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 .
Election/Restrictions
Claims 6, 9-12 and 14-16 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 7/22/25.
Claims 7, 8, 13 and 17-20 were cancelled in the amendment filed on 12/17/25.
Anti18a and Anti19b in claim 5 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 7/22/25.
Specification
The amendment to the specification (reference to sequence listing and table 4) and sequence listing filed on 12/17/25 were entered. However, the sequence listing on 12/17/25 was defective. Applicant provided another sequence listing and another amendment to the specification (reference to sequence and table 4) on 1/12/26, which were also entered. NOTE: applicant provided the original claims and abstract and amended table 4 again in the amendment to the specification filed on 1/12/26. The amendment to table 4 was not required since amended table 4 filed on 12/17/25 was already entered. The amendment to the specification including the abstract and original claims to address the objection to the sequences in the specification were not required. The abstract was not amended and did not need to be provided again. In the interest of expediting prosecution of the instant claims, the original claims and abstract provided on 1/12/26 were crossed-out since they were already of record.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Clarke (US 20110021607).
'607 claims: A method of altering tumorigenicity in a cancer stem cell, the method comprising: altering the activity of a microRNA expressed in said cell, selected from miR-214; miR-127; miR-142-3p; miR-199a; miR-409-3p; miR-125b; miR-146b; miR-199b; miR-222; miR-299-5p; miR-132; miR-221; miR-31; miR-432; miR-495; miR-150; miR-155; miR-338; miR-34b; miR-212; miR-146a; miR-126; miR-223; miR-130b; miR-196b; miR-521; miR-429; miR-193b; miR-183; miR-96; miR-200a; miR-200c; miR-141; miR-182; miR-200a; and miR-200b, wherein said altering step comprises administering to said cell an antisense that decreases the level of miRNA in said cell. See page 18-19 (claim 16). Pages 11-12 disclose chemically modifying the oligonucleotide to increase intracellular stability or binding affinity, including cholesterol conjugates, phosphorothioates linkages and 2'-OMe substitutions.
Figure3a of '607 shows the sequence for hsa-miR-200c. When a person of ordinary skill in the art makes the antisense oligonucleotide for this sequence, the sequence would read on a sequence comprising anti200bc (GGCAGTAUUA) in table 4 of page 28 of the as-filed specification.
'607 does not specifically teach a composition comprising an antisense oligonucleotide comprising a plurality of phosphorothioate linkers, wherein the oligonucleotide hybridizes to an miRNA binding site, wherein said miRNA antisense inhibitor is a SERPINC1 miRNA antisense inhibitor selected from the group consisting of antimir200bc, antimir200a+141, anti429, anti18a and anti19b.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to make the antisense oligonucleotide targeting hsa-miR-200c comprises phosphorothioate linkers to increase binding affinity or intracellular stability, namely to arrive at the claimed invention. One of ordinary skill in the art would have been motivated as a simple substitution to make an antisense oligonucleotide targeting miR-200c comprising a plurality of nucleic acids conjugated by phosphorothioate linkers to alter tumorigenicity in a cancer stem cell with a reasonable expectation of success. See MPEP 2143(I)A, B and E. In addition, it would have been obvious to add additional modifications, including a 2'-OMe modification to increase the stability of the oligonucleotide in a cell. The limitation 'wherein said miRNA antisense inhibitor is a SERPINC1 mRNA antisense inhibitor' in instant claim 1 would be an inherent property of the antisense oligonucleotide targeting miR-200c. In addition, since the antisense sequence complementary to hsa-miR-200c is identical to the anti miR-200bc described in the instant specification, the term is also inherent feature of the product made obvious by '607.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Response to Arguments
Applicant's arguments filed 12/17/25 have been fully considered but they are not persuasive.
Applicant argues that examiner appears to mischaracterized Clarke et al. and that Clarke teaches upregulation of miR-200c and miR-429 and not decreasing a level of a miRNA in a cell. See paragraph 14 of Clarke and Examples 4 and 5 of Clarke. The examples show that miR200c and miR-429 are downregulated in breast cancer and the goal of Clarke is to increase not decrease the amount present and there is not teaching of suggestion of downregulation of these miRNAs or antisense molecules for these two miRNAs. It would have been antithetical to the goals of Clarke to arrive at the claimed invention.
