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 .
Claims 1-2, 5, 13-14, 18, 21-24, 33, 45, 49, 51, 56, 58, and 60-64 are pending.
Status of the Application
Applicant’s response and amendment filed 23 September 2025 are acknowledged and entered.
Applicant has amended Claims 1-2, 5, 13-14, 18, 21-24, 33, 45, 49, 51, 56, and 58. Applicant has added Claims 60-64. Applicant has cancelled Claims 12, 40, 55, and 57.
Response to Amendment
Applicant states that they provided a marked up substitute specification to comply with the SEQ requirements on 13 July 2025. Note that no Spec. with that date appears in the application file. A substitute Spec. was submitted on 13 July 2022, but there is no marked up copy. The objections over the sequences are withdrawn but Applicant is advised to submit a properly marked up copy as required.
Applicant has amended Claims 2 and 58 to overcome objections; the previous objections are withdrawn.
Applicant has amended the claims to overcome the 112(a) rejection; the 112(a) rejection is maintained.
Applicant has canceled Claim 57 to overcome the 112(a) enablement rejection; the 112(a) enablement rejection is withdrawn.
Applicant has amended the claims to overcome the 112(b) rejection; some of the 112(b) rejections are maintained and others are withdrawn; see below.
Applicant has amended the claims to overcome 112(d) rejections; the 112(d) rejection is withdrawn.
Applicant has amended the claims to overcome 102 rejections; the 102 rejections are withdrawn.
Applicant has amended the claims to overcome 103 rejections; some of the 103 rejections are withdrawn; two 103 rejections, necessitated by the claim amendments, remain.
Applicant has amended the claims to overcome NSDP rejections; the NSDP rejections are maintained.
Claims 1-2, 5, 13-14, 18, 21-24, 33, 45, 49, 51, 56, 58, and 60-64 are examined.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
Claim Interpretation
The claims recite a pharmacokinetic (PK)-modifying and the Spec. defines that at ¶106:
the term "pharmacokinetic-modifying" or "PK-modifying" refers to a compound that can used to modify the concentration of a therapeutic agent (e.g., an RNAi agent) over time. In certain embodiments, a PK-modifying agent effects stability of a therapeutic agent in one or more locations (e.g., in the heart, kidney, liver, spleen, adrenal, pancreatic, lung, blood (e.g., plasma) and/or brain tissue) in a subject. Altered PK parameters include, but are not limited to, volume of distribution (Vd), area under the curve (AUC), clearance (CL), half-life (t1/2), maximum concentration, (Cmax), bioavailability (F) and the like.
Therefore the term is interpreted as encompassing any compound that affects any pharmacokinetic parameter.
Claim 1 recites …with complementarity to a target sequence… and Claim 5 recites the universal region…is partially complementary…. In the interest of compact prosecution complementarity and partially complementary, when recited without further limitation, are interpreted as encompassing even a single nucleotide of complementarity between the universal region and the target sequence.
Regarding Claims 1 and 13: Claim 1 recites …with complementarity to a target sequence for mediating silencing thereof…. Since an AS strand is known in the art to mediate silencing of a complementary target and that recitation is attributed to the AS strand, that function for mediating silencing thereof is interpreted as a function required of the AS strand. Therefore the claims recite an siRNA.
If for mediating silencing thereof is recited only as an intended use and not a required function, Claim 13 is subject to a 112(b) rejection for failing to provide a proper antecedent basis for siRNA. Currently Claim 13 is spared that rejection only because for mediating silencing thereof is interpreted as a required function of a compound comprising an antisense strand for mediating silencing thereof and a sense strand that is complementary to the AS strand and because a person of ordinary skill knows that is describing an siRNA.
Claim 58 recites …for enhancing gene therapy technologies…. That recitation is interpreted as an intended use that doesn’t affect the structure of patentability of the claimed system. The claim also recites …whereby hybridization of the anchor oligonucleotide to the universal region of the therapeutic oligonucleotide modifies the pharmacokinetics of the therapeutic oligonucleotide as compared … that is interpreted as an outcome that flows from the structure recited in the claim.
Claim Objections
Claims 13-14 and 58 are objected to because of the following informalities:
Claim 13: the ‘ symbol in 3’ is backwards and should be corrected.
Claim 14: The claim should punctuate as follows: The composition of claim 1, wherein: a)…., b)…, and c)…; or a)…., b)…, and c)…; or a)…., b)…, and c)…; or a)…., b)…, and c)….
Claim 58: the last line of the claim should recite …compared with the therapeutic….
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 5, 13-14, 18, 21-24, 33, 45, 49, 51, 56, 58, and 60-64 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claims 1-2, 5, 13-14, 18, 21-24, 33, 45, 49, 51, 56, 58, and 60-64 recite …a universal region positioned at the 3’end… a PK-modifying anchor comprising an anchor oligonucleotide… and at least one polymer, wherein the anchor oligonucleotide is 5 to 10 nucleotides in length… and is complementary to the universal region… wherein the at least one polymer is at least about 2000 Da. These broad claims encompass the large genera of any universal region that can be used to bind a PK-modifying anchor comprising an anchor oligont, any PK-modifying anchor comprising any PK modifier and any anchor oligont that can be used to bind any universal region, and any polymer that is at least about 2000 Da, 10 kDa, 20 kDa, or 40 kDa, and can be used for modifying pharmacokinetic properties. Any universal region comprises any kind of oligont that binds any 5 to 10 nt anchor. Any PK-modifying anchor comprises any PK modifier and any 5 to 10 nt anchor. Any polymer that is at least about 2000 Da comprises a huge genus of polymers. Any member of any of those genera would be encompassed by the claims as instantly presented.
Claim 2 recites wherein the universal region… is partially complementary or noncomplementary to the target sequence…. This broad claim encompasses the large genera of universal regions and anchor oligonts that possess any complementarity to any target sequence. Complementarity can mean any amount of complementarity which can be even a single nt, so the claims read on literally any target sequence. Any universal region or anchor oligont with those features or which targets literally any sequence would be encompassed by the claims as presented, meaning Applicant had in their possession at time of filing a representative number of species commensurate with that claim breadth.
Claims 13-14 recite that the sense and AS strands have any length between 13 and 30 nt and the AS strand can be a 21- to 30-mer, the sense strand can be 13-17 nt, and the anchor oligo can be 5-8 nt, which encompasses sequences of any length within those ranges.
Claim 18 recites …wherein nucleotides… do not hybridize with the target sequence. This broad claim encompasses oligonts wherein nts at certain positions do not hybridize with any target sequence. Since the nt do not hybridize with any target sequence, that encompasses a huge number of oligonts .
Claim 45 recites …at least one polymer comprises a PEG, a lipid, a sugar, a peptide, an aptamer, or a mixture thereof. This broad claim encompasses oligonts comprising a PK anchor and literally any polymer as long as that polymer is a PEG, lipid, sugar, peptide, aptamer, or mixture of those kinds of molecules.
Claim 58 recites: A universal, pharmacokinetic (PK)-modifying system for enhancing gene therapy technologies comprising: (a) an anchor oligonucleotide strand comprising:(i) 5-20 nucleotides in length…; and (ii) a polymer attached to the anchor oligonucleotide strand, wherein the polymer has a molecular weight of 2,000 to 100,000 Daltons; and (b) a therapeutic oligonucleotide selected from the group consisting of an antisense oligonucleotide, an miRNA, an mRNA, a single-stranded siRNA, and a CRISPR guide strand, wherein the therapeutic oligonucleotide comprises a universal region… complementary to the anchor oligonucleotide strand, whereby hybridization of the anchor oligonucleotide to the universal region of the therapeutic oligonucleotide modifies the pharmacokinetics of the therapeutic oligonucleotide as compared …. This broad claim encompasses the large genera of ASO, miRNAs, mRNAs, single-stranded siRNAs, and CRISPR guide strands as well as some large genera similar to those recited in Claim 1: any anchor oligont that is about 5-20 nt in length and comprises any PK-modifying anchor comprising (a) any PK modifier that can be used modify pharmacokinetics and can bind any oligont fragment complementary to it and (b) any polymer that is at about 2000 Da to about 100,000 Da and can be used to modify any aspect of pharmacokinetics. The claim further encompasses larger, broader genera than Claim 1: any universal, PK-modifying system that can be used to enhance any gene therapy; and any therapeutic oligont that is an ASO, miRNAs, mRNAs, single-stranded siRNAs, and CRISPR guide strand.
An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163.
The Spec. discusses the following genera at the following locations:
The universal region: ¶12, 22, 102, 104;
The anchor oligont: ¶103, 105;
The PK-modifiers: ¶36-38, 107, 156;
The polymers including polymers that are lipids/sugars/peptides/aptamers/mixtures thereof: ¶108, 111-121 and ¶26, 132-141 154, 234-240;
The target sequences when the target sequence is mRNA: ¶11, 167;
The gene therapies: ¶3;
The first and second oligonts (AS and sense strands) and therapeutic oligonts: ¶13-19;
The nts that do not hybridize with the target mRNA: ¶20-21, 167;
The GC content: ¶9, 110.
Notably most of those genera are discussed only in broad terms and little specific information is provided. Each genus is, therefore, interpreted within its broadest reasonable interpretation.
The Spec. provides the following examples:
Example 1 (¶243-256; Figs. 8-10, 17-23, 11, 28-29) discusses siRNAs comprising the PK-modifying polymer PEG, an 8-mer anchor, a 21-mer AS strand and a 13-mer sense strand. Various cholesterol conjugates were also used (¶254). The Spec. discloses (¶271) all experiments in Examples 1 and 2 were performed with sFlt-1 mRNA-targeting siRNA. Results show siRNAs comprising the anchors improve blood/plasma circulation times and allow delivery of the siRNAs to various tissues.
Example 2 (¶257-264; Figs. 31-35) discusses siRNAs comprising the PK modifying polymer PEG, an 8-mer anchor (as shown in Fig. 31), a 21-mer AS strand and a 13-mer sense strand, conjugation with cholesterol, DCA, DHA, or GalNAc. The siRNAs were tested in vivo via (¶259) intravenous or (¶262, ¶264) subcutaneous injection and (¶258) enhanced circulation time in blood/plasma and (¶260) enhanced tissue distribution. The Spec. discloses (¶271) all experiments in Examples 1 and 2 were performed with sFlt-1 mRNA-targeting siRNA.
Example 2.6 (¶265-266; Figs. 36-37) discuss the effect of a PK-modifying anchor on circulation time and biodistribution of aptamer-siRNA chimeras. The aptamer bound the EPCAM receptor. The siRNAs were injected subcutaneously into mice bearing breast cancer (4T1E cells) or mastocytoma (P815 cells) tumors. The 4T1E tumors took up the siRNA and the P815 tumors were negative control. Results show the anchor siRNAs circulated longer and were more distributed, although no significant differences are shown. That indicates that the aptamer-siRNA chimeras could be used to target breast cancer cells.
