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 .
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 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.
Priority
The instant application, filed 06/05/2023, is a 371 filing of PCT/US2021/062389, filed 12/08/2021, and claims domestic benefit to US provisional application 63/122,886, filed 12/08/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/27/2024, 04/15/2025, 11/18/2025, and 03/13/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Status of Claims/Application
Applicant’s amendment of 03/13/2026 is acknowledged. Claims 1 and 9-10 are amended and claims 2-3, 5, 11, 13-16, 18-30, 32-33, 35-36, 38, 40, 42, 44-61, 63-64, 66-67, 69, 71, 73-76, and 78-94 are cancelled. Claims 1, 4, 6-10, 12, 17, 31, 34, 37, 39, 41, 43, 62, 65, 68, 70, 72, and 77 are currently pending.
Election/Restrictions
Applicant's election with traverse of the following groups/species in the reply filed on 03/13/2026 is acknowledged.
In the restriction requirement of 12/16/2025, applicant was required to elect a single invention from the nucleic acid sequence (group I), the mammalian cell (group II), and a method of treating a patient (group III). Applicant elected group 1.
Applicant was further required to elect from the following species:
One cholesterol degrading protein. Applicant elected P450-FdxR-Fdx;
One structure for comprising the nucleic acid. Applicant elected a lipid nanoparticle; and
One method for transforming a mammalian cell. Applicant elected in vivo transforming as recited in claim 12.
The traversal is on the ground(s) that the groups share a special technical feature and meet the requirements of unity of invention. Upon further consideration, the restriction requirement is withdrawn.
Claims 1, 4, 6-10, 12, 17, 31, 34, 37, 39, 41, 43, 62, 65, 68, 70, 72, and 77 are examined on the merits herein.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 72 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 72 recites the limitation "the mammalian cell’s genome" in line 2. There is insufficient antecedent basis for the recitation “the mammalian cell” in the claim. Claim 72 depends on claim 62 which recites “at least one modified cell”. Neither claim recites a mammalian cell that could be being referenced.
Appropriate correction is required.
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, 6-8, 10, 12, 17, 31, 37, 39, 41, 43, 62, 68, 70, 72, and 77 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0179452 A1 (Honkanen, R.E., et al) 11 JUN 2020; effective filing date of 01 Nov 2018 in view of US 6,903,183 B1 (Stocco, D.M., et al) 7 JUN 2005 and Sugawara, T., et al (1995) Human steroidogenic acute regulatory protein: Functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13 Proc. Natl. Acad. Sci. USA 92; 4778-4782.
US’452 teaches compositions, methods, and systems for modifying sterol metabolism in a subject and compositions and methods useful in lowering cholesterol levels in a subject in need thereof (abstract). US’452 teaches methods to humanize and express the enzymes that aid in catalyzing cholesterol degradation, including side chain modification, ring modifications, and modifications leading to ring opening. US’452 teaches that the disclosed methods will aid in the development of genetic and cell-based therapies allowing for an entirely new approach for the management of cardiovascular disease (page 1, [0007]).
US’452 further teaches that the methods, compositions, and systems may be useful in modifying mammalian cells to express one or more non-mammalian enzymes active in sterol catabolism. In some embodiments, the mammalian cells may be immune cells, such as monocytes. In some embodiments, the monocytes are macrophages and the sterol is cholesterol (page 1, [0008]). US’452 teaches methods for modifying a mammalian cell with nucleic acid compositions that enable and/or promote expression of one or more proteins useful in degrading a sterol. The composition includes a vector having one or more control sequences for promoting the expression of one or more protein coding sequences. In some embodiments the vector is a viral vector or a transposable element (page 1, [0009]). US’452 also teaches that the methods and compositions are useful in creating modified human cells capable of degrading cholesterol (page 1, [0011]). US’452 also teaches the use of lentiviral integration and that the disclosed systems, methods, and compositions additionally may use transposon mediated integration of the disclosed cassettes (page 24, [0205]). The use of lentiviral integration and transposon, as taught by US’452, would result in integration of the disclosed cassettes into the genome of the host cell.
