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 .
DETAILED ACTION
Applicant’s amendments and remarks filed on July 28, 2025 are acknowledged. Claims 2-4, 13-15, 17, 18, 20, 21, 25, 26, 32, and 33 have been canceled. Claims 1, 6, and 16 were amended. Claims 1, 5-12, 16, 19, 22-24, and 27-31 are pending and are examined on the merits herein.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 28, 2025 has been entered.
Priority
This application claims priority to PCT/KR2020/000750 filed on January 15, 2020 which claims priority to KR10-2019-0005277 filed on January 15, 2019.
While certified copies of the foreign priority documents were received, translation of the priority document was not provided. Therefore, priority is given with the effective filing date of January 15, 2020, which is the PCT filing date.
Withdrawn Objections
In view of Applicant’s amendments and response, the objection to claims 1 and 6 is withdrawn.
Drawings
The drawings were received on April 24, 2025.
The drawings are objected to because 37 CFR 1.84 (u)(1) states “View numbers
must be preceded by the abbreviation "FIG."” In the current case, the view numbers for Figures 1-9 are preceded by the word "Figure" instead of the abbreviation "FIG.". In addition, Figures 1 through 6 are blurry and difficult to decipher.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 5, and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Keller et al. (US 2008/0293053) in view of Ui-Tei et al. (Nucleic Acids Research 2008).
Regarding claim 1, Keller et al. teaches methods and compositions for the treatment of soft tissue cancer. Further, Keller et al. demonstrates that inhibiting or otherwise decreasing the activity of DKK-1 using shRNA or siRNA molecules will be effective at reducing the cancer phenotype of prostate cancer cells [abstract]. Keller et al. teaches SEQ ID NO: 1 which is an exemplary DKK-1 sequence. SEQ ID NO: 2 (designated as Db in the alignment below) is a sequence to which shRNA molecules can be directed. SEQ ID NO: 2 is 21 nucleotides in length and has a match to instant SEQ ID NO: 72 (designated as Qy in the alignment below) [0141].
Qy 1 AUAAGUACCAGACCAUUG 18
|:|||:|||||||||::|
Db 4 ATAAGTACCAGACCATTG 21
Keller et al. does not teach a double-stranded oligonucleotide with a sense strand of 19 nucleotides and containing the sequence of SEQ ID NO: 72, and an antisense complementary thereto.
Although Keller et al. SEQ ID NOS: 2 and 84 are missing the last nucleotide of instant SEQ ID NO: 72, Keller et al. teaches that in one embodiment, the antisense compounds of the invention have antisense portions of 19 to 23 nucleobases [0069]. See also [0129] which discloses that Keller et al. synthesized and used an expression construct encoding an shRNA corresponding to Keller SEQ ID NO: 84 which comprises Keller SEQ ID NO: 2 and a sequence 100% complementary to it. Therefore, one skilled in the art would have understood that SEQ ID NO: 2 could have been extended at least one nucleotide in either direction. The disclosure of SEQ ID NO: 2 as a guide strand is implicitly a disclosure of a small genus of guide strands that can be a few nucleotides longer in either direction and thus one of skill would make those extended sequences complementary to the target with a reasonable expectation of success. It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to make a shRNA that targeted SEQ ID NO: 2 to treat soft tissue cancer and reduce the cancer phenotype of prostate cancer cells.
Regarding claims 5 and 6, Keller et al. teaches that oligomeric compounds can have one or more modified internucleoside linkages such as phosphorothioate [0078]. Keller et al. also teaches that oligomeric compounds may contain one or more substituted sugar moieties [0082] or nucleobase modifications or substitutions [0084].
However, Keller et al. does not teach that the DKK1-specific double-stranded oligonucleotide is DNA/RNA.
Ui-Tei et al. teaches that most mammalian genes could be effectively knocked down without substantial off-target effect by treating cells with a class of DNA-modified siRNAs possessing a DNA-seed-arm sequence [page 2137, left column, second full paragraph].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the DKK1-specific double-stranded oligonucleotide of Keller et al. wherein the sense strand is DNA and the antisense strand is RNA. One of skill in the art would have been motivated to do so because Ui-Tei et al. taught that siRNA with DNA/RNA enabled efficient knockdown of mammalian genes without substantial off-target effect.
Claims 1, 5-12, 16, 19, 22-24, and 27-31 are rejected under 35 U.S.C. 103 as being obvious over Chae et al. (US 2016/0122764) in view of Keller et al. (US 2008/0293053) and Ui-Tei et al. (Nucleic Acids Research 2008).