Example 2.7 (¶267; Fig. 38) discusses the effect of intravenous and subcutaneous injection on biodistribution of PK-modifying anchors unconjugated siRNAs and Di-siRNAs. The Spec. discloses (¶271) all experiments in Examples 1 and 2 were performed with sFlt-1 mRNA-targeting siRNA.
Examples 2.8 and 2.9 (¶268-269; Figs 39-40) discuss the effect of PK modifying anchors on biodistribution of unconjugated siRNAs to mouse placenta. Figs. 39-40 show the siRNAs comprise an PK-modifying moiety that is 40kd PEG, an 8-mer anchor, a 21-mer AS strand and a 13-mer sense strand. The Spec. discloses (¶271) all experiments in Examples 1 and 2 were performed with sFlt-1 mRNA-targeting siRNA. Example 2.9 explicitly discloses the siRNAs target sFLt-1 mRNA. Example 2.8 results show 10-fold enhanced delivery to placenta. Example 2.9 results show target mRNA silencing with PK-modifying anchors was comparable to siRNAs without PK-modifying anchors.
Example 2.10 (¶270; Fig. 41) discusses the effect of PK-modifying anchors on biodistribution to the liver using GalNAc-conjugated siRNAs. Example 2.10 used two siRNAs: (1) comprising an 8-mer anchor, an 21-mer antisense strand, and 13-mer sense strand; or (2) comprising an 8-mer anchor, an 25-mer antisense strand, and 17-mer sense strand. Results demonstrated that the PK-modifying anchors enhanced distribution to the liver compared to siRNAs without PK-modifying anchors, for both intravenous and subcutaneous delivery.
Example 3 (¶271-280; Figs. 42-49) discusses the effect of PK-modifying anchors appended to sFlt-1 and HTT mRNA-targeting siRNAs. The siRNAs comprise a 21-mer AS strand, 13-mer sense strand, and 8-mer anchor. The Spec. discloses (¶271) that the GC content of the universal region—although the Spec. calls it a tail sequence, not a universal region—is 87.5%. That ¶ discusses testing siRNA comprising a GC-poor sequence. The polymer used with each anchor is PEG. The Spec. discusses that (¶272) GC-poor sequence were insufficient to achieve binding of an anchor to a universal “tail” sequence. The Spec. discusses (¶273-274) varying the length of the anchor (5-, 6-, 7-, and 8-mer anchors) and AS strands (23- or 25-mer) and sense strands (14-, 15-, 16-, or 17-mer). Example 3 tested the effects of siRNAs targeting sFlt-1, HTT, and ApoE mRNA.
Altogether, Applicant’s Examples show that they used the polymer PEG, (¶271) 6- and 8-mer anchors with the sequences GUAUAUCA, GUAUAU, and GCGCUCGG; siRNAs targeting sFlt-1 and HTT mRNA comprising, respectively, SEQ ID NOs 1-2 (which are both 21-mers, and the sFlt-1-tareting siRNA comprises sense strand SEQ ID NO 3, which is a 13-mer).
The Spec. discusses (¶276) ApoE mRNA-targeting siRNAs but does not disclose the sequences. The Spec. discusses (Example 2.6; ¶265) using an aptamer but does not disclose its sequence. The claims recite various peptides, lipids, and sugars but the Spec. provides examples of only cholesterol and GalNAc. The claims recite any target mRNA, any gene therapy, and any therapeutic oligont but the Spec. describes only therapeutic siRNAs targeting sFlt-1, HTT, and ApoE, and no sequences are provided for ApoE. No gene therapies are described.
Regarding all the claims, the Spec. does not show possession of a compound or system comprising exemplary members of the broad genera of claimed PK-modulators aside from PEG. The Spec. does not show possession of a compound or system comprising exemplary members of the broad genera of claimed universal or anchor oligont sequences—and does not show possession of any anchors or universal regions comprising the recited % of GC content—aside from the anchor oligont and universal region recited in Claims 21-22. The Spec. does not show possession of a compound or system comprising exemplary members of the broad genus of claimed AS strands aside from SEQ ID NOs 1-2. The Spec. does not show possession of a representative number of species from any of those genera.
Regarding Claims 2, 5, and 18, the Spec. does not show possession of a compound or system comprising exemplary members of the broad genus of claimed target mRNAs aside from SEQ ID NOs 1 and 2 which target sFlt-1 and HTT mRNA. The Spec. does not show possession of a representative number of compounds or systems comprising exemplary members of the broad genus of claimed target sequences. Regarding Claim 2, the Spec. doesn’t demonstrate possession of a representative number of universal strands that are partially complementary or noncomplementary to the broad target sequence[s] claimed.
Regarding Claims 13-14, the Spec. does not show possession of nts with any of the recited lengths because it shows only 3 SEQ ID NOs which comprise either AS strands comprising 21 nt or sense strands comprising 13 nt.
Regarding Claim 45, the Spec. does not show possession of a representative number of PK-modifying anchors, wherein the anchor comprises any polymer or a polymer that can be any PEG, lipid, any sugar, any peptide, any aptamer, or a mixture thereof.
Regarding Claim 58, the Spec. does not show possession of or possession of a representative number of universal, PK-modifying systems for enhancing any gene therapy technology comprising anchor oligo strands, PK-modifying moieties attached to the anchor oligo strands, oligont fragments complementary to the anchor oligont strands, therapeutic oligonts of the species listed, or polymers comprising a molecular weight of about 2,000 to about 100,000 Daltons.
The Claims encompass all members of the claimed genera but has tested only anchors comprising PEG, and siRNAs targeting sFlt-1 and HTT (for which sequences are provided) and ApoE (for which no sequence is provided). PEG, GalNAc, and cholesterol are only three species of the large genus of possible polymers, GalNAc is only a single sugar out of the large genus of possible sugars, and cholesterol is only a single lipid out of the large genus of possible lipids. The Spec. discusses an aptamer but its sequence is not provided. Even so, that is only one single aptamer out of the large genus of possible aptamers. No polymer peptides are identified yet Applicant claims the entire large genus. Similarly, only two siRNA species are identified out of the large genus of possible siRNAs, one universal sequence is identified, and one anchor oligo sequence is identified.
Altogether the Spec. has provided no evidence that Applicant was in possession of the large genera claimed. The Specification does not provide specific guidance for determining which claimed species within the broad genera would or would not be acceptable to use in their invention. Although the claims recite functional characteristics (i.e., the universal region that binds the anchor oligont, the anchor oligont that comprises a PK modifier, the anchor oligont that binds a universal region, the various universal regions and anchors that comprise recited GC content or melting points, the oligonts that comprise complementarity or partial complementarity to target mRNA, the sense and AS strands, the various species of therapeutic oligonucleotides recited in Claim 58, the oligonts that do not hybridize with any target mRNA, any PEG/lipid/sugar/peptide/aptamer/mixture thereof that is a polymer, the technologies that enhance gene therapy, the oligonts that provide a therapeutic effect), none of the functional characteristics is coupled with a known structure.
Although the Specification teaches the examples discussed above, it does not identify a core structure necessary for any of the claimed functions:
binding the anchor oligont,
comprising a PK modifier,
binding a universal region,
comprising recited GC content,
comprising complementarity or partial complementarity or no complementarity to a target sequence,
sense and AS strands comprising complementarity,
hybridizing with any target sequence,
being a PK-modifying polymer comprising any PEG/lipid/sugar/peptide/aptamer/mixture thereof,
enhancing gene therapy, or
providing a therapeutic effect.
Among the evidences provided for any of the claimed functions, no core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for the claimed functions is disclosed in such a way to demonstrate possession of the full invention as claimed at time of filing. Sufficient data are not shown to substantiate claiming the broad genus of all PK modifiers or PK-modifying PEG/lipids/sugars/peptides/aptamers/mixtures thereof, universal regions, anchor oligonts, therapeutic oligonts recited in Claim 58, oligonts that target any sequence, and gene therapies. Finally, there are many target sequences and gene therapies, and the Specification does not teach any defining characteristics of such target sequences or gene therapies.
The specification teaches only a couple members from some of the genera or sub-genera. For example, the PEG polymer, the universal sequence and anchor sequences recited in Claims 21-22, the siRNAs comprising first oligont SEQ ID NOs 1 and 2 (which are 21-mers) and second oligont SEQ ID NO 3 (which is a 13-mer). However the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genus of compounds claimed.
While none of these elements is specifically required to demonstrate possession, in combination their lack means that one skilled in the art at the time of filing would conclude that the inventors lacked possession of the full invention claimed. Claims 1-2, 5, 13-14, 18, 21-24, 33, 45, 51, 58, and 60-64-are rejected for failing to demonstrate possession of the claimed invention. Claims 2, 5, 13-14, 18, 21-24, 33, 45, 49, 51, 56, and 60-64 are rejected because they depend from Claims 1-2, 23, 58, 60 and/or 62, and do not remedy the issues.
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 1-2, 5, 13-14, 18, 21-24, 33, 45, 49, 51, 56, 58, and 60-64 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.
Regarding Claim 1, the phrase "about" renders the claim(s) indefinite because the claim(s) include(s) elements not actually disclosed (those encompassed by "about [a number]"), thereby rendering the scope of the claim(s) unascertainable. See MPEP § 2173.05(d). In the interest of compact prosecution the term “about [a number]” is interpreted as that number ± 50% rounded to the closest whole number that provides greatest claim breadth:
…wherein the at least one polymer is at least 1,000 Da (Claim 1).
A claim may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173. In the present instance, Claims 1-2, 5, 14, 21, 23, 33, 50, 58, 60, and 62-64 recite anchor oligonucleotide or anchor. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. An anchor oligonucleotide or anchor is not a term of the art and neither the Spec. nor the claims defines what is anchor oligonucleotide or anchor. The Spec. describes some characteristics of a pharmacokinetic (PK)-modifying anchor at ¶107 but never defines the term anchor oligonucleotide or anchor. For those reasons, it is not clear what the term anchor actually encompasses.
Claims 1-2, 5, 14, 21, 23, 33, 50, 58, 60, and 62-64 are rejected for those reasons. Claims 2, 5, 13-14, 18, 21-24, 33, 45, 49, 51, 56, 58, and 60-64 are rejected because they depend from Claims 1-2, 14, 23, 58, and/or 60 and do not remedy the issues. In the interest of compact prosecution the terms anchor oligonucleotide and anchor are interpreted as any oligont sequence that connects a PK modulator to an antisense oligont via base-pairing.
Claim 13 recites the siRNA has a total length from the 3’end of the AS strand to the 3’end of the sense strand of 20-30 nt. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. Since the sense and AS strands are not attached to one another and since the anchor sequence may or may not be bound to the 3’ universal region of the AS strand, it is not clear what the “total length” comprises or how many nt—or which nt—are included in determining such length.
