DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Status
Applicant’s amendment filed 8/22/2024 has been entered. Claims 1-92 are cancelled. Claims 93-106 are pending and examined herein.
Specification
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure is objected to because it is not within the range of 50-150 words in length and further does not identity and use of lipid nanoparticles. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 38 (twice in para [000131] and page 83 (twice in para [000229]). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 93-106 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kariko (US20110143397A1; published 6/16/2011; Cite No. "AA" in IDS filed 10/9/2024), in view of Akinc (WO2010144740A1; published 12/16/2010; Cite No. "DP" in IDS filed 10/9/2024) and Knopov (US20130115274A1; filed 5/9/2013, effective filing date 11/4/2011; Cite No. "DD" in IDS filed 10/9/2024).
Kariko teaches compositions and methods for reprogramming somatic cells using purified RNA preparations comprising single-strand mRNA encoding an iPS cell induction factor (see abstract). Kariko further teaches aqueous solid lipid nanoparticle (SLN) dispersions (see para [0200]).
Regarding claim 93, Kariko teaches pharmaceutical compositions of an RNA molecule encapsulated in a lipid nanoparticle and describe a plurality of lipid nanoparticles (see para [0200]), where the lipid nanoparticles comprise an mRNA encoding a protein (see paras [0007] and [0019]-[0020]). Kariko further teaches that the lipid nanoparticles comprise a cationic compound and a PEG lipid (see paras [0034], [0177], and [0360]). Kariko further teaches that the mRNA comprises: (i) at least one 5'-cap structure (see para [0018]) and (ii) a 5'-UTR (see para [0036]). Kariko teaches that the mRNA comprises: (iii) an open reading frame encoding a polypeptide (a first iPS cell induction factor) and consisting of nucleotides including N1-methyl-pseudouridine, cytosine, adenine, and guanine (see paras [0020], [0140], and [0153]). Kariko further teaches (iv) a 3'-UTR that results in greater MRNA stability and higher expression of the mRNA in the cells (see para [0036]) and (v) a poly-A region of at least 100 nucleotides in length (see para [0036]).
Regarding claims 97-98, Kariko teaches that the at least one 5’ cap structure is cap0 (see para [0036]).
Regarding claim 99, Kariko teaches an alpha-globin-3' UTR that results in greater MRNA stability and higher expression of the MRNA in the cells (see para [0036]).
Regarding claim 100, Kariko teaches a poly-A region of at least 160 nucleotides in length (see para [0036]).
Regarding claim 101, Kariko teaches that the 5’-UTR comprises a Kozak sequence (see para [0121]).
However, Kariko does not specifically teach that the protein encoded by an mRNA is a secreted protein, that the lipid nanoparticles comprise a cationic lipid, a neutral lipid, cholesterol, and a PEG lipid, and does not teach that the plurality of lipid nanoparticles have a mean particle size of between 80 nm and 160 nm (claim 93). Kariko further does not teach that the cationic lipid is biodegradable (claim 94) and that the biodegradable cationic lipid comprises an ester linkage (claim 95) and comprises DLin-MC3-DMA with a terminal ester (claim 96). Kariko does not teach that the plurality of lipid nanoparticles has a mean PDI of between 0.02 and 0.2 (claim 102) or that the plurality of lipid nanoparticles has a mean lipid to polynucleotide ratio (wt/wt) of between 10 and 20 (claim 103). Kariko does not teach that upon administration to a mammalian cell, the mRNA has increased expression of the encoded secreted protein relative to a corresponding mRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine (claim 104) or that the mRNA has a longer half-life or greater area under the curve of secreted protein expression relative to a corresponding mRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine (claim 105). Kariko further does not specifically teach that upon administration to peripheral blood mononuclear cells, the mRNA induces detectably lower levels of IFN-α or TNF-α relative to a corresponding mRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine (claim 106).
Akinc teaches a cationic lipid of formula (I), an improved lipid formulation comprising a cationic lipid of formula I and a nucleic acid therapeutic agent, and corresponding methods of use (see abstract and claims 10-11, 25, and 30).
