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 07/10/25. Claims 109-110, 115 and 119 have been amended, new claims 143-156 have been added and claims 111, 122-124,127-129, 132, 134 and 140-142 have been canceled. Accordingly, claims 109-110, 112-115, 117, 119 and 143-156 are pending and 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Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn.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 § 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 109-110, 112-115, 117, 119, 143-151, 153 and 155-156 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) and Karve et al (WO 2020106946).
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).
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 a nucleic acid construct, a vector, or an isolated nucleic acid is/are formulated for administration to a subject. In some cases, the formulation includes a therapeutically effective amount of the nucleic acid construct encoding dynein axonemal intermediate chain 1 (See [0009]).
Lockhart et al disclose that the term “subject,” refers to a human, an animal, such as a horse, a rabbit, and various other animals (See [0044]).
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. Nucleic acid constructs encoding DNAI1 gene are disclosed in Examples 1-5 and Table 4 (See [0062] and [0241]-[0250]).
Disclosed is that in some cases, the said composition comprises a nucleic acid construct encoding armadillo repeat containing 4 (ARMC4), and upon translation within the cells of a subject the construct yields a polypeptide that treats a subject having or at risk of having of primary ciliary dyskinesia. The said protein has been shown to localize to the ciliary axonemes and at the ciliary base of respiratory cells (See [0064]).
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. The said fusogenic lipid may be DSPC (i.e. distearoylphosphatidylcholine, a SORT lipid) (See [0156] and claims 1-4 and 7-9).
Lockhart et al teach a composition comprising a polyribonucleotide for treating a subject having or at risk of having primary ciliary dyskinesia, wherein the composition comprises at least one additional nucleic acid construct that encodes a protein selected from the group consisting of: coiled-coil domain containing 39 (CCDC39), coiled-coil domain containing 40 (CCDC40), coiled-coil domain containing 65 (CCDC65), cyclin O (CCNO), dynein axonemal heavy chain 5 (DNAH5), etc, (See [0060]).
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, 6, 7, 8, 9, 10 lipids or another suitable number of lipids. A nanoparticle can be formed of any suitable ratio of lipids selected from the group consisting of C12-200, MD1, 98N12-5, DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, DLin-MC3-DMA, PLGA, PEG, PEG-DMG. The lipid may be a cationic lipid such as DLin-DMA, DLin-D-DMA, DLin-MC3-DMA, DLin-KC2-DMA and DODMA (See [0155]-[0156] and [0207]).
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 may contain about 40-60% lipidoid, about 40-60% cholesterol, and about 5-10% 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]).
For administration by inhalation, the active compounds can be in a 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 [0231] and [0245]).
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]).
Lockhart et al teach an engineered that polynucleotide can be delivered to any suitable cell including for example, ciliary epithelial cells, lung epithelial cells, expression of DNAI1 in fully differentiated human airway epithelial cells (See [0037], [0209] and [0235]).
DNAI1-HA protein was expressed at high levels in both the undifferentiated and fully-differentiated, ciliated human airway epithelial cells and in mouse tracheal epithelial cells (See [0271]).
The said composition, upon administration to a subject, can have a transfection efficiency of at least about 80%, 90%, or 95% by the cell of the subject (See [0235]).
It is also disclosed that Fig. 2 illustrates the translations of DNAI1 mRNA in HEK-293 cells at 6 hours, 24 hours, and 48 hours post-transfection and that in HEK293 cells, translation of DNAI1 nucleic acid construct in HEK293 cells peaks at 6 hours but is still present at 48 hours. A polyribonucleotide can be translated in vivo to provide a protein whose gene has been associated with primary ciliary dyskinesia, a functional fragment thereof, or a protein that is at least 70% homologous to a human DNAI1 or a human DNAH5 protein (See [0014], [0132], [0243] and [0270]).