In the interest of compact prosecution, the claims are interpreted as meaning that the total length of the AS strand is 20-30 nt. The claims are interpreted that way because there are some interpretations where the length from the 3’end of the AS strand to the 3’end of the sense strand is the same as the length of the AS strand. Applicant’s Fig. 1 shows such a case.
Claim 14 recites the sense strand is 13 nt and 17 nt in length. The metes and bounds are unclear because a strand cannot simultaneously be 13 and 17 nt long.
In the interest of compact prosecution the claim is interpreted as meaning the sense strand is 13 nt to 17 nt long.
The term “a first oligonucleotide” in Claim 18 is a relative term which renders the claim indefinite. The term “first” is first only in relation to a “second” but the claims recite no “second oligonucleotide”, so one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. An artisan would not know what structure is required by the claims.
Claim 18 is rejected for those reasons. In the interest of compact prosecution the first oligonucleotide is interpreted as the antisense strand..
Claim 61 recites the AS and the sense strands comprise PS linkages at the 5’ends . The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. The metes and bounds are unclear because it is not clear where the PS is located. Is it between the first and second nt of each strand, or at the 5’ end of each strand? If the latter, it is not a linkage because a PS linkage has to connect two things. A PS at the end of a strand wouldn’t connect anything, so it is not clear what the claims actually mean.
In the interest of compact prosecution, the claims are interpreted as requiring a PS linkage between the nts at positions 1 and 2 from the 5’end of either strand or requiring a PS group at the 5’end of either strand.
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.
Claim(s) 1-2, 5, 13-14, 18, 21-24, 33, 45, 49, 51, 56, 58, and 60-64 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2016/161374 (published 06 October 2016, “WO374”, of record on IDS), Chakraborty (et al. Nucleic Acid–Based Nanodevices in Biological Imaging. 2016. Annu. Rev. Biochem. 85:349–73, “Chakraborty”), ThermoFisher (Page archived on 25 July 2017. “Polyethylene Glycol [PEG] and Pegylation of Proteins. Available online at The Wayback Machine web.archive.org and accessed on 10 December 2025, “ThermoFisher”), Ikeda (and Nagasaki. 2014. Impacts of PEGylation on the Gene and Oligonucleotide Delivery System. J. Appl. Polymer Sci. Article No. 40293, “Ikeda”), evidence provided by Rouzina (and Bloomfield. 1999. Heat Capacity Effects on the Melting of DNA. 1. General Aspects. Biophys. J. 77:3242-3251, “Rouzina”), and in view of English translation of Japanese Patent Application Publication No. JP 2016103986, published 09 June 2016 (“JP986”, of record). This rejection is new and necessitated by the claim amendments. The JP986 reference is of record from the previous 103 rejection.
Regarding Claims 1(a)(i), 1(b), 14(a)(b)(c), and 58(b; partial): WO374 discloses (§Abstract, ¶3) therapeutic RNAs for targeting Huntingtin mRNA to treat Huntington’s disease. WO374 teaches (¶25-26) several different target sequences. WO374 teaches (¶25-26) dsRNAs comprising sense and antisense (AS) strands that can be 15-35 nt long wherein the AS strand comprises complementarity to a target and (¶200) the sense strand is complementary to and forms a duplex with the AS strand. WO374 describes (¶194) RNA silencing agents that are siRNAs, miRNAs, antisense oligont, GAPMER molecules, siRNA-like duplexes, and others. WO374 describes (¶470) dsRNA that have a 15-base pair duplex region. WO374 teaches (¶29) the dsRNA can be blunt-ended or can comprise at least one overhang on one strand, including a 1-7 nt overhang on the 3’end of the AS strand; Fig. 96 shows a dsRNA comprising a 12-base pair duplex region and an 8-nt overhang on the 3’end of the AS strand. Fig. 36 shows dsRNA wherein the sense strand is 15-mer and fully complementary to the AS strand. WO374 teaches (¶31) the RNA has a 5’end and a 3’end; having a 5’end and a 3’end is a feature inherent to any oligonucleotide.
Regarding Claims 2 and 18, WO374 teaches (¶226) the overhang can comprise (or consist of) nt corresponding to the target gene sequence or its complement. That indicates that the overhang can also not comprise or consist of nt corresponding to the target gene. Note that WO374 does not call the overhang a universal region but it describes part of the structure of the universal region (i.e., [a region] positioned at the 3’end of the first region [of the AS strand] that has a length of 5-10 nt). Note also that any two nt sequences in existence would be either at least partially complementary or noncomplementary. Since the AS strand can be 15-35 nt long and the overhang can be 1-8 nt long, that encompasses an AS that is 25 nt long and the nt at positions 18-25 from the 5’end to the 3’end are an 8-mer overhang that does not hybridize with the target sequence.
Regarding claims describing a chemically modified nt or PS linkage, (i.e., Claims 23-24, 33, 60-62) WO374 teaches (¶30) the dsRNA comprises at least one modified nt that can be a nucleotide comprising a 5’phosphorothioate group. WO374 teaches dsRNA comprising (¶31) alternating 2’-methoxy ribonucleotides and 2’-fluoro ribonucleotides. A person of ordinary skill knows that 2’-methoxy ribonucleotides is simply another way to write what the instant claims refer to as 2’-O-methyl ribonucleotides. WO374 teaches (¶31) the nt in the dsRNA are connected via PO or PS linkages. WO374 teaches (¶283) chemical modifications can make an oligonucleotide resistant to nuclease activity and that (¶572) PS bonds can be essential for passive uptake of a dsRNA and that they suspect that two PS tails enhance uptake but that the number of PS linkages must be optimized due to toxic effects. Those teachings indicate that there were known benefits to placing chemical modifications and PS linkages in RNA therapeutics.
Regarding the pharmaceutical composition and carrier of Claim 56, WO374 teaches (¶425) their invention encompasses pharmaceutical compositions suitable for administration and which can comprise a pharmaceutically acceptable carrier. WO374 teaches (same ¶) additional active compounds may be incorporated and any conventional agent can be included in the compositions as long as it’s not incompatible with the active compound.
WO374 teaches (¶7) unmodified siRNA is difficult to deliver to sensitive cell lines and to tissue in vivo. WO374 describes (¶36) delivering dsRNA to a cell and maintaining the cell for am amount of time sufficient to obtain degradation of the HTT mRNA transcript, thereby inhibiting HTT expression in the cell. WO374 teaches administration of the dsRNA to the brain via (¶38) intrastriatal, (¶151) intravenous, or cerebral spinal fluid infusion.
As discussed, WO374 teaches an overhang on the 3’end of the AS strand and the overhang has features of the structure of a universal region (including that it is 1-8 nt long), even though WO374 does not use that same term.
WO374 does not teach the dsRNA comprises at its 3’end a universal region comprising 5-10 nt and a GC content of 50-100% (Claim 1a part ii) and that the universal region is complementary to a PK-modifying anchor. WO374 does not teach a composition comprising the dsRNA and a PK modifying anchor comprising an anchor oligonucleotide that is 5-10 nt long and comprises a GC content of 50-100%, wherein the 5’end of the PK-modifying anchor is attached to at least one polymer that is at least about 2000 Da (Claim 1c).
However, Chakraborty, drawn to nucleic acid–based nanodevices in biological imaging, teaches methods used to image nucleic acids in cells. Chakraborty teaches (Fig. 2) FISH wherein fluorophore-labeled antisense oligos hybridize with an RNA or DNA target and show where within a cell the target occurs. Chakraborty teaches further techniques for localizing RNA or DNA in cells. Chakraborty teaches (§DNA-guided super-resolution imaging of cellular architectures, entire §) the DNA-PAINT method wherein a target bears a 9-10 nt docking strand and can be imaged by an imager strand which is a fluorescently labeled 9 to 10-mer oligonucleotide. Chakraborty teaches that the 9-10 nt are designed to have high Kd and low melting temperature to enable repeated binding and unbinding events. Chakraborty teaches that the fluorescence ON time can be adjusted by changing the concentration of imager strands and the fluorescence OFF time can be controlled by the length of the imager–docking strand duplex. Chakraborty teaches that a critical advantage of the DNA-PAINT system is its bleaching independence which enables imaging over long durations and use of diverse fluorophores.
Chakraborty further teaches (§Antisense-based recognition ¶1) live cell imaging techniques that use fluorescently labeled antisense probes that hybridize with a target RNA.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that the methods of Chakraborty could be modified to detect and image therapeutic dsRNA localization in a cell. Regarding the FISH method, although Chakraborty teaches (Fig. 2 caption) FISH detects endogenous RNA, including (§Visualization of Endogenous Nucleic Acids ¶2) mRNA, there is no reason why an antisense oligo couldn’t be designed to target a dsRNA and an artisan would have readily recognized that such fluorescently labeled antisense oligo could be designed to bind an overhang region on WO374’s dsRNA.
Regarding the PAINT and antisense-based recognition methods of Chakraborty, it would have been obvious to an artisan that the methods could be readily modified to detect and image dsRNA localization within a cell. Chakraborty described PAINT utilizing an immobilized DNA origami bearing a docking strand that binds to a fluorescently labeled imager strand and is used for imaging fixed cells. It would have been obvious to the artisan that there is no reason the PAINT strategy could not be used to visualize localization of any nucleic acid target, including therapeutic dsRNA of WO374, including in live cells. An artisan would have recognized that the overhang on the AS strand 3’end within WO374’s dsRNA could provide the same function as Chakraborty’s docking strand: a place for a complementary fluorescently labeled imager strand to bind. It would have been obvious to design fluorescently labeled antisense oligos comprising complementarity to the overhang/docking strand and those fluorescently labeled antisense oligos would serve as Chakraborty’s imager strand that binds via complementary hybridization to the target overhang/docking strand. Since Chakraborty’s imager and docking strands are up to 10-mer, it would have been obvious to make a complementary region and imager strand that is each up to 10-mer. It would have been obvious to use the strategy in fixed cells or, like the antisense recognition strategy, in live cells. It would have been obvious that binding between the overhang/docking and imager strands would indicate where within a cell or tissue the dsRNAs localize upon administration, at time points after administration, and/or with different modes of administration.
Chakraborty teaches that the imager strand has a high Kd and low melting temperature to enable repeated binding and unbinding events. It would have been obvious to an artisan to modify the high Kd and low melting temperature imager strand of Chakraborty to comprise a low Kd and higher melting temperature so that they would not enable repeated binding/unbinding events but would instead enable imaging of a single binding event that could be imaged at various time points.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNAs of WO374 with the teachings regarding nucleic acid imaging of Chakraborty for the benefit of visualizing the location within a tissue or cell a dsRNA is at any point in time or over a time course. One would have been motivated to do so because WO374 teaches (¶7) it can be difficult to deliver siRNA and ensuring both chemical stability and minimal toxicity while maximizing delivery remains a difficult task. One would have been motivated to do so because WO374 teaches (§cited above) different modes of infusion and an artisan would have wanted to know whether any of them provides more efficacious delivery. One would have been motivated to use Chakraborty’s PAINT method because Chakraborty teaches that (§cited above) the technique is bleaching independent and enables imaging over long durations and the antisense recognition technique can be used in live cells. That would have allowed an artisan to visualize the path of a dsRNA over time. One would have had a reasonable expectation of success because Chakraborty indicates that nucleic acid imaging techniques wherein a fluorescently labeled nucleotide binds via complementary base-pairing to a target were routine and customary in the art. It would have been obvious to modify the lengths of the overhang/docking–imager strands because Chakraborty teaches that the length of the duplex affects binding kinetics.