Regarding claim 93, Akinc teaches a plurality of lipid nanoparticles comprising a cationic lipid, a neutral lipid, a cholesterol, and a PEG lipid (see p. 5, para 5). Akinc further teaches that the plurality of lipid nanoparticles has a mean particle size of between 80 nm and 160 nm (see p. 019, para 2). Akinc teaches that the lipid nanoparticles comprise an mRNA encoding a secreted protein (see p. 105, para 3 and p. 135, para 1).
Regarding claims 94-96, Akinc teaches that the biodegradable cationic lipid nanoparticle comprises DLin-MC3-DMA with a terminal ester (p. 5, para 4).
Regarding claim 103, Akinc teaches that the plurality of lipid nanoparticles has a mean lipid to polynucleotide ratio (wt/wt) of between 10 and 20 (see p. 109, para 2).
Knopov teaches a method for preparing a liposome that efficiently encapsulates a negatively charged therapeutic polymer, e.g., siRNA, involving preparing a lipid mixture comprising a cationic lipid in a water miscible organic solvent, where the resulting nanoparticles have a mean size of 50 to 150 nm (see abstract).
Regarding claim 102, Knopov teaches that that the plurality of lipid nanoparticles has a mean PDI of between 0.02 and 0.2 (see para [0028]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Kariko’s lipid nanoparticle comprising a cationic lipid, a neutral lipid, cholesterol, and a PEG lipid and mRNA encoding a secreted protein as described by Akinc and to have used the method of Knopov to produce the nanoparticles. A person of ordinary skill in the art would be motivated to do so in order to have lipid nanoparticles that protect the encapsulated nucleic acid from degradation and clearance in serum, are suitable for systemic delivery, provide intracellular delivery of the encapsulated nucleic acid, are well-tolerated and provide an adequate therapeutic index, such that patient treatment at an effective dose of the nucleic acid is not associated with significant toxicity and/or risk to the patient (Akinc; p. 4, para 2). A person of ordinary skill in the art would have been further motivated to do so in order to have lipid nanoparticles that are uniform in size without extra steps required to mechanically process the particles (Knopov, para [0029]). Given the teachings of the prior art and the level of the ordinary skilled artisan at the time of the applicant’s invention, it must be considered, absent evidence to the contrary, that said skilled artisan would have had a reasonable expectation of success in practicing the claimed invention. Thus, the claimed invention as a whole is prima facie obvious.
Regarding the limitations “wherein, upon administration to a mammalian cell, the mRNA has increased expression of the encoded secreted protein relative to a corresponding mRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine” (claim 104); “wherein, upon administration to a mammalian cell, the mRNA has a longer half-life or greater area under the curve of protein expression relative to a corresponding MRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine” (claim 105); and “wherein, upon administration to peripheral blood mononuclear cells, the mRNA induces detectably lower levels of IFN-α or TNF-α relative to a corresponding mRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine” (claim 106); MPEP 2112.01 (II) recites “[P]roducts of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present”. This is the instant case. The limitations of claims 104-106 recite properties of the modified mRNA and do not change the structure of the claimed product. Because the mRNA of Kariko in view of Akinc and in view of Knopov is identical to that of the instant claims, then the claimed properties in claims 104-106 are necessarily present.
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
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 93-94 and 97-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 and 8-10 of U.S. Patent No. US10501512B2 (Cite No. “F*” in IDS filed 10/9/2024). Although the claims at issue are not identical, they are not patentably distinct from each other because there is significant overlap in the claims.
Claims 1-6 and 8-10 of the ‘512 patent teach a pharmaceutical composition comprising a plurality of lipid nanoparticles comprising a cationic lipid, a PEGylated lipid, cholesterol, and a phospholipid, wherein the mean particle size of the plurality of lipid nanoparticles is 80 nm to 160 nm and the lipid nanoparticles encapsulate a polynucleotide, where the polynucleotide comprises; (a) a first region of linked nucleosides, said first region encoding the secreted protein factor IX, wherein said first region of linked nucleosides consists of nucleotides selected from 1-methyl-pseudouridine, cytidine, adenosine, and guanosine; (b) a first flanking region located at the 5′-terminus of said first region comprising; (i) a 5′-untranslated region (5′-UTR); and (ii) 5′ terminal cap; (c) a second flanking region located at the 3′-terminus of said first region comprising; (i′) a 3′-untranslated region (3′-UTR); and (ii′) a 3′-tailing sequence of about 160 linked nucleosides (claim 93). Claim 3 of the ‘512 patent teaches 5′ terminal caps selected from Cap0, Cap1, ARCA, inosine, N1-methyl-guanosine, 2′-fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine (claims 97-98). Claims 6 and 7-8 of the ‘512 patent teach that the cationic lipid is selected from DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, 98N12-5, C12-200, DLin-MC3-DMA, DODMA, DSDMA, and DLenDMA (claims 94-96) and that at least one of the 5′-UTR or the 3′-UTR is not derived from beta-globin (claim 99). Thus, instant claims 93-94 and 97-100 are anticipated by claims 1-6 and 8-10 of U.S. Patent No. US10501512B2.