Lockhart et al disclose that treatment may be provided to the subject for a time period that is less than or equal to 12 months, 6 months, 1 month, 1 week, 1 day, 12 hours, 6 hours, after clinical onset of the disease. The said compositions can be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for about 1 month, for about 6 months, for about 12 months, or any appropriate length of time (See [0098]).
Thus, Lockhart et al teach a method of treating primary ciliary dyskinesia by administration of a composition comprising a heterologous polynucleotide encoding a dynein axonemal intermediate chain 1 (DNAI1) protein assembled with a lipid composition and wherein the lipid may be a combination of a cationic lipid and other lipids including a fusogenic lipid such as DSPC (a SORT lipid).
Lockhart et al do not expressly disclose that the lipid composition comprises 14:0 EPC, and a compound having a core-repeating unit-Terminating Group D-1. 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.
Cheng et al ‘220 teach compositions which shown 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). Similar to 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 teach 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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101
331
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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 substitu ted 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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218
652
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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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444
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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 D-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 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 into 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 disclose 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.
In a preferred embodiment, Karve et al disclose a concentration of the CO- hCFTR mRNA being 0.6 mg/ml, wherein a nebulizer was used to administer the CO- hCFTR composition by nebulization at a nebulization rate of approximately 0.3 mL/minute (See [0338)).
Karve et al teach that the nominal nitrogen/phosphorus (N/P) charge ratio which refers to the positively charged nitrogens in the cationic lipid and the negatively charged phosphodiester linkages within mRNA is about between 1 and 10 (See [0148)).
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 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 Lockhrat 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 a nucleic acid to the target cells with a lipid composition vehicle. Lockhart et al and Karve et al teach methods of treating a 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.
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.
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.
Claims 109-110, 112-115, 117, 119, 143-151, 153 and 155-156 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, Cheng et al, Karve et al and Zhou et al’s teachings are delineated above and incorporated.
The combined references lack a specific disclosure on the lipid composition comprising 14:0 TAP. This is remedied by the teachings of Angel et al.
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-trimethylammonium-propane (DOTAP / 18:1 TAP),
1,2-dioleoyl-3-dimethylammonium-propane (DODAP / 18:1 DAP), etc, (See pages 16-17 and Table 1 and claims 20 and 30).
Routes of administration for the said formulation includes inhalation and injection (See page 19, lines 15-18). The said formulations can be administered to treat a respiratory condition (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 Karve et al, Cheng et al as evidenced by Zhou et al and Angel et al with that of Lockhart et al to arrive at the instant invention.
The reasoning for combining Cheng et al and Karve et al were delineated above and incorporated herein.
It further would have been obvious to combine Angel et al’s teachings with that of the combined references because Angel et al, like other references teach delivery of nucleic acid to target cells by incorporating a lipid composition as the delivery vehicle. Angel et al teach formulations comprising nucleic acids and methods for delivering nucleic acids to cells, tissues, organs. Angel et al teach that the said 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, DODAP, etc.
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.
Thus, one of ordinary skill in the art would have been motivated to have combined Angel et al, Cheng et al, Karve et al and Lockhart et al’s teachings to prepare the claimed compositions comprising one or more effective lipids as taught by the references 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.
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 109-110, 112-115, 117, 119 and 143-156 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 12,337,068 in view of Cheng et al (WO 2020051220) and 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 Cheng et al and Angel et al.
Examined claim 109 is drawn to a method for treating a subject having or suspected of having primary ciliary dyskinesia (PCD), comprising administering to said subject a pharmaceutical composition comprising a heterologous polynucleotide assembled with a lipid composition, which heterologous polynucleotide encodes a dynein axonemal intermediate chain 1 (DNAI1) protein, thereby resulting in a heterologous expression of said DNAI1 protein within cells of said subject, wherein said lipid composition comprises 14:0 TAP or 14:0 EPC and a core-repeating unit terminating group (D-I).
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.
