in the art would have been motivated to have selected a suitable lipid from the suggested list of lipids with a reasonable expectation of success.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26-30 of U.S. Patent No. 12,257,318 in view of Karve et al (WO 2020106946). Although the claims at issue are not identical, they are not patentably distinct from each other because the examined claims would have been obvious over the reference claims in view of Karve et al.
Examined claim 1 is delineated above.
Reference claim 26 is directed to the composition of claim 1, wherein the wherein the ionizable cationic lipid is a compound having the structural formula:
Core-Repeating Unit-Terminating Group (D-I),
or a pharmaceutically acceptable salt thereof, wherein:
the core is linked to two to six repeating units by removing two to six hydrogen atoms from the core and replacing the hydrogen atoms with the repeating units; wherein:
the core has the formula:
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96
633
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wherein, in Formula (D-IV):
X3 is —NR6—, —O—, or optionally substituted alkylaminodiyl(c≤8); wherein R6 is hydrogen, alkyl(c≤8), or substituted alkyl(c≤8),
R3 and R4 are each independently amino, optionally substituted alkylamino(c≤12), or optionally substituted dialkylamino(c≤12);
wherein:
c and d are each independently 1, 2, 3, 4, 5, or 6;
the repeating unit comprises a degradable diacyl group of the formula:
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229
828
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wherein, in Formula (D-VII):
A1 and A2 are each independently —O—;
Y3 is —CH2CH2—; and
R9 is —CH3; and
the terminating group has the formula:
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154
623
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wherein, in Formula (D-VIII):
Y4 is alkanediyl(c≤18) or an alkanediyl(c≤18); and
R10 is hydrogen.
Claim 27 is directed to the pharmaceutical composition of claim 1, wherein the ionizable cationic lipid is:
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1875
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Reference claim 1 is drawn to a pharmaceutical composition comprising a synthetic polynucleotide assembled with a lipid composition, wherein said synthetic polynucleotide encodes a cystic fibrosis transmembrane conductance regulator (CFTR) protein that comprises a nucleic acid sequence having at least about 98% sequence identity to SEQ ID NO: 4, wherein said lipid composition comprises an ionizable cationic lipid at a molar percentage of about 5% to about 30%; a selective organ targeting (SORT) lipid separate from said ionizable cationic lipid at a molar percentage of about 5% to about 30%; a phospholipid at a molar percentage of about 5% to about 25%; a steroid or steroid derivative at a molar percentage of about 15% to about 46%; and a polymer-conjugated lipid at a molar percentage of about 0.5% to about 10%.
Reference claims 11 and 12 are directed to the pharmaceutical composition of claim 1, wherein the composition is an aerosol composition and wherein the droplet size of the aerosol droplets in said aerosol composition is from 0.5 μm to 10 μm.
The differences are that that examined claims recite DNAI1 while reference claims recite CFTR as the active agent. Also examined claims only recite 14:0 TAP, while reference claims recite a Markush of SORT lipids including 14:0 TAP.
The said differences are, however, obvious to one of ordinary skill in the art because the examined compositions 14:0 TAP is within the disclosed lipids of the reference claims. Additionally, as taught by Karve et al, the same formulations may have a therapeutic agent such as CFTR or DNA.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/596,141 (US 20240299310) (reference application) in view of Angel et al (WO 2016131052). Although the claims at issue are not identical, they are not patentably distinct from each other because the examined claims would have been obvious over the reference claims in view of Angel et al.
Examined claim 1 is delineated above.
Reference claim 1 is drawn to an aerosol composition comprising aerosol droplets, wherein the aerosol droplets comprise an mRNA assembled with a lipid composition, wherein the mRNA expresses a DNAI1 protein, and wherein the lipid composition comprises:
(i) a compound that is a compound of Formula (I-1):Core-Repeating Unit-Terminating Group (I-1),
or a pharmaceutically acceptable salt thereof,
wherein the core is linked to two to six repeating units; and
wherein:
the core has the formula:
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95
617
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wherein:
X3 is —NR6— or heterocycloalkanediylC≤8, wherein R6 is hydrogen or alkylC≤8;
R3 and R4 are each independently amino, alkylaminoC≤12, or dialkylaminoC≤12; wherein the alkylamino or dialkylamino are each optionally substituted with amino;
each repeating unit comprises a degradable diacyl having the formula:
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229
816
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wherein:
A1 and A2 are each independently —O—,
Y3 is —CH2CH2—, and …….
(ii) 1,2-dioleoyl-3-dimethylammonium-propane (DODAP);
(iii) a phospholipid;
(iv) a cholesterol; and
(v) a polyethylene glycol-conjugated lipid (PEG-lipid).