Claims 93-94 and 97-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 8-13, 15-16, and 18 of U.S. Patent No. US10493167B2 (Cite No. “V*” in IDS filed 10/9/2024). Although the claims at issue are not identical, they are not patentably distinct from each other because there is significant overlap in the claims.
Claims 1-3, 8-13, 15-16, and 18 of the ‘167 patent teach a method of expressing a secreted protein in a mammalian subject, the method comprising administering a pharmaceutical composition comprising a plurality of lipid nanoparticles encapsulating a polynucleotide, where the lipid nanoparticle comprising a biodegradable a cationic lipid, a neutral lipid, cholesterol, and a PEGylated lipid, and wherein the mean particle size of the plurality of lipid nanoparticles is 80 nm to 160 nm, and where the polynucleotide comprises; (a) an open reading frame encoding the secreted protein consisting of nucleotides selected from 1-methyl-pseudouridine, cytidine, adenosine, and guanosine; (b) a 5′-UTR; (c) at least one 5′ cap structure; (d) a 3′-UTR; and (e) a 3′ tailing sequence of linked nucleosides (claim 93). Claims 1-3, 8-13, 15-16, and of the ‘167 patent further teach that the 5′ terminal cap is selected from the group consisting of Cap0, Cap1, ARCA, inosine, N1-methyl-guanosine, 2′-fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine. Claims 1-3, 8-13, 15-16, and 18 of the ‘167 patent teach that the poly-A tail is approximately 160 nucleotides, that the plurality of lipid nanoparticles has a mean PDI of between 0.02 and 0.2, and that the plurality of lipid nanoparticles has a mean lipid to polynucleotide ratio (wt/wt) of between 10 and 20. Claims 1-3, 8-13, 15-16, and 18 of the ‘167 patent further teach that the 5′-UTR comprises a Kozak sequence. Thus, instant claims 93-94 and 97-100 are anticipated by claims 1-3, 8-13, 15-16, and 18 of U.S. Patent No. US-10493167-B2.
Claims 93-106 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. US10703789B2 (cited in the PTO-892) in view of Akinc (WO2010144740A1; of record).
Claims 1-14 of the ’789 patent teach a pharmaceutical composition comprising: a plurality of lipid nanoparticles comprising a cationic lipid, a neutral lipid, a cholesterol, and a PEG lipid, wherein the plurality of lipid nanoparticles has a mean particle size of between 80 nm and 160 nm; and wherein the lipid nanoparticles comprise an mRNA encoding a polypeptide, wherein the mRNA comprises: (i) at least one 5'-cap structure; (ii) a 5'-UTR; (iii) an open reading frame encoding the polypeptide and consisting of nucleotides including N1-methyl-pseudouridine, cytosine, adenine, and guanine; (iv) a 3'-UTR; and (v) a poly-A region of least 100 nucleotides in length (claim 93). Claims 2-3 of the ’789 patent further teach that the cationic lipid is a biodegradable (claim 94), comprises an ester linkage (claim 95), and comprises a DLin-MC3-DMA with a terminal ester (claim 96). Claims 5-6 and 7 of the ’789 patent teach cap0, cap1, or ARCA 5’-cap structures (claims 97-98) and an alpha-globin 3'-UTR (claim 99). Claims 8-11 of the ’789 patent further teach that the poly-A tail is at least 160 nucleotides in length (claim 100), the 5'-UTR comprises a Kozak sequence (claim 101), that the plurality of lipid nanoparticles has a mean PDI of between 0.02 and 0.2 (claim 102), and the plurality of lipid nanoparticles has a mean lipid to polynucleotide ratio (wt/wt) of between 10 and 20 (claim 103). Claims 12-14 of the ’789 patent further teach that upon administration to a mammalian cell, the mRNA has increased expression of the encoded polypeptide relative to a corresponding mRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine, that upon administration to a mammalian cell, the mRNA has a longer half-life or greater area under the curve of protein expression relative to a corresponding mRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine and that upon administration to peripheral blood mononuclear cells, the mRNA induces detectably lower levels of lFN-α or TNF-α relative to a corresponding mRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine (claims 104-106).