US’452 teaches a nucleic acid composition comprising: a coding sequence coding for one or more proteins and a control sequence for regulating the transcription of one or more of the coding sequences, wherein the proteins are sterol metabolism proteins (page 77, claim 1). US’452 teaches that the sterol metabolism proteins are selected from cholesterol dehydrogenase (CholD), 3-ketosteroid Δ1-dehydrogenase (Δ1-KstD), anoxic cholesterol metabolism B enzyme (acmB), 3-ketosteroid 9a-hydroxylase (KshAB), 3β-hydroxysteroid dehydrogenase 2 (HSD2), and P450-ferredoxin reductase-ferredoxin fusion protein (P450-FdxR-Fdx). Additionally, US’452 teaches that the control sequence is a eukaryotic transcription promoter sequence (page 77, claims 2-3).
US’452 further provides an amino acid sequence of the P450-FdxR-Fdx fusion protein construct. The construct includes the minimal structures of the P450scc cholesterol side chain cleavage enzyme (CYP11A1), ferredoxin reductase (FdxR), and ferredoxin (Fdx) enzymes fused using short linkers. The amino acid sequence also includes a mitochondrial targeting sequence (page 14, [0106]; Fig. 84). US’452 also teaches that the P450-FdxR-Fdx fusion protein removes the hydrophobic side chain of cholesterol (CL) to produce pregnenolone (PL) (pages 3-4, [0029]).
US’452 teaches a method of regulating a sterol concentration comprising the steps of modifying an immune cell of the subject by introducing the nucleic acid; allowing the immune cell to express one or more sequences from the nucleic acid, wherein the nucleic acid codes for one or more proteins involved in sterol metabolism; administering the modified cell to the subject; and allowing the modified cell to degrade the sterol (page 77, claim 6).
US’452 further studied the cholesterol side chain removal and 3-ketone production pathway and teaches that the rate-limiting step for initiating cholestane ring opening via the disclosed pathway is placed on the P450-FdxR-Fdx fusion protein. US’452 teaches that the bottleneck for degrading cholesterol is the P450 side chain cleavage enzyme, which also acts as the natural rate limiting enzyme in steroidogenesis (pages 23-24, [0203]).
US’452 further teaches that the cell-based approach disclosed can be used to help manage homozygous familial hypercholesterolemia (FH). FH patients lack functional LDL receptors, which prevents the uptake of low density lipoproteins (LDLs) by the liver and other tissues. As a result, high levels of circulating LDLs are presented to macrophages, which express scavenger receptors that take in LDLs. Because humans lack enzymes to degrade cholesterol, and SRs are not sterol responsive, the macrophages fill with cholesterol and cholesterol esters (CE) and become foam cells. Engineering human macrophages to express cholesterol ring opening enzymes can enable cholesterol catabolism in human cells (page 18, [0166]).
US’452, however, does not teach that the nucleic acid or modified cells comprises a coding sequence for StAR protein comprising at least one copy of residues 63-188 of SEQ ID NO: 7.
US’183 teaches compositions and methods for the regulation of steroidogenesis. More particularly, compositions and methods relating to the regulation of transport of cholesterol into the mitochondria of a cell for the synthesis of androgens, estrogens, glucocorticoids, mineralocorticoids, and progestogens. US’183 teaches methods for preparing recombinant proteins for StAR (col. 1, lines 11-28)
US’183 teaches compositions and methods including the nucleotide sequence of the gene encoding a steroidogenic acute regulatory protein (StAR) protein, or compositions that include a protein having the amino acid sequence of the StAR protein. The fundamental importance of the StAR protein is that it is the acute regulator of a key step in the steroidogenic biosynthetic pathway (col. 3, lines 26-38).
US’183 teaches that the rate-limiting enzymatic step in steroidogenesis is the conversion of the cholesterol to pregnenolone by the cholesterol side-chain cleavage complex (CSCC), which is localized to the mitochondrial inner membrane. However, the delivery of the substrate cholesterol from cellular stores and the outer mitochondrial membrane to the inner mitochondrial membrane and the CSCC are the true regulated, rate-limiting steps in the process (col. 2, lines 1-8).