Therefore a composition comprising (a) a dsRNA comprising an antisense strand comprising a 5’end and a 3’end and a nucleotide sequence comprising (i) a first region positioned at the 5’end with complementarity to a target sequence for mediating silencing and comprising at least 16 nt and (ii) a second region positioned at the 3’end of the first region; (b) a sense strand comprising a 5’end and a 3’end and a nt sequence comprising a region of complementarity to the first region of the AS strand; and (c) another nt sequence (i.e., the imager strand or what the instant claims call an anchor oligonucleotide) comprising a 3’end and 5’end and which is complementary to the second region at the 3’end of the AS strand would have been obvious in view of WO374 and Chakraborty.
Chakraborty’s imager strand has some of the same structure (up to 10-mer long but the length can vary; hybridizes via complementary base pairs to the docking strand) and performs the same function as what is claimed as an anchor oligonucleotide. Similarly, Chakraborty’s docking strand has some of the same structure (up to 10-mer long but the length can vary; hybridizes via complementary base pairs to the imager strand) and performs the same function as what is claimed as a universal region. The terms vary but are all parts of a composition that would have been obvious in view of the prior art.
Regarding the composition of Claim 1, it would have been obvious to administer the dsRNAs in a composition with the anchor/imager strand OR to combine the dsRNAs together with the anchor/imager strands to ensure that the anchors bind to the dsRNAs and fluoresce. One would have been motivated to do so because the purpose of using the anchor/imager strands (i.e., the methods of Chakraborty applied to the dsRNAs of WO374) is to visualize where, in a tissue or cell, a dsRNA is located. They would have been motivated to do that because WO374 teaches (¶7) delivering dsRNAs can be difficult and they would have wanted to see where the dsRNA is delivered, how long it takes to get there, and how long it takes to move through a tissue or cell, and whether any of those outcomes differs with any mode of delivery.
Regarding Claims 1(a)(b)(c), 14(a)(b)(c), and 58: the specific lengths of an AS strand that is 15-35 nt long (including 16-mer or 21- to 25-mer) and of a sense strand that is 15-35 nt long (including 10- to 20-mer or 13- to 17-mer) would have been obvious in view of the art. The 10- to 20-mer region of complementarity between the sense and AS strands would have been obvious. Regarding the length of the anchor/imager strand, shortening its length would have been obvious because WO374 teaches various lengths for the overhang and because Chakraborty teaches the length of the docking/imager duplex affects fluorescence kinetics, which would have motivated the artisan to shorten the strand lengths to 8-mer each.
Regarding Claims 5, 13, 51, and 58: The specific length of an anchor/imager strand that binds the universal/overhang/docking strand that is up to 10 nt long because Chakraborty teaches docking and imager strands that are up to 10-mer. Furthermore, the specific length of an anchor/imager strand that binds the universal/overhang/docking strand that is shorter than 10-mer would have been obvious in view of Chakraborty because Chakraborty teaches modifying the length of the strands to adjust fluorescence kinetics. Regarding Claim 5, the artisan would have made the overhang/universal/docking strand and the anchor/imager strands 100% complementary to ensure high specificity. Regarding Claims 13 and 51 specifically, an artisan would have modified the number of nt in the antisense strand, the sense strand, and the anchor/imager strand to determine which compounds work best at balancing a variety of factors including cell uptake, target RNA silencing, anchor/imager strand binding to the dsRNA target in vitro and in vivo, fluorescence kinetics, and imaging capabilities. In making those modifications to strand lengths, the number of nt in the AS would have been equal to the number of nt in the sense strand + anchor/imager strand and would have been 20-30 nt. Since, as discussed, WO374 describes not only dsRNAs but also (¶194) RNA silencing agents that are siRNAs, miRNAs, antisense oligont, GAPMER molecules, siRNA-like duplexes, and others, it would have been obvious to use the imaging strategies of Chakraborty comprising an imager strand to target any of those kinds of RNAs. Since Chakraborty teaches using FISH to visualize mRNA in a cell, it would have been obvious to use the PAINT technique to visualize mRNA.
Regarding the modifications and PS linkages in the dsRNA or anchor/imager strand of Claims 23-24, 33, 60-62, passages above discussed that WO374 teaches all those modifications including (¶13) the 5’ PS groups or PS linkages between nts, and reasons why an artisan would have applied them. It would have been obvious to a person of ordinary skill that the same modifications that increase cell uptake and nuclease resistance in a dsRNA would increase cell uptake and nuclease resistance in any RNA, including the anchor/imager strand. So they would have made the dsRNA and/or anchor/imager strands comprising any or all the recited modifications.
WO374 and Chakraborty do not teach the anchor/imager strand is attached to a polymer (or that the imager strand is attached to the fluorescent label via a polymer), or that the polymer is 2000 Da (Claim 1[c], or that the polymer can be PEG (Claim 45), or that the PEG is attached to the anchor/imager strand via an NHS ester reaction and that the PEG can be 10 kDa, 20 kDa, or 40 kDa (Claim 63).
However, ThermoFisher, drawn to PEG linkers, teaches (§PEG-containing Fluorescent Labeling Reagents) PEG improves the solubility and stability of fluorescent labels used for various applications. That indicates that it was routine and customary to adhere PEGylated fluorescent probes to various compounds.
Ikeda, drawn to impacts of PEGylation on oligonucleotide delivery, teaches (§Abstract) PEG is a gold standard in drug delivery and that (§PEGYLATION OF NUCLEIC ACID ¶1) it is commonly applied to nucleic acids including siRNA. Ikeda teaches (§Introduction ¶1) PEGylation can reduce a molecule’s immunogenicity and prolong its blood circulation time. Ikeda teaches (same §) PEGylation can increase molecule size which results in reduced filtration by the kidneys, and that PEGylation increases solubility, and protects a molecule from digestion and recognition by antibodies.
Regarding Claims 1c, 45, 58a(ii), and 63: Ikeda teaches (§PEGYLATION OF NUCLEIC ACID-PEGylation Effects on the Activity of Therapeutic Oligonucleotides-PEGylation Site Effect ¶1) PEG can be joined to the 3’ or 5’end of either strand of an siRNA. That teaching indicates that the PEG can be joined at the 3’- or 5’-end of the anchor/imager strand. Ikeda teaches (same §, ¶2) 20 kDa and 40 kDa PEG. Ikeda teaches (§PEGYLATION OF NUCLEIC ACID-Oligonucleotide PEGylation ¶3) that PEG can be joined to a nucleic acid using an NHS-activated ester reaction. Ikeda teaches (same §) that was a 5 kDa PEG.
Since ThermoFisher and Ikeda teach PEG improves the stability of what it’s attached to, PEG can be considered a pharmacokinetic-modifying molecule.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNA comprising an overhang/docking region and the anchor/imager strand of WO374 and Chakraborty with the teachings about PEG of ThermoFisher and Ikeda for the benefit of improving the stability of both the fluorescent label and the oligonucleotide to which it is attached (i.e., the anchor/imager strand of Chakraborty). One would have been motivated to do so with a reasonable expectation of success because ThermoFisher and Ikeda teach PEG improves the stability of what it’s attached to and because an artisan would know they were planning to use the anchor/imager strand to image the location of dsRNA in tissues/cells. One would have been motivated to do so because of Ikeda’s teachings about molecule size affecting filtration by the kidneys, increased solubility, and protection from digestion and recognition by antibodies, and the different sizes of PEG and the method of attaching PEG to an oligo (i.e., NHS ester reaction). Based on the teachings of ThermoFisher and Ikeda, attaching the fluorescently labeled oligonucleotide anchor/imager strand to PEG, or attaching the fluorescent label to the anchor/imager strand via PEG would be expected to increase the stability of the anchor/imager strand in vivo. Attaching the fluorescent label, PEG, and the anchor/imager strand in any combination (i.e., attaching the anchor/imager strand to the fluorescent label via PEG or attaching the fluorescently labeled anchor/imager strand to PEG) would have been a matter of routine optimization including because ThermoFisher (cited §) teaches PEGylated fluorescent labels and because Ikeda teaches (§PEGYLATION OF NUCLEIC ACID-PEGylation Effects on the Activity of Therapeutic Oligonucleotides-PEGylation Site Effect ¶1) it is routine in the art to test whether PEGylation placement alters efficacy. Therefore an artisan would have placed the PEG on the 5’end of the anchor/imager strand.
As discussed, Chakraborty teaches (§DNA-guided super-resolution imaging of cellular architectures) the imager strands have high Kd and low melting temperatures which allows for repeated binding and unbinding events. However, an artisan wanting to study a single binding event would have understood they should produce anchor/imager strands comprising the opposite: low Kd and high melting temperatures. A person of ordinary skill understands that high melting temperatures require a higher GC content. For example, Rouzina provides evidence to that effect: (§BASE COMPOSITION DEPENDENCE OF DNA MELTING ¶1) it is well known that GC-rich DNA melts at a higher temperature than AT-rich DNA, because GC base pairs have three hydrogen bonds, while AT base pairs have only two.
WO374, Chakraborty, ThermoFisher, and Ikeda do not teach the universal/docking and anchor/imager strands comprise a GC content of 50-100% (Claims 1[a][ii] and 1[c] and 58). WO374, Chakraborty, ThermoFisher, and Ikeda do not teach the anchor/imager strand sequences recited in Claims 21-22 and 64.
However, JP914, drawn to methods for manufacturing a DNA cassette, teaches the short 9-mer primer sequence SEQ ID NO 43 that is 100% identical to the sequence instantly claimed in Claim 22, as shown by the following alignment:
BCR44061
ID BCR44061 standard; DNA; 9 BP.
XX
AC BCR44061;
XX
DT 28-JUL-2016 (first entry)
XX
DE U6 gene specific forward PCR primer, SEQ ID 43.
XX
KW PCR; U6 gene; dna cassette; primer; ss.
XX
OS Synthetic.
OS Unidentified.
XX
CC PN JP2016103986-A.
XX
CC PD 09-JUN-2016.
XX
CC PF 01-DEC-2014; 2014JP-00242914.
XX
PR 01-DEC-2014; 2014JP-00242914.
XX
CC PA (UYTY ) UNIV TOKYO.
