DETAILED ACTION
Election/Restrictions
Applicants’ election without traverse of Group I and SEQ ID NO: 1605/5241 in the reply filed on July 6 2026 is acknowledged. Claims 1-3, 18-20, 23-24, 28, 30, 34-35, 37 and 42-45 are pending in the application. Claim 44 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention(species), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 6 2026. Accordingly, claims 1-3, 18-20, 23-24, 28, 30, 34-35, 37, 42-43 and 45 are being examined on the merits herein.
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 .
Priority
This application is a 371 of PCT/US2022/033995 (06/17/2022) which claims benefit of 63/213,054 (06/21/2021) as reflected in the filing receipt issued October 9 2024.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on December 27 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 42 and 45 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.
Claim 42 as currently written is vague and indefinite. The claim recites that at least one of the sense and antisense strand comprise a nucleoside sequence comprising 14-30 contiguous nucleosides of SEQ ID NO: 7599. The specification teaches that SEQ ID No: 7599 is the full-length human DKK2 mRNA (paragraph 0028). Claim 42 depends from claim 34 which states that the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. The specification teaches that one strand (antisense strand) is complementary to a DKK2 mRNA (paragraph 114).
Since there is no limiting definition of siRNA in the instant specification, the BRI of this limitation is its ordinary and customary meaning. As taught by Turner et al. (USPGPUB No. 20040053876), the term “antisense” refers to a sequence that is complementary to a sense strand of a DNA duplex. A “sense strand” of a DNA duplex refers to a strand in a DNA duplex that is transcribed by a cell in its natural state. Thus an ”antisense” sense is the same as the non-coding strand in a DNA duplex. The term “antisense RNA” refers to an RNA transcript that is complementary to all or part of a target mRNA and that blocks the expression of a target gene. Therefore, the sense strand would be expected to have a nucleoside sequence comprising 14-30 contiguous nucleosides of SEQ ID NO: 7599 whereas the anti-sense strand would be expected to be complementary. However, the claim recites that both the antisense and sense strand can be the same as SEQ ID NO: 7599. This creates confusion to the scope of the claim because it seems to describe antisense in a manner opposite to what is standard in the art.
Where possible, claims are to be complete in themselves. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.' Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)" (MPEP 2173.05(s)). MPEP 2173.05(t) states that Chemical compounds may be claimed by a name that adequately describes the material to one skilled in the art. See Martin v. Johnson, 454 F.2d 746, 172 USPQ 391 (CCPA 1972). Here, claim 45 refers to specific modification patterns. The claim does not indicate what the modification, for example, 1S corresponds to. This name does not adequately describe the chemical structure. Therefore, Applicants should incorporate into claim 45 the specific modification patterns. If applicants wish to include the, for example, 1S it should be put in parentheses following the pattern (see MPEP 2173.05(s) for a discussion on reference characters).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3, 34-35, 37 and 42-43 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Naito et al. (USPGPUB No. 20080113351).
The instant application claims a composition comprising an oligonucleotide that targets DKK2 and when administered to a subject in an effective amount increases a hair count in the subject. It is noted that the recitation “when administered” is directed to how the oligonucleotide performs in use and is interpreted as being directed to capabilities of the oligonucleotide. The examiner notes, however, that "the patentability of apparatus or composition claims depends on the claimed structure, not on the use orpurpose of that structure." Catalina Mktg. Int'l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801,809 (Fed. Cir. 2002). Note: MPEP 2111.02
As elected the oligonucleotide comprises SEQ ID NO: 1605 for the sense strand and SEQ ID NO: 5241 for the antisense strand.
The instant application claims a composition comprising an oligonucleotide that reduces the expression of DKK2 wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 contiguous nucleosides of any one of SEQ ID NOs: 1-7272. Thus, the BRI of these claims, in light of the election, is an oligonucleotide that is 14-30 nt long and “about” 14 or up to 30 contiguous nucleosides corresponds to SEQ ID NO: 1605 and/or 5241.