US’183 teaches nucleic acid molecules having a nucleotide sequence encoding a steroidogenic acute regulatory protein, the protein having an amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 18 (col. 4, lines 1-5). US’183, SEQ ID NO: 18 comprises residues 63-188 of instant SEQ ID NO: 7, as shown in the ABSS alignment below.
PNG
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469
630
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Greyscale
US’183 also teaches that the peptides include a mitochondrial targeting signal sequence that is cleaved during processing to the mature protein (col. 3 lines 40-49; Fig. 5; col. 21, lines 41-50; col. 40, lines 48-59).
US’183 further teaches a purified nucleic acid molecule that encodes a protein having a sequence of SEQ ID NO: 18 in a recombinant vector. The vector has been modified to contain a nucleic acid segment that encodes a StAR protein and may be further defined as an expression vector comprising a promoter operatively linked to said StAR encoding nucleic acid molecule. US’183 further teaches that the vector can include viral vectors including adenoviral vectors, retroviral vectors, or Baculovirus or Vaccinia virus vectors (col. 5, lines 31-47). US’183 also teaches a host cell made recombinant with a recombinant vector comprising the StAR gene and teaches that the host cell can be eukaryotic. US’183 teaches that the engineered cells have a gene or genes introduced through the hand of man and that the introduced genes will be either in the form of a cDNA, a copy of a genomic gene, or will include genes positioned adjacent to a promoter not naturally associated with the particular introduced gene, or combinations thereof (col. 5, lines 48-63).
Sugawara teaches that it has been recognized that proteins are required for the translocation of sterol substrates to the inner mitochondrial membrane where the P450 enzymes that catalyze these reactions reside. A 30-kDa phosphorylated protein rapidly appears in mitochondria of steroidogenic cells following tropical stimulation. This protein, steroidogenic acute regulatory protein (StAR), had recently been purified from a murine Leydig cell tumor line (MA-10) and its cDNA had been cloned. The cDNA encodes a protein with an N-terminal mitochondrial targeting sequence. Transient expression of the StAR cDNA in MA-10 cells resulted in enhanced steroidogenesis. Findings which are strong evidence that StAR is the factor responsible for the rapid movement of the substrate from the outer to the inner mitochondrial membranes (page 4778, left column, paragraph 1). To explore the role of StAR in human tissues, and its potential involvement in disorders of steroidogenesis, Sugawara isolated cDNAs encoding human StAR, examined the pattern of StAR expression, and mapped the StAR structural gene (page 4778, left column, paragraph 2).
Sugawara further teaches that, to document that human StAR has steroidogenesis enhancing activity, expression vectors for StAR and cholesterol side-chain cleavage enzyme and adrenodoxin were co-transfected into COS-1 cells and pregnenolone synthesis from exogenous substrates was determined. COS-1 cells do not express StAR protein or mRNA. Sugawara teaches that COS-1 cells did not secrete pregnenolone when transfected with a pSPORT vector lacking a cDNA insert or the pSPORT vector harboring the StAR cDNA. However, co-transfection with plasmids directing expression of bovine P450scc and adrenodoxin endowed the cells with steroidogenic activity. Triple transfection of the COS-1 cells with P450scc, adrenodoxin, and StAR expression plasmids consistently increased steroid secretion 4- to 20- fold over cells transfected with P450scc, adrenodoxin and the control pSPORT plasmid as shown in Table 1. In the absence of P450scc and adrenodoxin expression, there was no detectable pregnenolone synthesis. These findings document that the pSPORT plasmid “control” did not interfere with expression of the steroidogenic enzymes. The fact that an exogenous hydroxycholesterol did not augment steroid production stimulated by StAR also suggests that StAR promotes nearly maximal steroidogenic activity in the transfected COS cells (paragraph bridging pages 4780-4781; Table 1). The more than 4- to 20- fold increase in pregnenolone secretion promoted by the expression of StAR in the COS cell system provides unambiguous proof that StAR stimulates steroidogenesis at a step prior to the 3β-hdyroxysteroid dehydrogenase. Moreover, the fact that StAR works in a non-steroidogenic host cell (COS-1 cell) indicates that it does not require additional steroidogenic cell-specific factors to function beyond the side-chain cleavage system (paragraph bridging columns, page 4780).