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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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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wherein, in Formula (D-VIII):
Y4 is alkanediyl(c≤18) or an alkanediyl(c≤18); and
R10 is hydrogen.
The differences are including examined claim being directed to a method of treating a lung condition, while reference claims are directed to a method selectively delivering the compositions to a subject’s lung and in the combination of compounds of the lipid composition. While examined claims require 14:0 TAP or 14:0 EPC, reference claim 1 requires comprise an ionizable lipid, a phospholipid, a PEG-lipid, and a sterol. Reference claims 11, 13 and 15 recite specific cationic lipids and other lipids such as phospholipids. These compounds are added by way of dependent claims in the examined Application. However, as taught by Cheng et al and Angel et al, these modifications would have been obvious. Cheng et al teach compositions which shown preferential targeting or delivery of a nucleic acid composition to a particular organ, wherein the composition comprises a steroid or sterol, an ionizable cationic lipid, a phospholipid, a PEG lipid, and a permanently cationic lipid, Cheng et al teach that the said delivery to the lung treats lung conditions. Angel et al also teach that the delivery lipid formulation may comprise one or more lipid compounds including 14:0TAP, 14:0 EPC, phospholipids, DODAP, etc. 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 lipid composition of Cheng et al with a reasonable expectation of success.
Claims 109-110, 112-115, 117, 119 and 143-156 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6-13, 15, 17-23, 25-27 of copending Application No. 18/420,141 (US 20240245619) (reference application) in view of Lockhart et al (US 20190117796) and 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 Lockhart et al and Angel et al.
Examined claim 109 is drawn to a method for treating a subject having or suspected of having primary ciliary dyskinesia (PCD), comprising administering to said subject a pharmaceutical composition comprising a heterologous polynucleotide assembled with a lipid composition, which heterologous polynucleotide encodes a dynein axonemal intermediate chain 1 (DNAI1) protein, thereby resulting in a heterologous expression of said DNAI1 protein within cells of said subject, wherein said lipid composition comprises 14:0 TAP or 14:0 EPC and a core-repeating unit terminating group (D-I).
Reference claim 1 is drawn to a method for treating a subject having or suspected of a lung disorder, comprising: administering at a nebulization flow rate of at least 0.2 mL/min to said subject by inhalation aerosol droplets having an average droplet size from about to about 0.5 micron (µm) to about 10 µm, the aerosol droplets comprising a lipid composition and a heterologous polynucleotide assembled with the lipid composition, with a molar ratio of nitrogen in said lipid composition to phosphate in said polynucleotide (N/P ratio) of no more than about 20:1, wherein at least about 85% of said polynucleotide is encapsulated in said lipid composition, which heterologous polynucleotide is a messenger RNA (mRNA). The lipid composition comprises DODAP, a phospholipid, a sterol, a PEG-lipid and a core-repeating unit terminating group (D-I).
The differences are in the combination of compounds of the lipid composition. While examined claims require 14:0 TAP or 14:0 EPC, reference claims require DODAP. The lipid composition in reference claim 1 also requires a phospholipid, a sterol and a PEG-lipid. These compounds are added by way of dependent claims in the examined Application. Additionally, the reference claims require at least 80% of said polynucleotide be encapsulated in said lipid composition, while examine claims do not. However, as taught by Lockhart et al and Angel et al, these modifications would have been obvious. Lockhart et al teach that the lipid composition may be a delivery vehicle or encapsule the polynucleotide. Angel et al also 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 lipid composition of Lockhart et al 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.
Response to Arguments
Applicant’s arguments with respect to Claims 109-115, 117, 119, 122-124, 127-129, 132, 134 and 140-142 have been considered but are moot because the new ground of rejection does not rely on the prior rejections of record.
In particular, the arguments are essentially related to the limitations added to the claims by amendment. The said limitations are rejected by the modified rejection including new references.
In conclusion:
Claims 109-110, 112-115, 117, 119 and 143-156 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616