Regarding claim 7, Chae et al. teaches that in Structural Formula 1, one to three phosphate group(s) may be bonded to the 5’ end of the antisense strand of the double-helical oligo RNA structure containing a CTGF, Cyr61 or Plekho1-specific siRNA [0086].
Regarding claim 8, Chae et al. teaches a structure comprising double-helical oligo RNA, represented by the following Structural Formula 1: A-X-R-Y-B wherein A is a hydrophilic material, B is a hydrophobic material, X and Y are each independently a simple covalent bond or a linker-mediated covalent bond, and R is CTGF, Cyr61, or Plekho1-specific siRNA [claim 7]. Chae et al. also teaches that in order to improve an intracellular delivery efficiency of siRNA, technology of using a siRNA conjugate in which hydrophilic material which is a biocompatible polymer (for example, polyethylene glycol (PEG)) is conjugated to the siRNA by a simple covalent bond or a linker-mediated covalent bond, to thereby secure stability of siRNA and have effective cell membrane permeability [0010]. Chae et al. also teaches a conjugate in which a hydrophilic material and a hydrophobic material are conjugated to both ends of siRNA, for effective in vivo delivery and for improving stability of siRNA [0079].
Regarding claim 9, Chae et al. teaches Structural Formula 2:
A-X-S-Y-B
AS
wherein A, B, X and Y are the same as being defined in Structural Formula (1), S is a sense strand of the CTGF, Cyr61 or Plekho1-specific siRNA, and AS is an antisense strand of the CTGF, Cyr61 or Plekho1-specific siRNA [0083].
Regarding claim 10, Chae et al. teaches
A-X-5′S3′-Y-B
AS Structural Formula 3
A-X-3′S5′-Y-B
AS Structural Formula 4
wherein A, B, S, AS, X and Y are the same as being defined in Structural Formula 1, and 5′ and 3′ mean 5′ end and 3′ end of the sense strand of the CTGF, Cyr61 or Plekho1-specific siRNA [0084 and 0085].
Regarding claim 11, Chae et al. teaches that non-ionic hydrophilic polymer compounds such as polyethylene glycol, polyvinyl pyrrolidone, polyoxazoline, etc., are preferably used as the hydrophilic polymer material [0087].
Regarding claim 12, Chae et al. teaches that the hydrophilic material (A) in Structural Formula 1 may be used in a hydrophilic material block form represented by Structural Formula 5 or 6: (A′m-J)n - Structural Formula 5 and (J-A′m)n - Structural Formula 6 [0088]. Chae et al. also teaches that A′ is a hydrophilic material monomer, J is a linker for connecting hydrophilic material monomers (the sum is m) there between or a linker for connecting hydrophilic material monomers (the sum is m) to siRNA, m is an integer of 1 to 15, n is an integer of 1 to 10, and the repeating unit represented by (A′m-J) or (J-A′m) corresponds to a base unit of the hydrophilic material block [0089]. The hydrophilic material monomer A′ is preferably a monomer selected from the following compounds (1) to (3) shown in Table 1, more preferably, a monomer of the compound (1), and G in the compound (1) may be preferably selected from CH2, O, S and NH [0092].
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Regarding claim 16, Chae et al. teaches that the hydrophobic material may include a steroid derivative, a glyceride derivative, glycerol ether, polypropylene glycol, C12 to C50 unsaturated or saturated hydrocarbon, diacylphosphatidylcholine, fatty acid, phospholipid, lipopolyamine, etc. [0096]. Chae et al. also teaches that the steroid derivative may be selected from the group consisting of cholesterol, cholestanol, cholic acid, cholesteryl formate, cholestanyl formate, and cholesteryl amine, and the glyceride derivative may be selected from mono-, di- and tri-glyceride, etc., wherein the fatty acid of the glyceride is preferred to be C12 to C50 unsaturated or saturated fatty acid [0097].
Regarding claim 19, Chae et al. teaches that the covalent bond may be any one of a non-degradable bond or a degradable bond. Examples of the non-degradable bond may include an amide bond or a phosphorylation bond, and examples of the degradable bond may include a disulfide bond, an acid degradable bond, an ester bond, an anhydride bond, a biodegradable bond or an enzymatically degradable bond [0100].