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the nucleic acid, modified cells, and methods of US’452 by further including a coding sequence that encodes the StAR protein of SEQ ID NO: 18 as disclosed by US’183 which is further motivated by the teachings of Sugawara. An ordinarily skilled artisan would have been motivated to further include the coding region for StAR because US’183 teaches that, in addition to the enzymatic step in steroidogenesis being rate limiting, the delivery of cholesterol from the cellular stores and the outer mitochondrial membrane to the inner mitochondrial membrane is also a rate-limiting step in steroidogenesis, which can be overcome with nucleotide sequences encoding StAR. The inclusion of both cholesterol degrading enzymes and StAR is further motivated by Sugawara which demonstrates that, when co-transfected in combination, results in a 4- to 20- fold increase in pregnenolone secretion compared to StAR or enzyme (P450scc) alone. An ordinarily skilled artisan would have had a reasonable expectation of success as all of US’452, US’183, and Sugawara pertain to the degradation of intracellular cholesterol. Additionally, US’452 and US’183 both teach nucleic acids that can be expressed in host cells using vectors; US’183 and Sugawara both teach nucleic acids encoding StAR as a means to stimulate steroidogenesis; and US’452 and Sugawara teach the expression of the enzyme P450scc for degradation of cholesterol and both also teach that the degradation provides pregnenolone. Additionally, Sugawara demonstrates that StAR works in a non-steroidogenic host cell, indicating that it does not require additional steroidogenic cell-specific factors to function beyond the side-chain cleavage system.
Regarding claim 12, as discussed in detail above, US’452 teaches a method in which immune cells from a subject are modified by introducing the nucleic acid then administered to the subject; indicating that the nucleic acid disclosed can be used in transforming a mammalian cell in vitro.
While this limitation is taught by the combination of applied references, the limitation “for use in transforming a mammalian cell in vitro or in vivo” is an intended use limitation. The nucleic acid taught by the combination of applied references would be capable of performing the recited intended use and; therefore, meets the limitations of the claim.
MPEP 2111.02 II states that “During examination, statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. If so, the recitation serves to limit the claim. See, e.g., In re Otto, 312 F.2d 937, 938, 136 USPQ 458, 459 (CCPA 1963) (The claims were directed to a core member for hair curlers and a process of making a core member for hair curlers. The court held that the intended use of hair curling was of no significance to the structure and process of making.); In re Sinex, 309 F.2d 488, 492, 135 USPQ 302, 305 (CCPA 1962) (statement of intended use in an apparatus claim did not distinguish over the prior art apparatus). To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997) (anticipation rejection affirmed based on Board’s factual finding that the reference dispenser (a spout disclosed as useful for purposes such as dispensing oil from an oil can) would be capable of dispensing popcorn in the manner set forth in appellant’s claim 1 (a dispensing top for dispensing popcorn in a specified manner)) and cases cited therein. See also MPEP § 2112 - MPEP § 2112.02.”
Claims 4, 34, and 65 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0179452 A1 (Honkanen, R.E., et al) 11 JUN 2020; effective filing date of 01 Nov 2018 in view of US 6,903,183 B1 (Stocco, D.M., et al) 7 JUN 2005 and Sugawara, T., et al (1995) Human steroidogenic acute regulatory protein: Functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13 Proc. Natl. Acad. Sci. USA 92; 4778-4782 as applied to claims 1, 31, and 62 above, and in further view of US 2006/0110730 A1 (Bose, H.S., et al) 25 May 2006.