Naito et al. claims a polynucleotide for causing RNA interference against a target gene which has at least a double-stranded region, wherein one strand in the double-stranded region consists of a base sequence homologous to a prescribed sequence and the other strand in the double stranded region consist of a base sequence having a sequence complementary to the base sequence homologous to the prescribed sequence (claim 1). One specific sequence claimed is 210149 which has a total length of 19 nt (claim 7) and has a nucleotide sequence which has 15 contiguous nt to instantly claimed SEQ ID NO: 1605 (see alignment below) and 15 contiguous nt complementary to instantly claimed SEQ ID No: 5241 (see alignment below).
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Where selection of one named species from a list of alternatives is all that isrequired to arrive at the instantly claimed subject matter, that species is anticipated. Ex Parte A., 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990). See also In re Sivaramakrishnan, 213 USPQ 441 (CCPA 1982). MPEP 2131.02
Therefore, SEQ ID NO: 210149 anticipates claims 1-3, 34-35, 37 and 42-43 as Naito et al. teaches an siRNA (double strand RNA) that is 19 nt in total length and has 15 contiguous nt corresponding to SEQ ID NO: 1604/5241 and therefore consequently SEQ ID NO: 7599. While Naito et al. is silent to the expression of DKK2, this property is predicated on the structure of the oligonucleotide. Since Naito et al. teaches an oligonucleotide which anticipates/falls within the claimed scope, it must possess the claimed properties. Note MPEP 2112.01: "Products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Regarding claim 43, the instant claims do not limit the sugar. Since the oligonucleotide includes the normal 5’ or 3’ sugar associated with the nucleotide, it reads on claim 43.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 18-20, 23-24, 28, 30, 34-35, 37, 42-43 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (USPGPUB No. 20180200354, cited on PTO Form 1449) in view of Maier et al. (USPGPUB No. 20170275626) and GenBank (NM_01441.2, 2018, cited in the Office Action mailed on May 12 2026) as evidenced by Song et al. (Cell Reports, 2018, cited on PTO Form 1449).
Applicant Claims
The instant application claims a composition comprising an oligonucleotide that targets DKK2 and when administered to a subject in an effective amount increases a hair count in the subject. It is noted that the recitation “when administered” is directed to how the oligonucleotide performs in use and is interpreted as being directed to capabilities of the oligonucleotide. The examiner notes, however, that "the patentability of apparatus or composition claims depends on the claimed structure, not on the use orpurpose of that structure." Catalina Mktg. Int'l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801,809 (Fed. Cir. 2002). Note: MPEP 2111.02
As elected the oligonucleotide comprises SEQ ID NO: 1605 for the sense strand and SEQ ID NO: 5241 for the antisense strand.
The instant application claims a composition comprising an oligonucleotide that reduces the expression of DKK2 wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 contiguous nucleosides of any one of SEQ ID NOs: 1-7272. Thus, the BRI of these claims, in light of the election, is an oligonucleotide that is 14-30 nt long and “about” 14 or up to 30 contiguous nucleosides corresponds to SEQ ID NO: 1605 and/or 5241.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Wu et al. is directed to a pharmaceutical composition comprising a DKK2 depleting agent and a carrier (claim 30; paragraph 0141). DKK2 depleting agents include siRNA (claim 33). It is taught that DKK2 is a Wnt inhibitor (paragraph 0009). As taught by Wu et al., siRNA is an RNA molecule comprising a set of nucleotides that is targeted to a gene or polynucleotide of interest. As used herein, the term "siRNA" encompasses all forms of siRNA including but not limited to (i) a double stranded RNA polynucleotide, (ii) a single stranded polynucleotide, and (iii) a polynucleotide of either (i) or (ii) wherein such a polynucleotide, has one, two, three, four or more nucleotide alterations or substitutions therein. siRNAs and their use for inhibiting gene expression are well known in the art. In the present invention the siRNA is capable of interfering with the expression and/or the activity the gene of interest such as DKK2 (paragraph 0096). Effective amounts are taught. It is taught that an effective amount is one necessary to achieve a therapeutic effect and may vary according to factors such as the activity of the particular compound; the time of administration; the rate of excretion of the compound; duration of treatment; among other factors. Effective dose range from about 0.1 and 50 mg/kg of body weight/per day (paragraph 0147; 0148).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Wu et al. teaches siRNA which deplete DKK2, Wu et al. does not expressly discuss siRNA design. However, this deficiency is cured by Maier et al.