However, claims 1-14 of the ’789 patent do not teach that the mRNA encodes a secreted protein.
Akinc teaches a cationic lipid of formula (I), an improved lipid formulation comprising a cationic lipid of formula I and a nucleic acid therapeutic agent, and corresponding methods of use (see abstract and claims 10-11, 25, and 30).
Regarding claim 93, Akinc teaches that the lipid nanoparticles comprise an mRNA encoding a secreted protein (see p. 105, para 3 and p. 135, para 1).
Therefore, it would have been obvious to a person of ordinary skill at the time of the invention to formulate the pharmaceutical composition of claims 1-14 of the ’789 patent with an mRNA encoding a secreted protein to produce the nanoparticles. A person of ordinary skill in the art would be motivated to do so in order to have lipid nanoparticles that protect the encapsulated nucleic acid encoding a secreted protein from degradation and clearance in serum and are suitable for systemic delivery to treat a condition needing expression of the secreted protein to alleviate symptoms (Akinc; p. 4, para 2; p. 7, para 5). Given the teachings of the prior art and the level of the ordinary skilled artisan at the time of the applicant’s invention, it must be considered, absent evidence to the contrary, that said skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
Claims 93-106 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. US10577403B2 (Cite No. “X*” in IDS filed 10/9/2024) in view of Akinc (WO2010144740A1; of record).
Claims 1 and 12 of the ’403 patent teach a pharmaceutical composition comprising: a plurality of lipid nanoparticles comprising a cationic lipid, a neutral lipid, a cholesterol, and a PEG lipid, wherein the plurality of lipid nanoparticles has a mean particle size of between 80 nm and 160 nm; and wherein the lipid nanoparticles comprise an mRNA encoding a polypeptide, wherein the mRNA comprises: (i) at least one 5'-cap structure; (ii) a 5'-UTR; (iii) an open reading frame encoding the polypeptide and consisting of nucleotides including, N1-methyl-pseudouridine, cytosine, adenine, and guanine; (iv) a 3'-UTR; and (v) a poly-A region of least 100 nucleotides in length (claim 93). Claims 2-4 of the ‘403 patent further teach that the cationic lipid is a biodegradable (claim 94), comprises an ester linkage (claim 95), and comprises a DLin-MC3-DMA with a terminal ester (claim 96). Claims 5-6 and 7 of the ‘403 patent teach cap0, cap1, or ARCA 5’-cap structures (claims 97-98) and an alpha-globin 3'-UTR (claim 99). Claims 8-11 the ‘403 patent further teach that the poly-A tail is at least 160 nucleotides in length (claim 100), the 5'-UTR comprises a Kozak sequence (claim 101), that the plurality of lipid nanoparticles has a mean PDI of between 0.02 and 0.2 (claim 102), and the plurality of lipid nanoparticles has a mean lipid to polynucleotide ratio (wt/wt) of between 10 and 20 (claim 103). Claims 14-16 of the ’403 patent further teach that upon administration to a mammalian cell, the mRNA has increased expression of the encoded polypeptide relative to a corresponding mRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine (claim 104), that upon administration to a mammalian cell, the mRNA has a longer half-life or greater area under the curve of protein expression relative to a corresponding mRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine (claim 105) and that upon administration to peripheral blood mononuclear cells, the mRNA induces detectably lower levels of lFN-α or TNF-α relative to a corresponding mRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine (claim 106).
However, claims 1-16 of the ’403 patent do not teach that the mRNA encodes a secreted protein.
Akinc teaches a cationic lipid of formula (I), an improved lipid formulation comprising a cationic lipid of formula I and a nucleic acid therapeutic agent, and corresponding methods of use (see abstract and claims 10-11, 25, and 30).