The combination of US’452, US’183, and Sugawara teach the nucleic acid of claim 1, the mammalian cell of claim 31, and the method of claim 62 as discussed in detail above.
The combination of applied references; however, do not disclose that the StAR protein further comprises at least a portion of the TOMM20 protein.
US’730 teaches compositions and methods for identifying and using the site of regulation of transport of cholesterol into the mitochondria of a steroidogenic cell. The methods are exemplified by identification of a receptor on the outer mitochondrial membrane as the site of biological interaction of the StAR protein and the use of fusions of the StAR protein that alter its time on the outer membrane to alter the activity of the StAR protein thereby altering the rate of steroidogenesis (page 1, [0003]).
During import, mitochondrial proteins are typically processed by protein-import machinery consisting of Tom (translocase, outer membrane) proteins associated with the outer mitochondrial membrane (OMM) (page 1, [0006]). US’370 teaches methods and compositions for modulating steroidogenesis, increasing production of steroid hormones, and identifying specific agents that alter the rate of steroidogenesis (page 1, [0007]).
US’730 teaches the construction of vectors comprising Tom20 and teaches fusion proteins comprising Tom20 and StAR. Specifically, US’730 teaches Tom/StAR, which is Tom20 fused to 63-285 through GSDDDK, which contains BamHI and enterokinase sites as well as StAR/Tom, which is 1-285 StAR fused to Tom20 through a GFDDDDK linker (page 5, [0030]). Non-steroidogenic COS-1 cells were grown, transfected, and assayed for pregnenolone production. The cells were transfected with a vector expressing full length StAR, or a vector comprising N-62 StAR, Tom-StAR, and StAR-Tom. The cells were also transfected with a pECE vector expressing a fusion protein termed F2, consisting of the human cholesterol side-chain cleavage system: HN-P450scc-Adrenodoxin Reductase-Adrenodoxin-COOH. The substrate was endogenous cellular cholesterol or added 22R-hydroxycholesterol (22R-OH). After 48 hrs of incubation, the medium was collected and assayed for pregnenolone (pages 5-6, [0034]).
US’730 teaches that co-expression of Tom/StAR and F2 achieved maximal steroidogenesis. Thus, localizing StAR to the OMM substantially increased activity, but StAR localized to the IMS or matrix was inactive. Results are shown in Fig. 1a (page 6, [0035]). US’730 teaches that the system was only active with Tom/StAR affixed to the OMM or with exogenously added StAR (page 1, [0009]; Fig. 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the nucleic acid, mammalian cell, and method taught by the combination of US’452, US’183, and Sugawara by modifying the StAR protein by further comprising the Tom20 protein as disclosed by US’730. An ordinarily skilled artisan would have been motivated to further include the Tom20 protein because US’730 teaches that co-expression of Tom/StAR with the human cholesterol side-chain cleavage system (F2) achieved maximum steroidogenesis and that localizing StAR to the OMM substantially increases activity. An ordinarily skilled artisan would have had a reasonable expectation of success as US’730 also pertains to steroidogenesis and the impact of StAR and cholesterol side chain cleavage systems on the degradation of cholesterol. Additionally, US’730 used COS-1 cells, which are the same types of cells used in Sugawara that are taught to be non-steroidogenic, indicating that the results demonstrated do not require additional steroidogenic cell-specific factors to function beyond the side-chain cleavage system.
Claims 9 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0179452 A1 (Honkanen, R.E., et al) 11 JUN 2020; effective filing date of 01 Nov 2018 in view of US 6,903,183 B1 (Stocco, D.M., et al) 7 JUN 2005 and Sugawara, T., et al (1995) Human steroidogenic acute regulatory protein: Functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13 Proc. Natl. Acad. Sci. USA 92; 4778-4782 as applied to claim 1 above, and in further view of Zhao, Y., and L. Huang (2014) Lipid Nanoparticles for gene delivery Adv Genet 88; 13-36.
It is noted that claim 12 was rejected above over the combination of US’452, US’183, and Sugawara. The claim is further rejected here to demonstrate that the elected in vivo transformation of a mammalian cell would have been obvious.