Applicant’s arguments are acknowledged but are not found persuasive because even though Clarke teaches upregulating miR-200c and miR-429, claim 16 of Clarke recites a method of altering tumorigenicity in a cancer stem cell, the method comprising: altering the activity of a microRNA expressed in said cell, selected from miR-214; miR-127; miR-142-3p; miR-199a; miR-409-3p; miR-125b; miR-146b; miR-199b; miR-222; miR-299-5p; miR-132; miR-221; miR-31; miR-432; miR-495; miR-150; miR-155; miR-338; miR-34b; miR-212; miR-146a; miR-126; miR-223; miR-130b; miR-196b; miR-521; miR-429; miR-193b; miR-183; miR-96; miR-200a; miR-200c; miR-141; miR-182; miR-200a; and miR-200b, wherein said agent is an anti-sense oligonucleotide. The only difference between claim 16 of Clarke and the instant claims is the limitation nucleic acids of the oligonucleotide are not conjugated by phosphorothioate linkers, but this limitation is made obvious by the teaching of Clarke. “The disclosure of desirable alternatives does not necessarily negate a suggestion for modifying the prior art to arrive at the claimed invention.” In In re Fulton, 391 F.3d 1195, 73 USPQ2d 1141 (Fed. Cir. 2004). See MPEP 2143.01(I).
In addition, it would have been obvious to one of ordinary skill in the art to increase tumorigenicity in stem cells using the claimed antisense inhibitors comprising a plurality of nucleic acid conjugated by phosphorothioate linkers to study tumorigenicity in cancer stem cells or make cancer stem cells.
It is noted that applicant argues that Manoharan neither teaches or suggest these specific miRNA inhibitors and cannot anticipate the claims, but the rejection is under 103 and based on Clarke.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Clarke (US 20110021607) as applied to claims 1-3 above, and further in view of Manoharan et al. (US 20120035115).
Pages 11-12 of '607 disclose chemically modifying the oligonucleotide to increase intracellular stability or binding affinity, including cholesterol conjugates, phosphorothioates linkages and 2'-OMe substitutions.
'607 does not specifically teach attaching a GalNAc conjugate to the 3' end of the miRNA antisense inhibitor.
However, Manoharan et al. teach a composition comprising an antagomir (also known as a miRNA antisense inhibitor) comprising phosphorothioate linkers and 2'-OMe modifications. A cholesterol moiety (GalNAc) can be conjugated at the 3' end of an oligonucleotide to target liver cells (Paragraphs 294, 600, 605, 644 and Tables 2 and 6).
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of '607 taken with Manoharan et al. to attach a GalNAc conjugate to the 3' end of the miRNA antisense oligonucleotide, namely to arrive at the claimed invention. There are only two options for attaching the moiety to the antisense oligonucleotide (5' or 3' end). One of ordinary skill in the art would have been motivated to combine the teaching to assists in the delivery of the antisense oligonucleotide to cells.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Response to Arguments
Applicant's arguments filed 12/17/25 have been fully considered but they are not persuasive for the reasons set forth in the previous response to applicant’s arguments and no new arguments provides no additional arguments that requires addressing by the Office.
It is noted that applicant argues that Manoharan neither teaches or suggest these specific miRNA inhibitors and cannot anticipate the claims, but the rejection is under 103 and based on Clarke taken with Manoharan.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over
Cohen (WO 2013165320).
Claim 20 of '320: A method of treating a disease selected from the group consisting of cancer to a patient wherein the method comprises an antisense oligonucleotide sequestering a microRNA capable of decreasing SOCS6 protein levels, wherein the antisense oligonucleotide has at least one modified or substituted nucleotide.
Claim 21 of '320: The method of claim 20, wherein the modified nucleotides comprise modified bases selected from the group consisting of phosphorothioate, methylphosphonate, peptide nucleic acids, 2'-O-methyl, fluoro- and carbon, methylene and other locked nucleic acid (LNA) molecules.