Regarding claim 93, Akinc that the lipid nanoparticles comprise an mRNA encoding a secreted protein (see p. 105, para 3 and p. 135, para 1).
Therefore, it would have been obvious to a person of ordinary skill at the time of the invention to formulate the pharmaceutical composition of claims 1-16 of the ’403 patent with an mRNA encoding a secreted protein to produce the nanoparticles. A person of ordinary skill in the art would be motivated to do so in order to have lipid nanoparticles that protect the encapsulated nucleic acid encoding a secreted protein from degradation and clearance in serum and are suitable for systemic delivery to treat a condition needing expression of the secreted protein to alleviate symptoms (Akinc; p. 4, para 2; p. 7, para 5). Given the teachings of the prior art and the level of the ordinary skilled artisan at the time of the applicant’s invention, it must be considered, absent evidence to the contrary, that said skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
Claims 93-100 and 102-105 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. US10385106B2 (cited in the PTO-892) in view of Kariko (US20110143397A1; of record) and Akinc (WO2010144740A1; of record).
Claims 1-12 of the ‘106 patent teach a pharmaceutical composition comprising a plurality of lipid nanoparticles comprising a cationic lipid, a neutral lipid, a cholesterol, and a PEG lipid, wherein the plurality of lipid nanoparticles has a mean particle size of between 80 nm and 160 nm, a mean PDI of between 0.02 and 0.2, and a mean lipid to polynucleotide ratio (wt/wt) of between 10 and 20 and wherein the lipid nanoparticles comprise an mRNA encoding a polypeptide, wherein the mRNA comprises: (i) at least one 5'-cap structure; (ii) a 5'-UTR; (iii) an open reading frame encoding the polypeptide and consisting of nucleotides including 5-methoxy-uracil, cytosine, adenine, and guanine; (iv) a 3'-UTR; and (v) a poly-A region of least 160 nucleotides in length (claim 93). Claims 4 and 5 of the ‘106 patent teaches cap0, cap1, or ARCA 5’-cap structures (claims 97-98) and an alpha-globin 3'-UTR (claim 99). Claims 6-9 of the ‘106 patent further teach that the poly-A tail is at least 160 nucleotides in length (claim 100), the 5'-UTR comprises a Kozak sequence (claim 101), that the plurality of lipid nanoparticles has a mean PDI of between 0.02 and 0.2 (claim 102), and the plurality of lipid nanoparticles has a mean lipid to polynucleotide ratio (wt/wt) of between 10 and 20 (claim 103). Claims 10-12 of the ‘106 patent further teach that upon administration to a mammalian cell, the mRNA has increased expression of the encoded polypeptide relative to a corresponding mRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine and that the mRNA has a longer half-life or greater area under the curve of protein expression relative to a corresponding mRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine (claim 104).
However, claims 1-12 of the ‘106 patent do not teach that the mRNA encodes a secreted protein or that the ORF encoding the polypeptide comprises an mRNA including N1-methyl-pseudouridine (claim 93).
Kariko teaches compositions and methods for reprogramming somatic cells using purified RNA preparations comprising single-strand mRNA encoding an iPS cell induction factor (see abstract). Kariko further teaches aqueous solid lipid nanoparticle (SLN) dispersions (see para [0200]).
Regarding claim 93, Kariko teaches that the mRNA comprises: (iii) an open reading frame encoding a polypeptide (a first iPS cell induction factor) and consisting of nucleotides including N1-methyl-pseudouridine, cytosine, adenine, and guanine (see paras [0020], [0140], and [0153]).
Akinc teaches a cationic lipid of formula (I), an improved lipid formulation comprising a cationic lipid of formula I and a nucleic acid therapeutic agent, and corresponding methods of use (see abstract and claims 10-11, 25, and 30).
Regarding claim 93, Akinc teaches that the lipid nanoparticles comprise an mRNA encoding a secreted protein (see p. 105, para 3 and p. 135, para 1).