XX
CC PI Saito I;
XX
DR WPI; 2016-34562K/42.
XX
CC PT Preparing DNA cassette formed by several biological units, involves using
CC PT unit formed by biological unit, determining sequence of intrinsic region
CC PT of biological unit, forming biological unit, and connecting designed
CC PT recombinant units.
XX
CC PS Example 4; SEQ ID NO 43; 44pp; Japanese.
XX
CC The present invention relates to a method for preparing a DNA cassette
CC formed by several biological units. The method involves: using unit
CC formed by a biological unit; determining the sequence of intrinsic region
CC of the biological unit; forming biological unit; and connecting designed
CC recombinant units. The present sequence represents an U6 gene specific
CC PCR primer, which is useful in the method for preparing a DNA cassette
CC formed by several biological units as described in an exemplification of
CC the invention.
XX
SQ Sequence 9 BP; 1 A; 5 C; 3 G; 0 T; 0 U; 0 Other;
Query Match 100.0%; Score 8; Length 9;
Best Local Similarity 100.0%;
Matches 8; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CCGAGCGC 8
||||||||
Db 2 CCGAGCGC 9
That sequences comprises at least 50% GC content.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the DNA nanostructures for siRNA delivery of WO374, Chakraborty, ThermoFisher, and Ikeda with the short primer sequence of JP986 for the benefit of using a known sequence comprising a high melting temperature as the universal/docking sequence on the dsRNA and its complement as the anchor/imager strand comprising PEG and a fluorescent label. One would have been motivated to do so with a reasonable expectation of success because JP986 SEQ ID NO 43 was a known sequence and the teachings regarding an overhang of WO374 indicate the overhang sequence can be any sequence. One would have been motivated to do so with a reasonable expectation of success because the teachings of Chakraborty indicate that any sequence can be used and a 9-mer is exactly the length taught by Chakraborty. As discussed, an artisan would have wanted to use a sequence with a high melting temperature to ensure only a single binding event between the AS comprising the universal/overhang/docking sequence and the anchor/imager strand comprising a fluorescent label. From those teachings, an artisan would have realized the overhang could have comprised any sequence, and because the teachings of Chakraborty indicate that nt linkers with lengths 9 nt were common in the art of PAINT. It would have been a simple matter to produce a 9-mer overhang on the AS strand of the WO374 dsRNA that comprises the 9-mer primer sequence of JP986, and one would have done so during the process of routine optimization. Absent evidence to the contrary, choosing any particular length and sequence for the overhang on the siRNA would have been, simply, a design choice well within the constraints of what was routine and customary.
The rest of this rejection has explained how the art of WO374, Chakraborty, ThermoFisher, Ikeda makes obvious all the other limitations of the other claims. Therefore the limitations of Claims 1-2, 5, 13-14, 18, 22-24, 33, 45, 51, 56, 58, and 60-63 would have been obvious in view of WO374, Chakraborty, ThermoFisher, Ikeda, and JP986.
Then it would have been obvious to make the anchor/imager strand to comprise the complement of JP986’s 9-mer primer sequence SEQ ID NO 43, so that they would hybridize to the dsRNA’s universal/overhang/docking region. At least 8-mer of the complement of JP986 SEQ ID NO 43 comprises the anchor/imager sequence shown in Claim 21, as shown by the following alignment:
RESULT 1
NASEQ2_12112025_123534/c
Query Match 100.0%; Score 8; DB 1; Length 8;
Best Local Similarity 87.5%;
Matches 7; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GCGCUCGG 8 SEQ shown in Claim 21
||||:|||
Db 8 GCGCTCGG 1 8-mer of JP986 SEQ ID NO 43
Therefore the limitations of Claims 21 and 64 would have been obvious in view of WO374, Chakraborty, ThermoFisher, Ikeda, and JP986.
Claim(s) 1-2, 5, 13-14, 18, 21-24, 33, 45, 49, 51, 56, 58, and 60-64 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. US 2016/0281148 (published 29 September 2016, “App418”, of record on IDS) in view of Chakraborty (et al. Nucleic Acid–Based Nanodevices in Biological Imaging. 2016. Annu. Rev. Biochem. 85:349–73, “Chakraborty”), Ikeda (and Nagasaki. 2014. Impacts of PEGylation on the Gene and Oligonucleotide Delivery System. J. Appl. Polymer Sci. Article No. 40293, “Ikeda”), English translation of Japanese Patent Application Publication No. JP 2016103986, published 09 June 2016 (“JP986”, of record), and International Publication Number WO 2016/161374 (published 06 October 2016, “WO374”, of record on IDS). This rejection is new and necessitated by the claim amendments. The JP986 reference is of record from the previous 103 rejection.
App418 teaches methods of detecting an/or quantitating a target oligonucleotide (“oligo” or “oligont”) in a biological sample. App418 teaches (¶2) oligont comprising various modifications are used as therapeutic agents to reduce protein expression, and that such oligos can be single- or double-stranded. App418 teaches (¶3) it is desirable to detect or quantify the amount of therapeutic oligont in a sample from an animal who’s been administered the oligont.
App418 teaches (¶6) the target oligont can be 8-50 nt long and teaches (¶8-14) a capture probe bound to a solid support, wherein the capture probe is complementary to a first part of an oligont, and a detector probe that is complementary to a second portion of the target oligont. App418 teaches (same §) the detector probe comprises a covalently bound electrochemiluminescent moiety that can be detected by a detector. App418’s second portion of the target oligont is analogous to what is called in the instant claims the universal region. App418’s detector probe is what is called in the instant claims the anchor oligont. Since App418 teaches (¶2, ¶120-121) the agents can be used to reduce protein expression, they would have to be complementary to a target.
App418 teaches (Fig. 1) the following graphic overview of their invention:
PNG
media_image1.png
433
1109
media_image1.png
Greyscale
Regarding the lengths of the AS strand recited in Claims 1(a)(i), 13-14(a), App418 teaches (¶6) the target can be 8-50 nt.
Regarding Claims 1(a)(b), 14(b): App418 teaches (¶43) the target can be double stranded. That means it would comprise a sense strand that is complementary to the AS strand. Since (¶6) teaches the target oligont can be 8-50 nt in length, that encompasses sense strand lengths of 10-20 nt and 13-17 nt.
Regarding Claims 1(c), 14(c), 58: App418 teaches (¶61) the detector probe can be 10 nt long.
Regarding Claim 2, App418 teaches (¶129) complementary in reference to oligomeric compounds refers to the ability of such oligomeric compounds or regions thereof to hybridize to another oligomeric compound or region thereof. Therefore App418 teaches the limitations of Claim 2 wherein the AS strand is partially complementary to the target sequence.
Regarding Claims 5 and 18: App418 teaches (¶129) “complementary” can be 70-100% complementary. Therefore the teachings (¶120-121) that the detector probe is complementary to the second portion of the target encompass perfect complementarity. Since App418 teaches lengths of 8-50 nt and doesn’t require perfect complementarity between the AS strand and the target sequence, its teachings also encompass the limitations of Claim 18.
Regarding the chemical modifications and PS linkages of Claims 23-24, 33, 60-62, App418 teaches (¶54-58, ¶158, ¶196-204) the detector probe can comprise modified nt and the oligont of the invention can comprise, generally, PS linkages, alternating modification motifs, wherein each linkage can be PS, and wherein each nt comprises a chemical modification. App418 teaches (¶192-193) 2’F modifications and (¶135) 2’-OMe modifications. A situation wherein each linkage is PS would encompass wherein the nt at positions 1 and 2 from the 5’end of the target strand are PS linkages. Those modifications are, generally, for oligont described, so they can be applied to the target oligont or the detector probe. App418 describes (¶229) applying them to the detector probe. Therefore App418 teaches limitations of Claims 23-24, 33, and 60-62.
Regarding Claims 1, 45, and 63: App418 teaches (¶60, ¶210-212) the electrochemiluminescent moiety of the detector probe is conjugated to its 5’end and that it can be attached to the oligont of the detector probe via a conjugate linking group including PEG.
Regarding Claim 51: App418 teaches (¶6) dsRNA targets and that the length of the molecule can be 8-50 nt long. App418 also teaches (¶61) the detector can be 10 nt long. App418 teaches (¶18) a specific embodiment wherein the target is 10-40 nt long. If the AS strand of the target is 25 nt long and the detector oligont is 8 nt long, and the sense strand is 17 nt long, then the length of the AS strand (i.e., 25 nt) would be the same as the length of the sense strand + the detector (i.e., 17 nt + 8 nt). Therefore the limitations of Claim 51 are envisioned by App418.
Regarding Claim 58(b), App418 teaches the target can be a single-stranded ASO for reducing protein expression. Regarding the outcome recited in Claim 58: binding (i.e., hybridization) between the detector probe and the target would make the target–detector a larger molecule than the target alone, and it would bring to the target an electrochemiluminescence which would modify the pharmacokinetics of the target.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that the system of App418 could be used with any oligont target and need not comprise a capture probe bound to a solid support. Therefore it would have been obvious to use the system to detect any known RNA in any cell or tissue, including therapeutic RNAs specifically designed to comprise a second portion that is complementary to the detector probe. Such modification would have been obvious because Chakraborty teaches (§Visualization of Endogenous Nucleic Acids ¶1; Fig. 2; DNA-guided super-resolution imaging of cellular architectures ¶1; § Visualization of Endogenous Nucleic Acids ¶1) it was known in the art to use the similar techniques using hybridization of fluorescently labeled antisense oligont to visualize RNA including mRNA. Therefore most claim limitations would have been obvious in view of App418 or in view of App418 and Chakraborty.
App418 does not teach using PEG polymers with the instantly claimed weights: about 2000 Da, 10 kDa, 20 kDa, and 40 kDa. App418 does not teach attaching PEG to an oligo via an NHS ester reaction.
However, Ikeda, drawn to impacts of PEGylation on oligonucleotide delivery, teaches (§Abstract) PEG is a gold standard in drug delivery and that (§PEGYLATION OF NUCLEIC ACID ¶1) it is commonly applied to nucleic acids including siRNA. Ikeda teaches (§Introduction ¶1) PEGylation can reduce a molecule’s immunogenicity and prolong its blood circulation time. Ikeda teaches (same §) PEGylation can increase molecule size which results in reduced filtration by the kidneys, and that PEGylation increases solubility, and protects a molecule from digestion and recognition by antibodies.
Regarding Claims 1c, 45, 58a(ii), and 63: Ikeda teaches (§PEGYLATION OF NUCLEIC ACID-PEGylation Effects on the Activity of Therapeutic Oligonucleotides-PEGylation Site Effect ¶1) PEG can be joined to the 3’ or 5’end of either strand of an siRNA. That teaching indicates that the PEG can be joined at the 3’- or 5’-end of the anchor/imager strand. Ikeda teaches (same §, ¶2) 20 kDa and 40 kDa PEG. Ikeda teaches (§PEGYLATION OF NUCLEIC ACID-Oligonucleotide PEGylation ¶3) that PEG can be joined to a nucleic acid using an NHS-activated ester reaction. Ikeda teaches (same §) that was a 5 kDa PEG.