Claim 24 of '320: The method of claims 17 to 22, wherein the micro-RNA is selected from the group consisting of miR-203; miR-499/499-5p; miR-183; miR-23ab; miR-216/216b; miR-128; miR-204/211; miR-192/215; miR-15/16/195/424/497; miR-144; miR-218; miR-17-5p/20/93.mr/106/519.d; miR-30a/30a-5p/30b/30b-5p/30cde/384-5p; miR-216/216a; miR-182; miR-208/208ab; miR-21/590-5p; miR-26ab/1297; miR 25/32/92/92ab/363/367; miR-141/200a; miR-19; miR-190; miR-200bc/429; miR33/33ab; miR-130/301; miR-137; miR-27ab; miR-34a/34b-5p/34c/34c-5p/449/449abc/699; miR-142-3p; miR-138; miR-96/1271; miR-155; miR-193ab; miR-101; miR-139-5p; miR-338/338-3p; miR-24; miR-503; miR-494; miR-329/362- 3p; miR-186; miR-590/590-3p; miR-340/340-5p; miR-421; miR-296/296-3p; miR-377; miR-300; miR-376c; miR-431; miR-544; miR-382; miR-149; miR-592/599; miR-495/1192; miR-326/330/330-5p; miR-539; miR-378/422a; miR-361/361-5p; miR-758; miR-542/542-3p; miR-410; miR-342/342-3p; miR-339-5p; miR-504; miR-154; miR-374/374ab; miR-224; and miR-384.
In view of claim 24 of '320, the claim would read on a composition comprising an
antisense oligonucleotide targeting a microRNA, including miR-200bc/429, wherein the oligonucleotide has modified bases selected from the group consisting of phosphorothioate, methylphosphonate, peptide nucleic acids, 2'-O-methyl, fluoro- and carbon, methylene and other LNA molecules
'320 does not specifically teach a composition comprising an antisense oligonucleotide comprising a plurality of phosphorothioate linkers, wherein the oligonucleotide hybridizes to an miRNA binding site, wherein said miRNA antisense inhibitor is a SERPINC1 miRNA antisense inhibitor selected from the group consisting of antimir200bc, antimir200a+141, anti429, anti18a and anti19b.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to make the antisense oligonucleotide targeting has-miR-200bc comprise phosphorothioate linkers, namely to arrive at the claimed invention. One of ordinary skill in the art would have been motivated as a simple substitution to make a composition comprising the antisense oligonucleotide to study cancer targeting miR-200bc with a reasonable expectation of success. See MPEP 2143(I)A, B and E. In addition, it would have been obvious to add additional modifications, including phosphorothioates and a 2'-OMe modification to increase the stability of the oligonucleotide in a cell. The limitation 'wherein said miRNA antisense inhibitor is a SERPINC1 mRNA antisense inhibitor' in instant claim 1 would be an inherent property of the antisense oligonucleotide targeting miR-200bc because it would have the same structural limitations as recited in the instant claims.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Response to Arguments
Applicant's arguments filed 12/17/25 have been fully considered but they are not persuasive.
Applicant argues that claim 1 is now amended to recite that the miRNA antisense inhibitor is a SERPINC1 miRNA inhibitor and the inhibitor taught by Cohen is drawn to a SOCS6 inhibitor and there is no teaching or suggestion in Cohen that would lead one of skill in the art to believe that the modified SOCS6 inhibitor of Cohen would have been effective inhibitor of SERPINC1.
Applicant’s argument is acknowledged, but is not found persuasive because applicant appears to be arguing an intended use of the product or functional limitation (an effective antisense inhibitor of SERPINC1) and the instant claims are directed to a product made obvious by Cohen. Although Cohen is silent with respect to the limitations (an effective antisense inhibitor of SERPINC1) as recited in the instant claims, Cohen makes obvious all of the claimed structural limitations, so the functional effects of the claimed product are considered to be inherent in the product made obvious by Cohen. Where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke 441 F.2d 660, 169 USPQ 563 (CCPA 1971). Whether the rejection is based on "inherency" under 35 USC 102, or "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
Conclusion
See attached PTO-326 for disposition of claims.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brian Whiteman whose telephone number is (571)272-0764. The examiner can normally be reached on Monday thru Friday; 6:00 AM to 3:00PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (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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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636