Therefore, it would have been obvious to a person of ordinary skill at the time of the invention to formulate the pharmaceutical composition of claims 1-12 of the ‘106 patent with an mRNA encoding a secreted protein to produce the nanoparticles. A person of ordinary skill in the art would be motivated to do so in order to have lipid nanoparticles that protect the encapsulated nucleic acid encoding a secreted protein from degradation and clearance in serum and are suitable for systemic delivery to treat a condition needing expression of the secreted protein to alleviate symptoms (Akinc; p. 4, para 2; p. 7, para 5). Given the teachings of the prior art and the level of the ordinary skilled artisan at the time of the applicant’s invention, it must be considered, absent evidence to the contrary, that said skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
Claims 93-95, 97-98 and 100-106 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 14-15, and 17 of U.S. Patent No. US10583203B2 (Cite No. “M*” in IDS filed 10/9/2024) in view of Akinc (WO2010144740A1; or record).
Claims 1-12 and 17 of the ‘203 patent teach a method of expressing a protein in a mammalian subject, the method comprising administering a pharmaceutical composition comprising a plurality of lipid nanoparticles encapsulating a polynucleotide, wherein the lipid nanoparticle comprises a biodegradable cationic lipid, a neutral lipid, cholesterol, and a PEGylated lipid and the plurality of lipid nanoparticles has a mean particle size of between 80 nm to 160 nm, and wherein the polynucleotide comprises (a) an open reading frame encoding the protein consisting of nucleotides selected from 1-methyl-pseudouridine, cytidine, adenosine, and guanosine; (b) a 5′-UTR; (c) at least one 5′ cap structure; (d) a 3′-UTR; and (e) a 3′ tailing sequence of linked nucleosides (claim 93). Claim 2 of the ‘203 patent teaches that the biodegradable cationic lipid comprises an ester linkage (claims 94-95). Claims 8-10 of the ‘203 patent further teach that the at least one 5′ cap structure is selected from the group consisting of Cap0, Cap1, ARCA, inosine, N1-methyl-guanosine, 2′fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine (claim 97-98) and that the poly-A tail comprises approximately 160 nucleotides (claim 100). Claim 14 of the ‘203 patent teaches the 5’ UTR comprising a Kozak sequence (claim 101).
However, claims 1-12, 14-15, and 17 of the ‘203 patent do not teach that the mRNA encodes a secreted protein.
Akinc teaches a cationic lipid of formula (I), an improved lipid formulation comprising a cationic lipid of formula I and a nucleic acid therapeutic agent, and corresponding methods of use (see abstract and claims 10-11, 25, and 30).
Regarding claim 93, Akinc teaches that the lipid nanoparticles comprise an mRNA encoding a secreted protein (see p. 105, para 3 and p. 135, para 1).
Therefore, it would have been obvious to a person of ordinary skill at the time of the invention to formulate the pharmaceutical composition of claims 1-12, 14-15, and 17 of the ‘203 patent with an mRNA encoding a secreted protein to produce the nanoparticles. A person of ordinary skill in the art would be motivated to do so in order to have lipid nanoparticles that protect the encapsulated nucleic acid encoding a secreted protein from degradation and clearance in serum and are suitable for systemic delivery to treat a condition needing expression of the secreted protein to alleviate symptoms (Akinc; p. 4, para 2; p. 7, para 5). Given the teachings of the prior art and the level of the ordinary skilled artisan at the time of the applicant’s invention, it must be considered, absent evidence to the contrary, that said skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
The polynucleotide of claims 1-12, 14-15, and 17 of the ‘203 patent in view of Akinc is identical to that of the instant claims, therefore the claimed properties in claims 104-106 are necessarily present as discussed above in the U.S.C. 103(a) rejection above. Accordingly, claims 1-12, 14-15, and 17 of the ‘203 patent and Akinc render obvious claims 93-95, 97-98 and 100-106.
Claims 93-106 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. US10772975B2 (Cite No. “A*” in IDS filed 10/9/2024) in view of Akinc (WO2010144740A1; of record).