Maier et al. is directed to modified double-stranded RNA agents. Taught are double-stranded RNA (dsRNA) agent capable of inhibition the expression of a target gene (abstract). Double-stranded RNA (dsRNA) molecules with good gene-silencing properties are needed for drug development based on RNA interference (RNAi) (paragraph 0004). However, there is an ongoing need for iRNA duplex agents to improve the gene silencing efficacy of siRNA gene therapeutics (paragraph 0009). Taught are effective nucleotide or chemical motifs for dsRNA agents optionally conjugated to at least one ligand which are advantageous for inhibition of target gene expression (paragraph 0010). It is taught that the terms “dsRNA”, “siRNA” and “iRNA agent” are used interchangeably to agents that can mediate silent of a target RNA(paragraph 0502). The dsRNA is one that is sufficiently complementary to a target RNA such that the dsRNA agent silences production of protein encoded by the target mRNA (paragraph 0505). The antisense strand of the dsRNA is 100% complementary to a target RNA to hybridize thereto and inhibit expression through RNA interference (paragraph 0107). Each of the sense and antisense strands have 15-30 nucleotides (claim 27).
While Wu et al. suggests siRNA which interfere with expression of DKK2, Wu et al. does not expressly teach the mRNA sequence of DKK2. However, this deficiency is cured by GenBank NM_014421.2
GenBank NM_014421.2 teaches the mRNA sequence of DKK2 which has 100% identity to instantly claimed SEQ ID NO: 7599 as shown from the blast result below (only part of the sequence is shown for brevity).
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Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claims 1, 34-35, 37 and 42-43, It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Wu et al., Maier et al. and GenBank NM_014421.2 and design a 15-30 nt siRNA which is double stranded and wherein the antisense strand is complementary to a portion of the gene. One skilled in the art would have been motivated to form a siRNA in order to inhibit expression of the gene as taught by Wu et al. and Maier et al.
Regarding the claimed sequence, as shown above GenBank NM_014421.2 has 100% identity to instant SEQ ID NO: 7599. Therefore, using GenBank NM_014421.2 as the target gene sequence, one skilled in the art based on the teachings of Wu et al. and Maier et al. would select any 15-30 nt portion to utilize as a target for inhibition. As shown in the alignment below instantly claimed SEQ ID NO: 1605 corresponds to
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positions 1605-1623 of SEQ ID NO: 7599. Since the instant specification fails to provide any data establishing an unexpected effect with any of the specifically taught sequences, it is the examiners position that any siRNA designed would be expected to possess the same or similar effect. Therefore, it would be obvious to design any dsRNA of 15-30 nt to target GenBank NM_014421.2 with a reasonable expectation of success and form a sequence of SEQ ID NO: 1605.
Regarding the claimed “when administered to a subject in an effective amount increases a hair count in the subject”, the instant specification provides no limiting definition of effective amount nor provides any examples of an effective amount. Wu et al. teaches effective amounts. Wu et al. teaches that an effective amount is one necessary to achieve a therapeutic effect and may vary according to factors such as the activity of the particular compound; the time of administration; the rate of excretion of the compound; duration of treatment; among other factors. Effective dose range from about 0.1 and 50 mg/kg of body weight/per day. This suggests one skilled in the art would manipulate the concentration in order to achieve the desired effect. While Wu et al. does not teach increasing a hair count, but Wu et al. does teach an siRNA for DKK2. As evidenced by Song et al. deletion of mouse Dkk2 causes formation of mature, regenerative plantar hair and that DKK2 specifies development of hairless vs hairy skin. Song et al. teaches that the Wnt inhibitor DKK2 suppresses plantar hair follicle development and permits the formation of plantar hair follicle (page 2981 summary; examples). This suggests inhibition of DKK2 would result in an increase in hair count. Since the combination of Wu et al. and Maier et al. suggest siRNA of DKK2 (aka inhibition of DKK2), the claimed functional language would be expected to flow from the siRNA.