Regarding claim 22, Chae et al. teaches a double-helical oligo RNA structure in which a ligand (L), particularly, a ligand specifically bonded to a receptor that promotes target cell internalization through receptor-mediated endocytosis (RME), is additionally bonded to the structure according to Structural Formulas (1) to (4), (7) and (8). For example, the form in which the ligand is bonded to the double-helical oligo RNA structure according to Structural Formula (1), has a structure represented by Structural Formula 15: (Li-Z)-A-X-R-Y-B [0129].
Regarding claim 23, Chae et al. teaches that the ligand in Structural Formula 15 may be preferably selected from the group consisting of a target receptor-specific antibody or aptamer, peptide that has properties of RME for promoting cell internalization in a target cell-specific manner; or folate (generally, folate and folic acid are intersectionally used, and the folate in the present invention means folate in a natural state or in an activated state in a human body), chemicals such as sugar, carbohydrate, etc., including hexoamines such as N-acetyl galactosamine (NAG), etc., glucose, mannose [0131].
Regarding claim 24, Chae et al. teaches that the amine group or the polyhistidine group may be linked to the hydrophilic material or the hydrophilic material block through at least one linker [0116].
Regarding claim 27, Chae et al. teaches a nanoparticle including the double-helical oligo RNA structure containing the CTGF, Cyr61, or Plekho1-specific siRNA [0153].
Regarding claim 28, Chae et al. teaches that the nanoparticles may be formed of only the double-helical oligo RNA structure containing siRNAs each having the same sequence as each other, or may be formed of the double-helical oligo RNA structure containing siRNAs each having different sequence, wherein it is construed in the present invention that the siRNAs each having different sequence includes siRNA having different target genes, for example, CTGF, Cyr61, or Plekho1-specific siRNA, or siRNA having the same target gene-specificity, but having different sequence [0155].
Regarding claim 29, Chae et al. teaches that it is preferred to provide the composition prepared as a lyophilized formulation [0170].
Regarding claims 30-31, the clause “for preventing hair loss or promoting hair growth” is the preamble and is interpreted as intended use of the invention while the body of the claim sets forth all the limitations. See MPEP 2111.02(II).
However, Chae et al. does not teach the DKK1-specific double-stranded oligonucleotide according to claim 1.
Keller et al. teaches methods and compositions for the treatment of soft tissue cancer. Further, Keller et al. demonstrates that inhibiting or otherwise decreasing the activity of DKK-1 using shRNA or siRNA molecules will be effective at reducing the cancer phenotype of prostate cancer cells [abstract]. Keller et al. teaches SEQ ID NO: 1 which is an exemplary DKK-1 sequence. SEQ ID NO: 2 (designated as Db) is a sequence to which shRNA molecules can be directed. SEQ ID NO: 2 is 21 nucleotides in length and has a match to instant SEQ ID NO: 72 (designated as Qy) as shown in the alignment below [0141]. Although Keller et al. SEQ ID NOS: 2 and 84 are missing the last nucleotide of instant SEQ ID NO: 72, Keller et al. teaches that in one embodiment, the antisense compounds of the invention have antisense portions of 19 to 23 nucleobases [0069]. See also [0129] which discloses that Keller synthesized and used an expression construct encoding an shRNA corresponding to Keller SEQ ID NO: 84 which comprises Keller SEQ ID NO: 2 and a sequence 100% complementary to it. Therefore, one skilled in the art would have understood that SEQ ID NO: 2 could have been extended at least one nucleotide in either direction. The disclosure of SEQ ID NO: 2 as a guide strand is implicitly a disclosure of a small genus of guide strands that can be a few nucleotides longer in either direction and thus one of skill would make those extended sequences complementary to the target with a reasonable expectation of success. Thus, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to make a shRNA that targeted SEQ ID NO: 2 to treat soft tissue cancer and reduce the cancer phenotype of prostate cancer cells.
Qy 1 AUAAGUACCAGACCAUUG 18
|:|||:|||||||||::|
Db 4 ATAAGTACCAGACCATTG 21
Ui-Tei et al. teaches that most mammalian genes could be effectively knocked down without substantial off-target effect by treating cells with a class of DNA-modified siRNAs possessing a DNA-seed-arm sequence [page 2137, left column, second full paragraph].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the double-stranded RNA structure of Chae et al. to include the composition for the specific inhibition of DKK-1 by double-stranded RNA of Keller et al. and Ui-Tei et al. for the purpose of creating a nanoparticle that is formed through hydrophilic/hydrophobic interactions of hydrophilic/hydrophobic substances to improve in vivo stability and efficient delivery of the double-stranded RNA. A person of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated and expected reasonable success to combine the teachings of Chae et al., Keller et al., and Ui-Tei et al. for the purpose of treating soft tissue cancer.
