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 .
Claim Rejections - 35 USC § 112
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.
Claims 2 and 20 are 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.
Claims 2 and 20 are vague and indefinite because it is unclear of what are the metes and bound for the phrase “or another morpholino of Formula I”.
Regarding claim 20, the phrase "such as", in the phrase “R³ is a protecting group that can be removed following synthesis of an oligonucleotide, such as cyanoethyl or methyl”, renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,230,565; and over claims 1-23 of U.S. Patent No.12,084,468. Although the claims at issue are not identical, they are not patentably distinct from each other because they both claim an oligonucleotide containing at least one monomer of identical formula and method of synthesizing same, comprising similar steps.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 3-6, 8, 9, 11 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fox US 2009/0131632.
Fox teaches an oligomer (para [0030], A "morpholino oligomer" refers to a polymeric molecule having a backbone which supports bases capable of hydrogen bonding to typical polynucleotides), comprising a monomer subunit comprising the chemical structure of formula II: wherein each B is independently a nucleic acid base (adenosine, guanosine, uracil, thymine, cytosine, inosine); X is an amine substituted with C1 alkyl; and Y is oxygen; and one R is a phosphorus derivative, and the other R is a DNA or RNA oligonucleoside/oligonucleotide (abstract; see also Figure 1).
Fox teaches a morpholino oligomer is composed of "morpholino subunit" structures, such as shown below, which in the oligomer are preferably linked together by phosphoramidate or phosphorodiamidate linkages, or their thio analogs, joining the morpholino nitrogen of one subunit to the 5' exocyclic carbon of an adjacent subunit. Each subunit includes a purine or pyrimidine base-pairing moiety Pi which is effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide [0030]. In a thiophosphorodiamidate linkage, one oxygen atom, typically the oxygen pendant to the backbone in the oligomers described herein, is replaced with sulfur [0033]. (this is viewed to be inclusive of claim 11).
Fox further teaches wherein the nucleic acid base protecting group (para [0034], "Base-protected" refers to protection of the base-pairing groups, eg purine or pyrimidine bases, on the morpholino subunits with protecting groups suitable to prevent reaction or interference of the base-pairing groups during stepwise oligomer synthesis) is the third formula in the second row of the group of substructures in the instant claim (para [0023], The triarylmethyl protecting group is selected from the group consisting of trityl (triphenylmethyl), 4-methoxytrityl).
Fox further teaches the oligomer comprising 2 monomeric subunits (abstract; see also Figure 1).
Fox discloses a method of synthesizing a morpholino oligomer, the method comprising:
(a) reacting a solid-phase-supported morpholino subunit, having an unprotected ring nitrogen, with a base-protected morpholino subunit monomer, having a triarylmethyl-protected ring nitrogen and an activated phosphoramidate group on a 5'-exocyclic carbon, thereby forming a phosphorodiamidate linkage between the 5'-exocyclic carbon and the unprotected ring nitrogen;
(b) deprotecting the protected ring nitrogen, to form an unprotected ring nitrogen; and
(c) repeating steps (a) and (b) one or more times with further base-protected morpholino subunit monomers;
wherein said deprotecting comprises exposing the triarylmethyl-protected ring nitrogen to a reagent solution comprising a heterocyclic amine salt in a trifluoroethanol-containing solvent, the salt being a salt of a heterocyclic amine, having a pKa in the range of 1-4 in its protonated form, with an acid selected from a sulfonic acid, trifluoroacetic acid, and hydrochloric acid. The triarylmethyl protecting group is selected from the group consisting of trityl (triphenylmethyl), 4-methoxytrityl, 4-methyltrityl, 4,4'-dimethyltrityl, and 4,4',4''-trimethyltrityl. Typically, the synthesis further comprises cleaving the morpholino oligomer from the solid phase and deprotecting the bases, in accordance with standard procedures. (Summary). Fox teaches a polystyrene support (see example 4).
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.
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, 3-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fox in view of Udea US 20130197220 in view of Sinha et al. US 2012/0296087
Fox is discussed above.
However Fox does not disclose using a commercial DNA synthesizer.
Udea provides a useful morpholino nucleic acid derivative for synthesizing a morpholino nucleic acid oligomer. Udea teaches “All of the steps described .. can be carried out by liquid phase methods or solid phase methods (using manuals or commercially available solid phase automatic synthesizers). When a morpholino nucleic acid oligomer is produced by a solid phase method, a method using an automatic synthesizer is desirable in view of simplification of operational procedures and accuracy of synthesis” [0046].
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the primary reference in the manner of the claims, without exercising inventive skill, to achieve the expected benefits, optimizations and/or expanded applications as this is well known practice in the art.
With regards to claim 7, Udea provides also cleaving each of the morpholino nucleic acid oligomers supported on the aminoethylpolystyrene resins with a concentrated aqueous ammonia/ethanol mixture solution and the morpholino nucleic acid oligomers were cleaved from the solid phase supports [0144]. MPEP states wherein the “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Alter, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Routine optimization is not considered inventive and no evidence has been presented that the selection of a specific solvent (like ethylene diamine) was other than routine, that the products resulting from the optimization have any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art.