App418 and Ikeda do not teach the universal and anchor strands comprise a GC content of 50-100% (Claims 1[a][ii] and 1[c] and 58). App418 and Ikeda do not teach the anchor/imager strand sequences recited in Claims 21-22 and 64.
However, JP914, drawn to methods for manufacturing a DNA cassette, teaches the short 9-mer primer sequence SEQ ID NO 43 that is 100% identical to the sequence instantly claimed in Claim 22, as shown by the following alignment:
BCR44061
ID BCR44061 standard; DNA; 9 BP.
XX
AC BCR44061;
XX
DT 28-JUL-2016 (first entry)
XX
DE U6 gene specific forward PCR primer, SEQ ID 43.
XX
KW PCR; U6 gene; dna cassette; primer; ss.
XX
OS Synthetic.
OS Unidentified.
XX
CC PN JP2016103986-A.
XX
CC PD 09-JUN-2016.
XX
CC PF 01-DEC-2014; 2014JP-00242914.
XX
PR 01-DEC-2014; 2014JP-00242914.
XX
CC PA (UYTY ) UNIV TOKYO.
XX
CC PI Saito I;
XX
DR WPI; 2016-34562K/42.
XX
CC PT Preparing DNA cassette formed by several biological units, involves using
CC PT unit formed by biological unit, determining sequence of intrinsic region
CC PT of biological unit, forming biological unit, and connecting designed
CC PT recombinant units.
XX
CC PS Example 4; SEQ ID NO 43; 44pp; Japanese.
XX
CC The present invention relates to a method for preparing a DNA cassette
CC formed by several biological units. The method involves: using unit
CC formed by a biological unit; determining the sequence of intrinsic region
CC of the biological unit; forming biological unit; and connecting designed
CC recombinant units. The present sequence represents an U6 gene specific
CC PCR primer, which is useful in the method for preparing a DNA cassette
CC formed by several biological units as described in an exemplification of
CC the invention.
XX
SQ Sequence 9 BP; 1 A; 5 C; 3 G; 0 T; 0 U; 0 Other;
Query Match 100.0%; Score 8; Length 9;
Best Local Similarity 100.0%;
Matches 8; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CCGAGCGC 8
||||||||
Db 2 CCGAGCGC 9
That sequences comprises at least 50% GC content.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods of detection of App418 with the teachings about molecule size affecting filtration by the kidneys, increased solubility, and protection from digestion and recognition by antibodies, and the different sizes of PEG and the method of attaching PEG to an oligo (i.e., NHS ester reaction)of Ikeda with the short primer sequence of JP986. One would have done so for the benefits of using a known technique to attach PEG to the oligo and modulating kidney filtration, protecting the oligos from digestion and recognition by antibodies, and using a known sequence (i.e., that of JP986) as the universal sequence. One would have been motivated to do so with a reasonable expectation of success because an artisan would want to lower immunogenicity, and because JP986 SEQ ID NO 43 was a known sequence and the teachings of App418 teach detecting any target oligont. An artisan would have been motivated to add a “second portion” of JP986 as the portion wherein the detector probe binds to the target oligont because they would have wanted to produce a target oligont wherein the detector probe binds without the perturbing the mRNA-binding function of the target oligo. To clarify, they would have wanted to retain the target oligont’s ability to fully bind its target mRNA so they would have added the sequence of JP986 to the target oligont to extend the target oligont; that way the target oligont would retain the full length that binds target mRNA.
An artisan would have realized the binding region on the target oligo could have comprised any sequence or any size PEG. Absent evidence to the contrary, choosing any particular length and sequence for the binding region on the target sequence would have been, simply, a design choice well within the constraints of what was routine and customary.
Therefore the limitations of Claims 1-2, 5, 13-14, 18, 22-24, 33, 45, 51, 58, and 60-63 would have been obvious in view of App418, Chakraborty, Ikeda, and JP986.
Then it would have been obvious to make the anchor/imager strand to comprise the complement of JP986’s 9-mer primer sequence SEQ ID NO 43, so that they would hybridize to the target oligo. At least 8-mer of the complement of JP986 SEQ ID NO 43 comprises the anchor/imager sequence shown in Claim 21, as shown by the following alignment:
RESULT 1
NASEQ2_12112025_123534/c
Query Match 100.0%; Score 8; DB 1; Length 8;
Best Local Similarity 87.5%;
Matches 7; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GCGCUCGG 8 SEQ shown in Claim 21
||||:|||
Db 8 GCGCTCGG 1 8-mer of JP986 SEQ ID NO 43
Therefore the limitations of Claims 21 and 64 would have been obvious in view of App418, Chakraborty, Ikeda, and JP986.
App418, Chakraborty, Ikeda, and JP986 do not teach a pharmaceutical composition comprising the composition of Claim 1 and a pharmaceutically acceptable carrier.
Regarding the pharmaceutical composition and carrier of Claim 56, WO374, drawn to dsRNAs, teaches (¶425) their invention encompasses pharmaceutical compositions suitable for administration and which can comprise a pharmaceutically acceptable carrier. WO374 teaches (same ¶) additional active compounds may be incorporated and any conventional agent can be included in the compositions as long as it’s not incompatible with the active compound.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to put the composition of Claim 1 into a pharmaceutical composition so it could be administered to cells, tissues, or animals. An artisan would have been motivated to do so with a reasonable expectation of success because Chakraborty teaches imaging techniques for visualizing nucleic acids, including in living tissues. Therefore an artisan would have administered the compounds and then taken biological samples to determine whether or not the compounds localized to the sample tissue within a given period of time. Alternatively an artisan would have used the pharmaceutically acceptable carrier to mimic physiological conditions when performing an in vitro assay. Therefore the limitations of Claim 56 would have been obvious in view of App418, Chakraborty, Ikeda, JP986, and WO374.
Regarding placing the detector probe binding region at the 3’end of the AS strand, it would have been obvious to place that region at either end of the strand. In addition, WO374 teaches (¶29) their dsRNA can comprise at least one overhang on one strand, including a 1-7 nt overhang on the 3’end of the AS strand; Fig. 96 shows a dsRNA comprising a 12-base pair duplex region and an 8-nt overhang on the 3’end of the AS strand. Fig. 36 shows dsRNA wherein the sense strand is 15-mer and fully complementary to the AS strand. WO374 teaches (¶226) the overhang can comprise (or consist of) nt corresponding to the target gene sequence or its complement. That indicates that the overhang can also not comprise or consist of nt corresponding to the target gene. Note that WO374 does not call the overhang a universal region but it describes part of the structure of the universal region (i.e., [a region] positioned at the 3’end of the first region [of the AS strand] that has a length of 5-10 nt).
It would have been obvious to an artisan before the effective filing date of the claimed invention to add the primer sequence of JP986 to the 3’end of an ASO or the AS strand of a dsRNA as an overhang for the fluorescently tagged detector probe to bind. Doing so would have been obvious because an artisan could have added any sequence at either end and would have done so during the process of routine optimization. As discussed above, an artisan would have been motivated to add a “second portion” of JP986 as the portion wherein the detector probe binds to the target oligont because they would have wanted to produce a target oligont wherein the detector probe binds without the perturbing the mRNA-binding function of the target oligo.
Altogether all the limitations of the claims would have been obvious in view of App418, Chakraborty, Ikeda, JP986, and WO374.
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 1-2, 5, 13-14, 18, 21-24, 33, 45, 49, 51, 56, 58, and 60-64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-44 of U.S. Patent No. 11492619, issued 08 November 2022 (“US619”, of record on IDS) in view of English translation of Japanese Patent Application Publication No. JP 2016103986, published 09 June 2016 (“JP986”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are directed to:
a composition comprising (a) an AS strand comprising a 5' end, a 3' end, with a nucleotide sequence comprising: (i) a first region positioned at the 5' end with complementarity to a target sequence for mediating silencing thereof comprising at least 16 nucleotides; and (ii) a universal region positioned at the 3' end of the first region that has a length of 5 to 10 nucleotides, wherein the universal region comprises a GC content of between 50 to 100%; (b) a sense strand comprising a 5' end, a 3' end, and a nucleotide sequence comprising 10 to 20 nucleotides that are complementary to the first region of the antisense strand: and (c)_a pharmacokinetic (PK)-modifying anchor comprising an anchor oligonucleotide comprising a 3' end, and a 5' end, wherein the 5' end of the PK-modifying anchor is attached to at least one polymer, wherein the anchor oligonucleotide is10 nucleotides in length, comprises a GC content of between 50 to 100%, and is complementary to the universal region at the 3' end of the antisense strand, and wherein the at least one polymer is at least about 2,000 Da
and to:
universal, pharmacokinetic (PK)-modifying system for enhancing gene therapy technologies comprising: (a) an anchor oligonucleotide strand comprising:(i) 5-20 nucleotides in length, and having a GC content of between 50 to 100%; and(ii) a polymer attached to the anchor oligonucleotide strand, wherein the polymer has a molecular weight of 2,000 to 100,000 Daltons; and (b) a therapeutic oligonucleotide selected from the group consisting of an antisense oligonucleotide, an miRNA, an mRNA, a single-stranded siRNA, and a CRISPR guide strand, wherein the therapeutic oligonucleotide comprises a universal region comprising a GC content of between 50 to 100% and is 5 to 20 nucleotides in length and complementary to the anchor oligonucleotide strand, whereby hybridization of the anchor oligonucleotide to the universal region of the therapeutic oligonucleotide modifies the pharmacokinetics of the therapeutic oligonucleotide as compared the therapeutic oligonucleotide without the anchor nucleotide
The claimed compounds have additional features including universal and anchor regions comprising a certain GC content, , length requirements, wherein the polymer is attached to the anchor oligont, wherein the at least one polymer can comprise a PEG/lipid/sugar/peptide/aptamer/mixture thereof; wherein: the number of nucleotides in the AS strand is the same as the number of nucleotides in the sense strand and the anchor oligonucleotide combined, wherein the anchor oligont and universal sequence comprise the sequences recited in Claims 21-22, wherein the anchor and AS strands can comprise a modification or wherein the anchor oligont can comprise alternating 2’-OMe and 2’-fluoro modifications, to the compounds comprising a pharmaceutically active carrier or to a pharmaceutical composition comprising the compounds plus a pharmaceutically acceptable carrier, and to the composition wherein the PEG is attached to the anchor oligo via an NHS ester reaction, and wherein the polymer or PEG has specific molecular weights.