Response to Arguments
Applicant's arguments filed July 28, 2025 have been fully considered but they are not persuasive.
Applicant asserts that RNAi agents such as siRNA or shRNA typically comprise short nucleotide sequences ranging from approximately 19 to 31 nucleotides in length and as such, even a single nucleotide change within a sequence can result in a dramatically different and unpredictable effect.
This argument is not found persuasive. It is noted that an opinion has been made; however, no evidentiary support has been provided for the opinion. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP 2145(I) and 716.01(c)(II).
Applicant asserts that SEQ ID NO: 2 of Keller et al. relates to a different and distinct sequence from instant SEQ ID NO: 72. Specifically, Keller et al. proposes exemplary sequences targeted by shRNA (SEQ ID NOS: 2 through 5) for the purpose of suppressing DKK-1 expression. Applicant further asserts that in order to derive the sequence of the present invention, whose superiority has been demonstrated, a person ordinarily skilled in the art would have to experimentally test a vast number of antisense compounds based on the DKK-1 sequence, each having antisense portions of 19 to 23 nucleobases. Furthermore, Applicant asserts that Keller et al. does not disclose that the DKK1-specific double-stranded oligonucleotide is DNA/RNA, the sense strand is DNA and the anti-sense strand is RNA as recited in amended claim 1.
The Examiner agrees with Applicant’s assertion that Keller et al. does not disclose that the DKK1-specific double-stranded oligonucleotide is DNA/RNA as recited in amended claim 1. Therefore, a new ground of rejection is made in view of Ui-Tei et al. (Nucleic Acids Research 2008). However, the remaining arguments are not found persuasive. As discussed in the original 35 U.S.C. 103 rejection, Keller et al. teaches SEQ ID NO: 1 which is an exemplary DKK-1 sequence. SEQ ID NO: 2 is a sequence to which shRNA molecules can be directed. Keller et al. also synthesized and used an expression construct encoding an shRNA corresponding to Keller et al. SEQ ID NO: 84 which comprises Keller et al. SEQ ID NO: 2 and a sequence 100% complementary to it. Although Keller et al. SEQ ID NOS: 2 and 84 are missing the last nucleotide of instant SEQ ID NO: 72, Keller et al. teaches that in one embodiment, the antisense compounds of the invention have antisense portions of 19 to 23 nucleobases [0069]. At the time of the claimed invention, Keller et al. taught that prostate cancer is the second leading cause of cancer-related deaths in men [0003]. Therefore, one skilled in the art would have been motivated to design a DKK1-specific double-stranded oligonucleotide capable of treating soft tissue cancer because Keller et al. demonstrated that inhibiting or decreasing DKK-1 activity using shRNA or siRNA is effective at reducing the cancer phenotype of prostate cancer cells. One of ordinary skill in the art would have had a reasonable expectation of success designing a DKK1-specific double-stranded oligonucleotide because the disclosure of SEQ ID NO: 2 as a guide strand is implicitly a disclosure of a small genus of guide strands that can be a few nucleotides longer in either direction and thus one of skill would make those extended sequences complementary to the target. Even if a vast number of antisense compounds would need to be experimentally tested as Applicant asserts, this is a finite number of antisense compounds.
Applicant asserts that the DKK1-specific double-stranded oligonucleotide according to the present claimed invention demonstrates remarkably enhanced efficacy. Applicant indicates that Examples 2-3 and Figures 3-4 demonstrate that the selected hDKK1 oligonucleotide showed excellent inhibitory activity for all ten sequences with inhibitory activity of 55% or more. Further, human follicular dermal papilla cells were repeatedly transfected three times with the ten sequences which showed high DKK1 mRNA inhibitory activity. Applicant also indicates that of the ten sequences, SEQ ID NO: 72 exhibited inhibitory activity of 80% or more as shown in Figure 5. While the Examiner appreciates the experimental studies reported in the Examples and Figures, the Examiner maintains that for the reasons discussed herein, the combination of the prior art teaches and suggests Applicant’s claimed invention. Based on the teachings of the cited references, the result of enhanced efficacy as Applicant asserts is an expected result because Ui-Tei et al. taught that siRNA with DNA/RNA enabled efficient knockdown of mammalian genes without substantial off-target effect.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637