With regards to claims 12-14, they merely recite a plethora of conventional nucleic acid manipulation of reagents and methodologies. Fox teaches “Phosphorodiamidate-linked morpholino oligomers, or PMO, are nucleic acid analogs which bind tightly and sequence specifically to complementary RNA and are useful in modulating protein synthesis and thus gene expression” [0010]. And Sinha et al. teaches “The binding, or hybridization, of antisense nucleic acid sequences to a specific mRNA target will, through a number of different mechanisms, interrupt normal cellular processing of the genetic message of a gene. This interruption, sometimes referred to as "knock-down" or "knock-out" depending upon whether or not the message is either partially or completely eliminated, allows researchers to determine the function of that gene” [0002] ; “first generation antisense oligonucleotides that were designed as short stretches of DNA (18-22mers) that form RNA-DNA hybrids with the target mRNA and act as substrates for RNase H to degrade the mRNA. The target mRNA is cleaved by RNase H and the fragments are subsequently broken down by nuclease activity. DNA oligonucleotides have had very limited applicability in developmental studies, both because they have non-specific toxic side effects and because degraded mRNAs are continually replaced by new transcription, making continued treatment with oligonucleotides a necessity [0004]. (Which is also viewed to be inclusive of instant claims 12-13).
With regards to claim 14, Sinha et al. teaches: [0020] It is a further object of the present invention to provide for improved cationic morpholino-based antisense agent that is soluble in culture medium and is sufficient far cell penetration thus eliminating the need for injecting the antisense agents into the cells. (see also example 13).
Therefore, one of ordinary skill in the art would have been motivated to modify the primary references in the manner of the claims to achieve the expected benefits, optimizations and/or expanded applications as this is well known practice in the art. It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to carry out the claimed methods.
Claims 15, 17-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sinha et al. US 2012/0296087 in view of Vargeese et al. US 7,205,399 B1.
Sinha teaches a method of preparing a phosphorodiamidite monomer comprising a. contacting a 5'-O-Dimethoxytrityl ribo-base with sodium periodate and ammonium borohydride reagent to produce a dihydroxyribose morpholino monomer, wherein the base is one of thymidine, cytosine, adenine, and guanine, and is unprotected at the nucleoside amino groups by a protecting group (Scheme 1, step ii, NalO4, (NH4)2B4H7:4H20, MeOH, rt. for R = H); b. reducing hydroxyl groups on the dihydroxyribose morpholino monomer with sodium cyanoborohydride to produce a morpholino monomer (Scheme 1, step iii, NaCNBH3, AcOH, 4A MS, MeOH, rt); Sinha further teaches wherein the protecting group at the nucleoside amino groups is the protecting group described in claim 5 (para [0077], A-Morpholino monomer subunit 2b, R1 = Bz).
Sinha does not teach c. phosphitylating the morpholino monomer with 2-cyanoethyl-N,N,N',N’-tetraisopropylphosphordiamidite and 4,5-dicyanoimidazole (DCI) in dichloromethane to produce a phosphorodiamidite monomer.
However, Vargeese teaches a method for in situ formation of an activated 5'-phosphorus species (col 2, In 60 to col 3, In 2, wherein 5'-activation comprises the in situ formation of an activated 5'-phosphorus species and coupling comprises the nucleophilic attack of the activated 5'-phosphorus species under conditions suitable for covalent attachment) and Vargeese further teaches c. phosphitylating the morpholino monomer with 2-cyanoethyl-N,N,N',N'- tetraisopropylphosphorodiamidite (col 52, In 62 to col 53, In 12, Formula XXVII) and 4,5-dicyanoimidazole (DCI) (col 40, In 51-57, The nucleoside phosphoramidite or phosphoramidate can be activated by using an activator reagent such as 4,5-dicyanoimidazole (DCI)), and Vargeese still further teaches wherein a detritylation step is performed in dichloromethane (col 55, In 21-44, detritylation solution is 3% TCA in methylene chloride (ABI)), but Vargeese does not teach a specific solvent for the phosphitylating step.
However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform the phosphitylating step in dichloromethane by routine experimentation in order to identify the optimum solvent for this step. It would have been further obvious to combine Vargeese with Sinha because Vargeese teaches a method for in situ formation of an activated 5’-phosphorus species (col 2, In 60 to col 3, In 2, wherein 5'-activation comprises the in situ formation of an activated 5'-phosphorus species and coupling comprises the nucleophilic attack of the activated 5’-phosphorus species under conditions suitable for covalent attachment) and Sinha teaches a soluble cell penetrating antisense agent based on morpholino phosphorus backbone (abstract, 5-substituted pyrimidines of morpholino compound that is soluble in culture medium and sufficient for cell penetration thereby eliminating the need for injecting into the cells).
Therefore, one of ordinary skill in the art would have been motivated to modify the primary references in the manner of the claims to achieve the expected benefits, optimizations and/or expanded applications as this is well known practice in the art. It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to carry out the claimed methods.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEZIA RILEY whose telephone number is (571)272-0786. The examiner can normally be reached 7:30-6:00pm.
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/JEZIA RILEY/Primary Examiner, Art Unit 1681 17 September 2026
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