The issued US619 claims are directed to compounds and pharmaceutical compositions comprising a first 16-25-mer oligonucleotide that comprises complementarity to a target gene or a target mRNA, a second 12-17-mer oligonucleotide, and a pharmacokinetic (PK)-modifying anchor comprising an anchor oligonucleotide comprising about 5 to about 15 nucleotides in length, wherein the polymer is at least about 2000 Da, wherein the anchor and/or first oligont and/or second oligont can comprise a modification or wherein the first oligont and/or anchor oligont can comprise alternating 2’-OMe and 2’-fluoro modifications, to the compounds comprising a pharmaceutically active carrier or to a pharmaceutical composition comprising the compounds plus a pharmaceutically acceptable carrier, and wherein the anchor oligont is complementary to a portion of the first oligonucleotide. The invention of the US619 claims comprises a linker, complementarity to a target gene, various numbers of polymers, oligonts of various lengths, modified bonds, wherein the anchor comprises mismatches to the first oligont, and wherein: the number of nucleotides in the first oligonucleotide is the same as the number of nucleotides in the second oligonucleotide and the anchor oligonucleotide combined.
Both claim sets are directed to the same subject matter: siRNA comprising a universal region that binds a PK-modifying anchor. It would not be possible to possess or use the invention of instant Claims 1-2, 5, 13-14, 18, 23-24, 33, 45, 49, 51, 56, 58, and 60-64 without using the compound of the US619 claims.
The US619 claims do not teach the anchor and universal region sequences recited in instant claims 21-22.
However, However, JP914, drawn to methods for manufacturing a DNA cassette, teaches the short 9-mer primer sequence SEQ ID NO 43 that is 100% identical to the sequence instantly claimed in Claim 22, as shown by the following alignment:
BCR44061
ID BCR44061 standard; DNA; 9 BP.
XX
AC BCR44061;
XX
DT 28-JUL-2016 (first entry)
XX
DE U6 gene specific forward PCR primer, SEQ ID 43.
XX
KW PCR; U6 gene; dna cassette; primer; ss.
XX
OS Synthetic.
OS Unidentified.
XX
CC PN JP2016103986-A.
XX
CC PD 09-JUN-2016.
XX
CC PF 01-DEC-2014; 2014JP-00242914.
XX
PR 01-DEC-2014; 2014JP-00242914.
XX
CC PA (UYTY ) UNIV TOKYO.
XX
CC PI Saito I;
XX
DR WPI; 2016-34562K/42.
XX
CC PT Preparing DNA cassette formed by several biological units, involves using
CC PT unit formed by biological unit, determining sequence of intrinsic region
CC PT of biological unit, forming biological unit, and connecting designed
CC PT recombinant units.
XX
CC PS Example 4; SEQ ID NO 43; 44pp; Japanese.
XX
CC The present invention relates to a method for preparing a DNA cassette
CC formed by several biological units. The method involves: using unit
CC formed by a biological unit; determining the sequence of intrinsic region
CC of the biological unit; forming biological unit; and connecting designed
CC recombinant units. The present sequence represents an U6 gene specific
CC PCR primer, which is useful in the method for preparing a DNA cassette
CC formed by several biological units as described in an exemplification of
CC the invention.
XX
SQ Sequence 9 BP; 1 A; 5 C; 3 G; 0 T; 0 U; 0 Other;
Query Match 100.0%; Score 8; Length 9;
Best Local Similarity 100.0%;
Matches 8; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CCGAGCGC 8
||||||||
Db 2 CCGAGCGC 9
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the compounds used in the US619 claims with the short primer sequence of JP986 for the benefit of using a known sequence as the universal sequence on the siRNA and its complement as the overhang molecule (anchor) on the strands comprising the tetrahedron. One would have been motivated to do so with a reasonable expectation of success because JP986 SEQ ID NO 43 was a known sequence and an artisan would have realized the universal sequence could have comprised any sequence within the bounds of the US619 claims. It would have been a simple matter to use the 9-mer primer sequence of JP986 and one would have done so during the process of routine optimization. Absent evidence to the contrary, choosing any particular length and sequence for the universal region would have been, simply, a design choice well within the constraints of what was routine and customary. Therefore the limitations of Claim 22 would have been obvious in view of the US619 claims and JP986.
It would have been obvious to make the anchor oligont sequence comprise the complement of JP986’s 9-mer primer sequence SEQ ID NO 43, so that it would hybridize to the siRNA’s universal region. The complement of JP986 SEQ ID NO 43 comprises the anchor sequence shown in instant Claim 21, as shown by the following alignment:
BCR44061/c
ID BCR44061 standard; DNA; 9 BP.
XX
AC BCR44061;
XX
DT 28-JUL-2016 (first entry)
XX
DE U6 gene specific forward PCR primer, SEQ ID 43.
XX
KW PCR; U6 gene; dna cassette; primer; ss.
XX
OS Synthetic.
OS Unidentified.
XX
CC PN JP2016103986-A.
XX
CC PD 09-JUN-2016.
XX
CC PF 01-DEC-2014; 2014JP-00242914.
XX
PR 01-DEC-2014; 2014JP-00242914.
XX
CC PA (UYTY ) UNIV TOKYO.
XX
CC PI Saito I;
XX
DR WPI; 2016-34562K/42.
XX
CC PT Preparing DNA cassette formed by several biological units, involves using
CC PT unit formed by biological unit, determining sequence of intrinsic region
CC PT of biological unit, forming biological unit, and connecting designed
CC PT recombinant units.
XX
CC PS Example 4; SEQ ID NO 43; 44pp; Japanese.
XX
CC The present invention relates to a method for preparing a DNA cassette
CC formed by several biological units. The method involves: using unit
CC formed by a biological unit; determining the sequence of intrinsic region
CC of the biological unit; forming biological unit; and connecting designed
CC recombinant units. The present sequence represents an U6 gene specific
CC PCR primer, which is useful in the method for preparing a DNA cassette
CC formed by several biological units as described in an exemplification of
CC the invention.
XX
SQ Sequence 9 BP; 1 A; 5 C; 3 G; 0 T; 0 U; 0 Other;
Query Match 100.0%; Score 8; Length 9;
Best Local Similarity 87.5%;
Matches 7; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GCGCUCGG 8
||||:|||
Db 9 GCGCTCGG 2
Therefore the limitations of Claim 21 would have been obvious in view of the US619 claims and JP986.
Claims 1-2, 5, 13-14, 18, 21-24, 33, 45, 49, 51, 56, 58, and 60-64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 12180477, issued 21 December 2024 (“US477”, of record on IDS) in view of English translation of JP986.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are directed to:
a composition comprising (a) an AS strand comprising a 5' end, a 3' end, with a nucleotide sequence comprising: (i) a first region positioned at the 5' end with complementarity to a target sequence for mediating silencing thereof comprising at least 16 nucleotides; and (ii) a universal region positioned at the 3' end of the first region that has a length of 5 to 10 nucleotides, wherein the universal region comprises a GC content of between 50 to 100%; (b) a sense strand comprising a 5' end, a 3' end, and a nucleotide sequence comprising 10 to 20 nucleotides that are complementary to the first region of the antisense strand: and (c)_a pharmacokinetic (PK)-modifying anchor comprising an anchor oligonucleotide comprising a 3' end, and a 5' end, wherein the 5' end of the PK-modifying anchor is attached to at least one polymer, wherein the anchor oligonucleotide is10 nucleotides in length, comprises a GC content of between 50 to 100%, and is complementary to the universal region at the 3' end of the antisense strand, and wherein the at least one polymer is at least about 2,000 Da
and to:
universal, pharmacokinetic (PK)-modifying system for enhancing gene therapy technologies comprising: (a) an anchor oligonucleotide strand comprising:(i) 5-20 nucleotides in length, and having a GC content of between 50 to 100%; and(ii) a polymer attached to the anchor oligonucleotide strand, wherein the polymer has a molecular weight of 2,000 to 100,000 Daltons; and (b) a therapeutic oligonucleotide selected from the group consisting of an antisense oligonucleotide, an miRNA, an mRNA, a single-stranded siRNA, and a CRISPR guide strand, wherein the therapeutic oligonucleotide comprises a universal region comprising a GC content of between 50 to 100% and is 5 to 20 nucleotides in length and complementary to the anchor oligonucleotide strand, whereby hybridization of the anchor oligonucleotide to the universal region of the therapeutic oligonucleotide modifies the pharmacokinetics of the therapeutic oligonucleotide as compared the therapeutic oligonucleotide without the anchor nucleotide
The claimed compounds have additional features including universal and anchor regions comprising a certain GC content, , length requirements, wherein the polymer is attached to the anchor oligont, wherein the at least one polymer can comprise a PEG/lipid/sugar/peptide/aptamer/mixture thereof; wherein: the number of nucleotides in the AS strand is the same as the number of nucleotides in the sense strand and the anchor oligonucleotide combined, wherein the anchor oligont and universal sequence comprise the sequences recited in Claims 21-22, wherein the anchor and AS strands can comprise a modification or wherein the anchor oligont can comprise alternating 2’-OMe and 2’-fluoro modifications, to the compounds comprising a pharmaceutically active carrier or to a pharmaceutical composition comprising the compounds plus a pharmaceutically acceptable carrier, and to the composition wherein the PEG is attached to the anchor oligo via an NHS ester reaction, and wherein the polymer or PEG has specific molecular weights.
The issued US477 claims are directed to methods of treating a disease or disorder in a patient comprising administering a compound comprising a first 16-25-mer oligonucleotide that comprises complementarity to a target gene or a target mRNA, a second 12-17-mer oligonucleotide, and a pharmacokinetic (PK)-modifying anchor comprising an anchor oligonucleotide between 5 to 8 nucleotides in length and at least one 2000-40000 Da polymer, and wherein the at least one polymer is not a polypeptide, wherein a portion of the 5′ end of the first oligonucleotide is complementary to the second oligonucleotide and a portion of the 3′ end of the first oligonucleotide is complementary to the anchor oligonucleotide. The invention of the US477 claims can comprise a linker, complementarity to a target gene, various numbers of polymers, oligonts of various lengths, modified bonds, wherein: the number of nucleotides in the first oligonucleotide is the same as the number of nucleotides in the second oligonucleotide and the anchor oligonucleotide combined.
Both claim sets are directed to the same subject matter: siRNA comprising a universal region that binds a PK-modifying anchor. It would not be possible to possess or use the invention of instant Claims 1-2, 5, 13-14, 18, 23-24, 33, 45, 49, 51, 56, 58, and 60-64 without using the method or the compound of the US477 claims.
The US477 claims do not teach the anchor and universal region sequences recited in instant claims 21-22.