The difference is that the examined claimed composition requires the phospholipid 14:0 TAP, while the reference claims require DODAP. However, as taught by Angel et al, this modification would have been obvious. Angel et al teach that the delivery lipid formulation may comprise one or more lipid compounds including 14:0TAP, 14:0 EPC or DODAP. Thus, one of ordinary skill in the art would have been motivated to have selected one or more lipid compounds as taught by Angel et al for the said lipid compositions with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/596,148 (US 20240261432) (reference application) in view of Angel et al (WO 2016131052). Although the claims at issue are not identical, they are not patentably distinct from each other because the examined claims would have been obvious over the reference claims in view of Angel et al.
Examined claim 1 is delineated above.
Reference claim 1 is drawn to an aerosol composition comprising aerosol droplets, wherein the aerosol droplets comprise an mRNA assembled with a lipid composition, wherein the mRNA expresses a DNAI1 protein, and wherein the lipid composition comprises:
(i) a compound that is a compound of Formula (I-1):
Core-Repeating Unit-Terminating Group (I-1),
or a pharmaceutically acceptable salt thereof,
wherein the core is linked to two to six repeating units; and
wherein:
the core has the formula:
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105
623
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wherein:
X3 is —NR6— or heterocycloalkanediylC≤8, wherein R6 is hydrogen or alkylC≤8;
R3 and R4 are each independently amino, alkylaminoC≤12, or dialkylaminoC≤12; wherein the alkylamino or dialkylamino are each optionally substituted with amino;
each repeating unit comprises a degradable diacyl having the formula:
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229
811
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wherein:
A1 and A2 are each independently —O—,
Y3 is —CH2CH2—, and
R9 is —CH3; and ……
(ii) 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (14:0 EPC);
(iii) a phospholipid;
(iv) a cholesterol; and
(v) a polyethylene glycol-conjugated lipid (PEG-lipid).
The difference is that the examined claimed composition requires the phospholipid 14:0 TAP, while the reference claims require 14:0 EPC. However, as taught by Angel et al, this modification would have been obvious. Angel et al teach that the delivery lipid formulation may comprise one or more lipid compounds including 14:0TAP, 14:0 EPC or DODAP. Thus, one of ordinary skill in the art would have been motivated to have selected one or more lipid compounds as taught by Angel et al for the said lipid compositions with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/778,439 (US 20240374512) (reference application) in view of Angel et al (WO 2016131052) and Karve et al (WO 2020106946). Although the claims at issue are not identical, they are not patentably distinct from each other because the examined claims would have been obvious over the reference claims in view of Angel et al and Karve et al.
Examined claim 1 is delineated above.
Reference claim 1 is drawn to an aerosol composition comprising aerosol droplets, wherein the aerosol droplets comprise an mRNA assembled with a lipid composition, wherein the mRNA expresses a CFTR protein, and wherein the lipid composition comprises:
(i) a compound that is a compound of Formula (I-1):Core-Repeating Unit-Terminating Group (I-1),
or a pharmaceutically acceptable salt thereof,
wherein the core is linked to two to six repeating units; and
wherein:
the core has the formula:
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94
618
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wherein:
X3 is —NR6— or heterocycloalkanediylC≤8, wherein R6 is hydrogen or alkylC≤8;
R3 and R4 are each independently amino, alkylaminoC≤12, or dialkylaminoC≤12; wherein the alkylamino or dialkylamino are each optionally substituted with amino;
each repeating unit comprises a degradable diacyl having the formula:
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237
807
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wherein:
A1 and A2 are each independently —O—,
Y3 is —CH2CH2—, and
R9 is —CH3; and
the terminating group is selected from the group consisting of: ……
(ii) 1,2-dioleoyl-3-dimethylammonium-propane (DODAP);
(iii) a phospholipid;
(iv) a cholesterol; and
(v) a polyethylene glycol-conjugated lipid (PEG-lipid).
The differences are that the examined claimed composition requires the phospholipid 14:0 TAP, while the reference claims require DODAP. The other difference is that examined claims recite that the mRNA expresses a DNAI1 while reference claims recite that the mRNA expresses a CFTR protein. However, as taught by Angel et al, these modifications would have been obvious. Angel et al teach that the delivery lipid formulation may comprise one or more lipid compounds including 14:0TAP, 14:0 EPC or DODAP. Angel et al also teach that mRNA expression may be CFTR. Additionally, Karve et al teach that the mRNA expression in a lipid nucleotide composition can be DNA or CFTR. Thus, one of ordinary skill in the art would have been motivated to have selected one or more lipid compounds as taught by Angel et al for the said lipid compositions and an mRNA expression that is either DNAI1 or CFTR with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/778,429 (US 20240374511) (reference application) in view of Angel et al (WO 2016131052) and Karve et al (WO 2020106946). Although the claims at issue are not identical, they are not patentably distinct from each other because the examined claims would have been obvious over the reference claims in view of Angel et al and Karve et al.
Examined claim 1 is delineated above.