The combination of US’452, US’183, and Sugawara teach the nucleic acid of claim 1 as discussed in detail above.
The combination of applied references; however, do not disclose that the nucleic acid is comprised in a lipid nanoparticle or transforming a mammalian cell in vivo.
Zhao teaches that nonviral vectors offer a safer and versatile alternative to viral vectors and have been developed to overcome problems caused by viral vectors. However, their transfection efficacy or level of expression is substantially lower than viral vectors. Among various nonviral gene vectors, lipid nanoparticles are an ideal platform for the incorporation of safety and efficacy into a single delivery system. Zhao provides a review of the current lipidic vectors that have been developed for gene therapy (abstract). Zhao teaches that lipid nanoparticles (LNPs) have been developed and used extensively as nonviral (or synthetic) vectors to treat genetic and acquired disorders in gene therapy. LNPs are safer than viral vectors due to the absence of immunogenic viral proteins and have shown robust capability to condense and deliver various nucleic acid molecules to cells. LNPs are also easy to scale up due to established construction protocols and can be easily modified by the incorporation of targeting ligands (page 13, paragraph 1).
Zhao teaches that it is well known that systemic delivery of naked DNA and siRNA alone often leads to fast clearance and degradation. A variety of lipid vectors hold the potential to improve gene therapy. As long as the nucleic acids are fully encapsulated in stable vectors, the system could provide protection to the nucleic acids from degradation. LNPs are able to provide better biodistribution and pharmacokinetic profiles of genes in vivo (page 10, paragraph 1).
Zhao further teaches clinical trials using LPNs with several agents to target various types of diseases, including ALN-PCS02, which targets PCSK9 to lower cholesterol for the treatment of hypercholesterolemia (page 11, paragraph 3).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention modify the nucleic acid disclosed by the combination of US’452, US’183, and Sugawara by including the nucleic acid in a lipid nanoparticle and to use the nucleic acid to transform a mammalian cell in vivo as disclosed by Zhao. An ordinarily skilled artisan would have been motivated to include the nucleic acid in a lipid nanoparticle because Zhao teaches that LNPs are safer than viral vectors due to the absence of immunogenic viral proteins and have a robust capability to condense and deliver nucleic acid molecules to cells. It would have bene obvious to use the nucleic acid to transform a mammalian cell in vivo as Zhao demonstrates that in vivo cell transformation with nucleic acids had been studied in the art and also teaches studies in which in vivo modification was performed for the purposes of lowering cholesterol for the treatment of hypercholesterolemia, which is a disease disclosed by US’452 for treatment with the nucleic acids. An ordinarily skilled artisan would have had a reasonable expectation of success as Zhao is teaching alternative methods for transforming cells with nucleic acids.
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, 6-10, 12, 17, 31, 37, 39, 41, 43, 62, 68, 70, 72, and 77 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12,544,402 B2 in view of US 2020/0179452 A1 (Honkanen, R.E., et al) 11 JUN 2020; effective filing date of 01 Nov 2018, US 6,903,183 B1 (Stocco, D.M., et al) 7 JUN 2005 and Sugawara, T., et al (1995) Human steroidogenic acute regulatory protein: Functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13 Proc. Natl. Acad. Sci. USA 92; 4778-4782
US’402 claims a method of reducing lipid concentration in at least one liver cell of a subject in need of treatment for a cholesterol related disease or condition, the method comprising the steps of:
Contacting a vector comprising a construct with the liver cell of the subject, where the construct comprises a nucleic acid sequence of SEQ ID NO: 1 or 13; allowing the construct to enter the liver cell and create a modified liver cell; allowing the modified liver cell to degrade lipid within the modified cell and reduce the size of at least one atheroma in the subject;
Wherein the lipid is cholesterol and the atheroma is located at or near the aorta of the subject.