However, However, JP914, drawn to methods for manufacturing a DNA cassette, teaches the short 9-mer primer sequence SEQ ID NO 43 that is 100% identical to the sequence instantly claimed in Claim 22, as shown by the following alignment:
[truncated to save space]
Query Match 100.0%; Score 8; Length 9;
Best Local Similarity 100.0%;
Matches 8; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CCGAGCGC 8
||||||||
Db 2 CCGAGCGC 9
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the compounds used in the US477 claims with the short primer sequence of JP986 for the benefit of using a known sequence as the universal sequence on the siRNA and its complement as the overhang molecule (anchor) on the strands comprising the tetrahedron. One would have been motivated to do so with a reasonable expectation of success because JP986 SEQ ID NO 43 was a known sequence and an artisan would have realized the universal sequence could have comprised any sequence within the bounds of the US477 claims. It would have been a simple matter to use the 9-mer primer sequence of JP986 and one would have done so during the process of routine optimization. Absent evidence to the contrary, choosing any particular length and sequence for the universal region would have been, simply, a design choice well within the constraints of what was routine and customary. Therefore the limitations of Claim 22 would have been obvious in view of the US477 claims and JP986.
It would have been obvious to make the anchor oligont sequence comprise the complement of JP986’s 9-mer primer sequence SEQ ID NO 43, so that it would hybridize to the siRNA’s universal region. The complement of JP986 SEQ ID NO 43 comprises the anchor sequence shown in instant Claim 21, as shown by the following alignment:
[truncated to save space]
Query Match 100.0%; Score 8; Length 9;
Best Local Similarity 87.5%;
Matches 7; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GCGCUCGG 8
||||:|||
Db 9 GCGCTCGG 2
Therefore the limitations of Claim 21 would have been obvious in view of the US477 claims and JP986.
Response to Arguments
Applicant's arguments filed 23 September 2025 have been fully considered but they are not persuasive. Each rejection is addressed below. Arguments that are no longer relevant are not addressed.
Objections
Some claims are objected to for minor errors.
112(a) Rejections
Applicant argues that (pp. 10-12) their claims are to a platform technology and their examples show enough of a proof-of-concept that a person of ordinary skill could mass produce an off-the-shelf PK-modifying anchor that can be applied to any therapeutic oligont.
Those arguments are not found persuasive because 112(a) requires that Applicant was in possession of the full breadth of the claims at time of filing. Nor is it persuasive that the invention is described in full, clear, concise, and exact terms that a person of ordinary skill would be able to make and use it to the full breadth of the claims.
The claims recite siRNA that mediates silencing of a target sequence—any target sequence—and an oligont attached to any polymer that is at least about 2000 Da. The claims recite any therapeutic oligonucleotide that is an ASO, miRNA, mRNA, single-stranded siRNA, or CRISPR guide strand. The claims recite the term anchor oligont which is not a term of the art and not defined in the Spec. Although Applicant argues that (p. 11) with respect to the PK-modifying properties of the anchor, the Spec. describes how the PK properties are determined by its size, the passage Applicant cites is hardly specific. It merely describes PK-modifying anchors described dynamically modulate the size of therapeutic oligonucleotides leading to the modulation of clearance kinetics versus tissue uptake and distribution. The dynamic nature of this concept is achieved through optimization of anchor size and chemical composition. While Applicant states the Spec. highlights a direct correlation between molecular dimensions and PK behavior, that is not persuasive because there are more variables that determine PK behavior than merely molecular dimensions and Applicant’s claims recite diverse polymer species. But the Spec. hasn’t shown how those various species, when attached to an anchor, affect its behavior, or how they affect the silencing or targeting capability. Furthermore, it is not clear what optimization means in the context of the claims or how it would change depending on target sequence. Is rapid clearance by the kidneys a positive if the target sequence is in the kidneys, or is it always better for circulation time to be extended no matter what or where the target sequence is? If therapeutic oligonucleotides that are under 6 kDa are rapidly cleared, what are the benefits of polymers/anchors that total about 2000 Da? What is or isn’t considered “optimization” is a relative term. Applicant’s remarks do not reference any passages that provide clarity .
Altogether, Applicant hasn’t demonstrated that they were in possession of the full breadth of the claims, and a person of ordinary skill would reasonably determine that the claims are so broad that it is unlikely that they were in possession of the full invention as claimed. For those reasons the WD rejection is maintained.
112(b) Rejections
Claim 1 still recites about. The claims still recite anchor oligonucleotide or anchor. An artisan wouldn’t know what is comprised by the length in Claim 13. Claim 14 is missing at least one word. Claim 18 wasn’t amended to change first oligont. An artisan wouldn’t know what is comprised by the PS linkages at the 5’ends in Claim 61.
Regarding the terms anchor oligont and anchor, Applicant argues (p. 13) that the words of a claim must be given their plain meaning as it would be understood by a person of ordinary skill in the art. Applicant argues that in the context of the specification, the term “anchor” carries its plain and ordinary meaning—namely “something that serves to hold an object firmly” and has provided ample evidence from the dictionary to support that. Applicant argues that in the specification the terms is used to refer to “molecular anchors” that hybridize to a therapeutic oligonucleotide. Applicant references ¶7, ¶107, and Example 1. ¶7 discusses what a PK-modifying anchor does but does not explain what it is, apart from explaining its function. Therefore an artisan wouldn’t know what a PK-modifying anchor is or what structure(s) it possesses. The passage cited at ¶107 uses the problematic term “oligonucleotide anchor” in the purported definition of a PK-modifying anchor, providing an unsatisfactory “definition”. Such circular definition that uses within itself the very same term being defined is reasonably deemed indefinite. The rest of that ¶ provides features that a PK-modifying anchor can have: it can be complementary to an oligont. That doesn’t define the term. While Example 1 uses the term “molecular anchor”, it describes the “PK-modifying molecular anchors” solely in terms of their function. For those reasons, it is not clear what the term anchor actually encompasses.
Regarding the dictionary definitions provided, none of those has any context in biology or biotechnology. Regarding Applicant’s argument that anchor means “something that serves to hold an object firmly”, how that applies to the claims is still indefinite because it raises the questions: what is considered “firmly”? how is the object held? Altogether, nothing Applicant has provided makes the term any clearer or less indefinite.
Amending the claims to remove the term anchors and to recite the specific “anchor” sequences currently recited in Claims 21-22 could obviate this rejection.
103
Applicant’s arguments with respect to the references Charoenphol, Lee, App278, US206, and Hu as they apply to claim(s) 1-2, 5, 13-14, 18, 21-24, 33, 45, 49, 51, 56, 58, and 60-64 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant's arguments filed 23 September 2025 with respect to JP986 have been fully considered but they are not persuasive.
Applicant argues (pp. 19-20) that JP986 does not bridge the gap of the other references because it is directed to methods for manufacturing a DNA cassette and there is no rational underpinning for modifying the dsRNAs with the sequence in JP986. That is not found persuasive because an artisan would have been motivated to use any 9-10-mer sequence as the universal/anchor region because the prior art of WO374 places no limit on what sequence may be incorporated into or comprised by an acceptable overhang region and because Chakraborty specifically teaches 9- to 10-mer anchor sequences. An artisan would have known from Chakraborty’s teachings that an imager strand with a low melting temperature enable repeated binding and unbinding events. They would have found repeated binding/unbinding dissatisfactory for the purposes that would have been obvious in view of the prior art, namely observing the location of a single binding event or a dsRNA in a tissue/cell, or tracking the location/movement of a single binding event of dsRNA within or through a tissue/cell over time. That would have motivated the artisan to seek out 9-mer sequences with high melting temperatures which would have led them to the UP986 sequence.
Briefly, App418 teaches a detection system that is largely encompassed by the instant claims. In addition, WO374 discloses dsRNAs (and modifications for RNA) for treating Huntington’s disease. WO374 teaches it can be difficult to deliver dsRNAs to desired tissues and cells. Chakraborty teaches techniques for imaging nucleic acids including RNA, including its location in cells. An artisan would have been motivated to modify the methods described in Chakraborty for the benefit of observing where in cells and tissues dsRNAs localize and for determining whether any of the different modes of administration discussed in WO374 affect where the dsRNAs localize and how fast they travel there. Chakraborty teaches that a low melting temperature allows for repeated binding and unbinding between a fluorescently labeled antisense and its target but an artisan wouldn’t have wanted repeated binding and unbinding so they would have used sequences with a higher melting temperature, which are sequences with a higher GC content. ThermoFisher and Ikeda teach using PEG was known and widely used in the art for various purposes: to attach fluorophores to a biological material for imaging or to improve the stability of the nucleic acid or fluorophore to which PEG is attached. JP986 teaches a short sequence with high GC content that an artisan would have incorporated into the dsRNAs of WO374 in order to adhere (via base pairing) a complementary, fluorescently labeled oligo. Therefore all of the limitations of the current claims would have been obvious in view of what was discussed in the prior art and what would have been obvious to a person of ordinary skill and creativity.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.
In addition to the factors above, Office personnel may rely on their own technical expertise to describe the knowledge and skills of a person of ordinary skill in the art. The Federal Circuit has stated that examiners and administrative patent judges on the Board are "persons of scientific competence in the fields in which they work" and that their findings are "informed by their scientific knowledge, as to the meaning of prior art references to persons of ordinary skill in the art." In re Berg, 320 F.3d 1310, 1315, 65 USPQ2d 2003, 2007 (Fed. Cir. 2003). In addition, examiners "are assumed to have some expertise in interpreting the references and to be familiar from their work with the level of skill in the art ." PowerOasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299, 86 USPQ2d 1385 (Fed. Cir. 2008) (quoting Am. Hoist & Derrick Co. v. Sowa & Sons, 725 F.2d 1350, 1360, 220 USPQ 763, 770 (Fed. Cir. 1984). See MPEP § 2141.03 for a discussion of the level of ordinary skill.
MPEP §2141(II)(c)
NSDP
The NSDP rejections are maintained because the claimed invention and the patented claim sets are directed to the same subject matter: siRNA comprising a universal region that binds a PK-modifying anchor. It would not be possible to possess or use the invention of instant Claims 1-2, 5, 13-14, 18, 23-24, 33, 45, 49, 51, 56, 58, and 60-64 without using the compounds and/or methods of the patented claims. Furthermore, the rejections explain that JP986 provides the sequences recited in Claims 21-22.
Applicant argues that there is no rationale for modifying the inventions of the granted claims because JP986 isn’t directed to multistrand duplexes. That is not persuasive because, as the NSDP rejections state:
JP986 SEQ ID NO 43 was a known sequence and an artisan would have realized the universal sequence could have comprised any sequence within the bounds of the US477 claims. It would have been a simple matter to use the 9-mer primer sequence of JP986 and one would have done so during the process of routine optimization. Absent evidence to the contrary, choosing any particular length and sequence for the universal region would have been, simply, a design choice well within the constraints of what was routine and customary.
Using that sequence would have inherently provided an oligonucleotide comprising at least 50% GC content.
Therefore the NSDP rejections are maintained.
Conclusion
Claims 1-2, 5, 13-14, 18, 21-24, 33, 45, 49, 51, 56, 58, and 60-64 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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RUTHIE S ARIETI
Examiner (Ruth.Arieti@uspto.gov)
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636