Reference claim 1 is drawn to an aerosol composition comprising aerosol droplets, wherein the aerosol droplets comprise an mRNA assembled with a lipid composition, wherein the mRNA expresses a CFTR protein, and wherein the lipid composition comprises:
(i) a compound that is a compound of Formula (I-1):Core-Repeating Unit-Terminating Group (I-1),
or a pharmaceutically acceptable salt thereof, ……
(ii) 1,2-dioleoyl-3-dimethylammonium-propane (14:0 EPC);
(iii) a phospholipid;
(iv) a cholesterol; and
(v) a polyethylene glycol-conjugated lipid (PEG-lipid).
The differences are that the examined claimed composition requires the phospholipid 14:0 TAP, while the reference claims require 14:0 EPC. The other difference is that examined claims recite that the mRNA expresses a DNAI1 while reference claims recite that the mRNA expresses a CFTR protein. However, as taught by Angel et al, these modifications would have been obvious. Angel et al teach that the delivery lipid formulation may comprise one or more lipid compounds including 14:0TAP, 14:0 EPC or DODAP. Angel et al also teach that mRNA expression may be CFTR. Additionally, Karve et al teach that the mRNA expression in a lipid nucleotide composition can be DNA or CFTR. Thus, one of ordinary skill in the art would have been motivated to have selected one or more lipid compounds as taught by Angel et al for the said lipid compositions and an mRNA expression that is either DNAI1 or CFTR with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 and 18-19 of copending Application No. 18/797,360 (US 20240390272) (reference application) in view of Angel et al (WO 2016131052). Although the claims at issue are not identical, they are not patentably distinct from each other because the examined claims would have been obvious over the reference claims in view of Angel et al.
Examined claim 1 is delineated above.
Reference claim 1 is drawn to an aerosol composition comprising aerosol droplets, wherein the aerosol droplets comprise a therapeutic agent assembled with a lipid composition, and wherein the lipid composition comprises:
(i) a compound that is a compound of Formula (I-1):Core-Repeating Unit-Terminating Group (I-1),
or a pharmaceutically acceptable salt thereof, ………
(ii) a compound selected from: 1,2-dimyristoyl-3-trimethylammonium-propane chloride salt (14:0 TAP), 1,2-dipalmitoyl-3-trimethylammonium-propane chloride salt (16:0 TAP), and 1,2-stearoyl-3-trimethylammonium-propane chloride salt (18:0 TAP);
(iii) a phospholipid;
(iv) a cholesterol; and
(v) a polyethylene glycol-conjugated lipid (PEG-lipid).
The difference is that the examined claimed composition recites that the droplets comprise an mRNA, while the reference claims state a therapeutic agent. However, the claimed mRNA is encompassed by the therapeutic agent of reference claims. Also as taught by Angel et al, lipid compositions can comprise a therapeutic agent such as mRNA. The other modification would have also been obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
1- Hefesha et al (US 20180263907).
Hefesha et al teach lipid particles comprising at least one cationic lipid, at least one water-soluble therapeutically effective compound and RNA, and pharmaceutical compositions comprising such particles for delivery to target cells (See title, abstract and [0009]).
It is disclosed that the said particles comprise at least one helper lipid, including 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine (DOPE), cholesterol (Chol), 1-palmitoyl-2-oleoyl-sn-glycero-3phosphocholin (POPC) and/or 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), preferably DOPC, DOPE and/or Chol. The at least one cationic lipid comprises 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (DMEPC), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA) and/or 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), preferably DOTAP and/or DOTMA (See [0017]-[0018]).
Suitable cationic lipids comprise one cationic charge and include 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (DMEPC), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA) and/or 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), 1,2-dimyristoyl-3-trimethylammonium propane (DMTAP), etc, (See [0093]).
The particles have an average diameter in the range of from about 50 nm to about 1000 nm (See [0019]).
The said RNA maybe mRNA (See [0107]).
Typical systemic routes of administration include administration by introducing the agent directly into the vascular system or oral, pulmonary, or intramuscular administration wherein the agent is adsorbed, enters the vascular system, and is carried to one or more desired site(s) of action via blood (See [0162]).
2- Mautone et al (EP 0607118).
Mautone et al teach a phospholipid delivery system and an aerosol delivery of therapeutically active substances which can be suspended in aqueous media to serve as a drug delivery system (See abstract). The system is a complex mixture of lipids, proteins and carbohydrates (See [0005]).
Mautone et al disclose that the diameter of aerosol particles was determined in a cascade impactor. Flow through the impactor was the same as aerosol flow from the nebulizer, 200 microliters/second (i.e. 0.2 mL/s). About 95% of the particles were equal to or less than 4 microns (See [0030]).
It is also claimed that the aerosolized droplets have a mean aerodynamic diameter in the range of from 1 to 50 microns (See claim 13).
Claims 1-20 are rejected. Claims 21-29 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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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616