US’402 further claims that the construct is a nucleic acid comprising a eukaryotic promoter sequence of CMV promoter sequence, that the liver cell is a hepatocyte, and that the cholesterol related condition includes one or more of non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). US’402 further claims that the liver cell is derived form a stem cell including an induced pluripotent stem cell. US’402 further claims that the subject is administered the liver cell. US’402 claims that the vector is a viral vector or that the vector is a lipid nanoparticle.
It is noted that US’402, SEQ ID NO: 1 is a nucleic acid that encodes a protein that is identical to the P450-FdxR-Fdx fusion protein construct of US’452, SEQ ID NO: 5; indicating that the method claimed in US’402 uses a construct that encodes a P450-FdxR-Fdx fusion protein.
The claims of US’402 differ from the instantly claimed invention in that US’402 does not claim that the nucleic acid further comprises a coding sequence for StAR protein comprising at least one copy of residues 63-188 of SEQ ID NO: 7.
The teachings of US’452, US’183, and Sugawara are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’402 by further including a coding sequence that encodes the StAR protein of SEQ ID NO: 18 as disclosed by US’183 which is further motivated by the teachings of Sugawara. An ordinarily skilled artisan would have been motivated to further include the coding region for StAR because US’183 teaches that, in addition to the enzymatic step in steroidogenesis being rate limiting, the delivery of cholesterol from the cellular stores and the outer mitochondrial membrane to the inner mitochondrial membrane is also a rate-limiting step in steroidogenesis, which can be overcome with nucleotide sequences encoding StAR. The inclusion of both cholesterol degrading enzymes and StAR is further motivated by Sugawara which demonstrates that, when co-transfected in combination, results in a 4- to 20- fold increase in pregnenolone secretion compared to StAR or enzyme (P450scc) alone. An ordinarily skilled artisan would have had a reasonable expectation of success as all of US’402, US’183, and Sugawara pertain to the degradation of intracellular cholesterol. Additionally, US’402 and US’183 both teach nucleic acids that can be expressed in host cells using vectors; US’183 and Sugawara both teach nucleic acids encoding StAR as a means to stimulate steroidogenesis; and US’402 and Sugawara teach the expression of the enzyme P450scc for degradation of cholesterol. Additionally, Sugawara demonstrates that StAR works in a non-steroidogenic host cell, indicating that it does not require additional steroidogenic cell-specific factors to function beyond the side-chain cleavage system.
Claims 4, 34, and 65 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12,544,402 B2 in view of US 2020/0179452 A1 (Honkanen, R.E., et al) 11 JUN 2020; effective filing date of 01 Nov 2018, US 6,903,183 B1 (Stocco, D.M., et al) 7 JUN 2005 and Sugawara, T., et al (1995) Human steroidogenic acute regulatory protein: Functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13 Proc. Natl. Acad. Sci. USA 92; 4778-4782 as discussed above, and in further view of US 2006/0110730 A1 (Bose, H.S., et al) 25 May 2006.
The claims of US’402 modified by US’452, US’183, and Sugawara render obvious the nucleic acid of claim 1, the mammalian cell of claim 31, and the method of claim 62 as discussed in detail above.
The combination of applied references; however, do not disclose that the StAR protein further comprises at least a portion of the TOMM20 protein.
The teachings of US’730 are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the nucleic acid, mammalian cell, and method taught by the combination of US’402 modified by US’452, US’183, and Sugawara by modifying the StAR protein by further comprising the Tom20 protein as disclosed by US’730. An ordinarily skilled artisan would have been motivated to further include the Tom20 protein because US’730 teaches that co-expression of Tom/StAR with the human cholesterol side-chain cleavage system (F2) achieved maximum steroidogenesis and that localizing StAR to the OMM substantially increases activity. An ordinarily skilled artisan would have had a reasonable expectation of success as US’730 also pertains to steroidogenesis and the impact of StAR and cholesterol side chain cleavage systems on the degradation of cholesterol. Additionally, US’730 used COS-1 cells, which are the same types of cells used in Sugawara that are taught to be non-steroidogenic, indicating that the results demonstrated do not require additional steroidogenic cell-specific factors to function beyond the side-chain cleavage system.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