Claims 1-11 of the ‘975 patent teach a pharmaceutical composition comprising a plurality of lipid nanoparticles comprising a cationic lipid, a neutral lipid, a cholesterol, and a PEG lipid, wherein the plurality of lipid nanoparticles has a mean particle size of between 80 nm and 160 nm; and where the lipid nanoparticles comprise an mRNA encoding a polypeptide, wherein the mRNA comprises: (i) at least one 5′-cap structure; (ii) a 5′-UTR; (iii) an open reading frame encoding the polypeptide and consisting of nucleotides including uracil, cytosine, adenine, and guanine; (iv) a 3′-UTR; and (v) a poly-A region of least 160 nucleotides in length. Claims 1-11 of the ‘975 patent further teach that the biodegradable cationic lipid comprises an ester linkage and comprises DLin-DMA with an internal ester, DLin-DMA with a terminal ester, DLin-MC3-DMA with an internal ester, or DLin-MC3-DMA with a terminal ester. Claims 1-11 of the ‘975 patent further teach that the at least one 5′ cap structure is selected from the group consisting of Cap0, Cap1, ARCA, inosine, N1-methyl-guanosine, 2′ fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine. Claims 1-11 of the ‘975 patent teach that the 3′-UTR is an alpha-globin 3′-UTR, the 5′-UTR comprises a Kozak sequence, that the plurality of lipid nanoparticles has a mean PDI of between 0.02 and 0.2, and that the plurality of lipid nanoparticles has a mean lipid to polynucleotide ratio (wt/wt) of between 10 and 20.
However, claims 1-11 of the ‘975 patent do not teach that the mRNA encodes a secreted protein.
Akinc teaches a cationic lipid of formula (I), an improved lipid formulation comprising a cationic lipid of formula I and a nucleic acid therapeutic agent, and corresponding methods of use (see abstract and claims 10-11, 25, and 30).
Regarding claim 93, Akinc teaches that the lipid nanoparticles comprise an mRNA encoding a secreted protein (see p. 105, para 3 and p. 135, para 1).
Therefore, it would have been obvious to a person of ordinary skill at the time of the invention to formulate the pharmaceutical composition of claims 1- of the ‘975 patent with an mRNA encoding a secreted protein to produce the nanoparticles. A person of ordinary skill in the art would be motivated to do so in order to have lipid nanoparticles that protect the encapsulated nucleic acid encoding a secreted protein from degradation and clearance in serum and are suitable for systemic delivery to treat a condition needing expression of the secreted protein to alleviate symptoms (Akinc; p. 4, para 2; p. 7, para 5). Given the teachings of the prior art and the level of the ordinary skilled artisan at the time of the applicant’s invention, it must be considered, absent evidence to the contrary, that said skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
The polynucleotide of claims 1-11 of the ‘975 patent in view of Akinc is identical to that of the instant claims, therefore the claimed properties in claims 104-106 are necessarily present as discussed above in the U.S.C. 103(a) rejection above. Accordingly, claims 1-11 of the ‘975 patent and Akinc render obvious claims 93-106.
Claims 93-95 and 97-98 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6-9 of U.S. Patent No. US10463751B2 (Cite No. “S*” in IDS filed 10/9/2024) in view of Akinc (WO2010144740A1; of record).
Claims 1 and 6-9 of the ‘715 patent teach a pharmaceutical composition comprising a plurality of lipid nanoparticles comprising a cationic lipid, a non-cationic lipid, cholesterol, and a PEG lipid, wherein the plurality of lipid nanoparticles has a mean particle size of between 80 nm and 160 nm and encapsulate an mRNA comprising: (a) an open reading frame encoding a cytoskeletal protein and consisting of nucleotides selected from N1-methyl-pseudouridine, cytidine, adenosine, and guanosine; (b) a 5′-untranslated region (UTR); (c) at least one 5′ cap structure; (d) a 3′-UTR; and (e) a 3′ tailing sequence of linked nucleosides (claim 93). Claims 1 and 6-9 of the ‘715 patent further teach that the cationic lipid is biodegradable (claim 94) and comprises at least one ester linkage (claim 95). Claim 6 of the ‘715 patent teaches that the 5’ cap can be Cap0, Cap1, ARCA, inosine, N1-methyl-guanosine, 2′ fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine (claims 97-98).
However, claims 1 and 6-9 of the ‘715 patent do not specifically teach that the mRNA encodes a secreted protein.
Akinc teaches a cationic lipid of formula (I), an improved lipid formulation comprising a cationic lipid of formula I and a nucleic acid therapeutic agent, and corresponding methods of use (see abstract and claims 10-11, 25, and 30).