Regarding claims 2-3, Song et al. teaches that plantar skin retains all of the mechanisms needed to form hair follicles and that relief from DKK2-mediated Wnt inhibition is sufficient to initiate this process (page 2989, left column). The instant specification does not teach any particular structure associated with any degree of increase in hair count or the type of hair count. Therefore, the expectation is that any siRNA which targets DKK2 and inhibits expression would be expected to possess the claimed function. Since the design and use of DKK inhibitors is obvious for the reasons set forth above, absent a demonstration of the criticality, the examiner’s position is that any siRNA formed would possess the claimed function.
Regarding claims 18-20, 23-24, 28 Maier et al. teaches it may be possible to enhance stability by including particular bases in overhangs or to include modified nucleotides or nucleotide surrogates. Modifications include modifications at the 2’position of the sugar, the use of deoxyribonucleotides and modifications in the phosphate group. Modifications in the phosphate include phosphorothioate modifications (paragraph 0280; claims). It is taught that in one embodiment each of the sense and antisense strands of the dsRNA agent is independently modified with cyclic nucleotides, LNA, HNA, CeNA, 2′-methoxyethyl, 2′-O-methyl, 2′-O-allyl, 2′-C-allyl, 2′-deoxy, 2′-fluoro, 2′-O—N-methylacetamido (2′-O-NMA), a 2′-O-dimethylaminoethoxyethyl (2′-O-DMAEOE), 2′-O-aminopropyl (2′-O-AP), or 2′-ara-F (paragraph 0100). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Wu et al., Maier et al. and GenBank NM_014421.2 and utilize known modifications including those to both the sugar as well as the phosphate linkages. One skilled in the art would have been motivated to utilize these types of modification with a reasonable expectation of success as they are expected to improve stability as taught by Maier et al.
Regarding claim 30 and 43, Maier et al. teaches that ligands can improve transport, hybridization and specificity properties and may also improve nuclease resistance of the resultant natural or modified oligoribonucleotides (paragraph 0462). General examples of ligands include lipids (paragraph 0463). Lipids can also include targeting groups (paragraph 0464). Preferred ligands include lipids (paragraph 0470-0473). Ligands can be attached at the 3’ end or 5’ end of the sense or antisense strand (paragraph 0111). Ligands also include ASGPR ligands (paragraph 0110-0111; claim 35-38). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Wu et al., Maier et al. and GenBank NM_014421.2 and utilize a lipid ligand or ASGPR ligand attached to either the 3’ end or 5’ of either the sense or antisense strand. One skilled in the art would have been motivated to attach a ligand such as a lipid or an ASGPR (i.e. a sugar moiety) with a reasonable expectation of success in order to improve transport, hybridization and other properties as taught by Maier et al.
Regarding claim 45, Maier et al. teaches nucleotide or chemical motifs for dsRNA agents (paragraph 0010). Various motifs are taught these include, for example, motif 1 which includes six phosphorothioate internucleotide linkage modifications to the sense and antisense strand, four 2’-F modifications at position 7 and 9-11 of the sense strand from the 5’-end of the sense strand, and four 2’-F modifications at positions 2, 6, 14 and 16 of the antisense strand from the 5’ end of the antisense strand (paragraph 0659). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Wu et al., Maier et al. and GenBank NM_014421.2 and manipulate the modification pattern in order to achieve the optimal motif for activity. Absent demonstration of the criticality of a particular pattern, it would have been obvious to one of ordinary skill in the art based on the teachings of Maier et al. to vary not only the type but the location of the modification and choose from known modifications to achieve the optimal level of silencing.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached on 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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