Regarding claim 93, Akinc teaches that the lipid nanoparticles comprise an mRNA encoding a secreted protein (see p. 105, para 3 and p. 135, para 1).
Therefore, it would have been obvious to a person of ordinary skill at the time of the invention to formulate the pharmaceutical composition of claims 1 and 6-9 of the ‘715 patent with an mRNA encoding a secreted protein instead of a cytoskeletal protein to produce the nanoparticles. A person of ordinary skill in the art would be motivated to do so because it amounts to a simple substitution. Given the teachings of the prior art and the level of the ordinary skilled artisan at the time of the applicant’s invention, it must be considered, absent evidence to the contrary, that said skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
Claims 93-98 and 100-106 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of copending Application No. 16/860121 (PGPub 20220273555, cited in the PTO-892) in view of Akinc (WO2010144740A1; of record).
Claims 1-10 of copending Application No. 16/860121 teach a composition comprising a plurality of lipid nanoparticles, wherein the lipid nanoparticles encapsulate an mRNA encoding a polypeptide, wherein the mRNA comprises: (i) at least one 5'-cap structure; (ii) a 5'-UTR; (iii) an open reading frame encoding the polypeptide and consisting of nucleotides including modified 1-methyl-psuedouridine, cytosine, adenine, and guanosine; (iv) a 3'-UTR; and (v) a poly-A region of least 160 nucleotides in length (claims 93 and 100). Claims 1-10 of copending Application No. 16/860121 teach that upon administration to a mammalian cell, the mRNA has increased expression of the encoded polypeptide relative to a corresponding mRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine (claim 104). Claims 1-10 of copending Application No. 16/860121 teach cationic lipid nanoparticles comprising a PEGylated lipid, a cholesterol, and a phospholipid, wherein the plurality of lipid nanoparticles has a mean particle size of between 80 nm and 160 nm (claim 93), that the plurality of lipid nanoparticles has a mean PDI of between 0.02 and 0.2 (claim 102), and the plurality of lipid nanoparticles has a mean lipid to polynucleotide ratio (wt/wt) of between 10 and 20 (claim 103). Claim 6 of copending Application No. 16/860121 further teaches the 5’-cap structures are Cap0, Cap1, or ARCA 5’-cap structures (claims 97-98). Claims 1-10 of copending Application No. 16/860121 that upon administration to a mammalian cell, the mRNA has a longer half-life or greater area under the curve of protein expression relative to a corresponding MRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine and upon administration to peripheral blood mononuclear cells, the mRNA induces detectably lower levels of IFN-α or TNF-α relative to a corresponding MRNA comprising an open reading frame consisting of nucleotides including uracil, cytosine, adenine, and guanine (claims 104-106).
However, claims 1-10 of copending Application No. 16/860121 do not teach that the mRNA encodes a secreted protein (claim 93) and further does not teach that the lipid nanoparticles comprise DLin-MC3-DMA with a terminal ester (claim 95-96).
Akinc teaches a cationic lipid of formula (I), an improved lipid formulation comprising a cationic lipid of formula I and a nucleic acid therapeutic agent, and corresponding methods of use (see abstract and claims 10-11, 25, and 30).
Regarding claim 93, Akinc teaches that the lipid nanoparticles comprise an mRNA encoding a secreted protein (see p. 105, para 3 and p. 135, para 1).
Regarding claims 95-96, Akinc teaches that the biodegradable cationic lipid nanoparticle comprises DLin-MC3-DMA with a terminal ester (p. 5, para 4).
Therefore, it would have been obvious to a person of ordinary skill at the time of the invention to formulate the pharmaceutical composition of the instant invention from the method of claims 1-10 of copending Application No. 16/860121 with an mRNA encoding a secreted protein to produce the nanoparticles comprising DLin-MC3-DMA with a terminal ester. A person of ordinary skill in the art would be motivated to do so in order to have lipid nanoparticles that protect the encapsulated nucleic acid encoding a secreted protein from degradation and clearance in serum and are suitable for systemic delivery to treat a condition needing expression of the secreted protein to alleviate symptoms (Akinc; p. 4, para 2; p. 7, para 5). Given the teachings of the prior art and the level of the ordinary skilled artisan at the time of the applicant’s invention, it must be considered, absent evidence to the contrary, that said skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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/KHALEDA B HASAN/Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
