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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/17/2026 has been entered.
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 07/17/2026 is acknowledged. Claim 10 was cancelled. Claims 1,17 and 30 were amended. Claim 52 is new. Claims 1,2,4,8,9,11,16,17,130,30,34 and 52 are pending and under examination.
Withdrawn Objections/Rejections
Applicant’s arguments and amendments, see page 5, filed 07/17/2026, with respect to the objection to claims 1 and 17 reciting “PB2 promoter” have been fully considered and are persuasive due to the amendments to claims 1 and 17 removing “PB2 promoter” from the claims. The objection to claims 1 and 17 has been withdrawn.
Applicant’s arguments and amendments, see pages 5-6, filed 07/17/2026, with respect to the non-statutory double patenting rejections over U.S. Patent No. 12,194,108, and co-pending applications 18/967,535 and 18/707,207 have been fully considered and are persuasive due to the amendments to independent claims 1 and 17 reciting that the promoter comprises the sequence set forth in SEQ ID NO: 3 which was indicated as free of the art. The non-statutory double patenting rejections have been withdrawn.
Applicant’s arguments and amendments, see page 7, filed 07/17/2026, with respect to the 35 U.S.C. 112(b) rejection of claims 1,2,4,8,9,11,16,17 and 34 as indefinite based on the metes and bounds of “PB2 promoter” not being clear and claim 30 not being clear whether the nucleic acid comprises one or both of SEQ ID NO: 3 and 9, have been fully considered and are persuasive due to the amendments to claims 1 and 17 removing “PB2 promoter” and reciting that the promoter comprises the sequence set forth in SEQ ID NO: 3, and the amendment to claim 30 to clarify the nucleic acid comprises both the sequence set forth in SEQ ID NO: 3 and the sequence set forth in SEQ ID NO: 9. The 35 U.S.C. 112(b) rejection of claims 1,2,4,8,9,11,16,17 and 34 has been withdrawn.
Applicant’s arguments and amendments, see page 7, filed 07/17/2026, with respect to the rejection(s) of claim(s) 1,2,4,8,9,11,16,17 and 34 under 35 U.S.C. 112(a) Written description have been fully considered and are persuasive due to the amendment to claim 1 removing “wherein the OC specific promoter comprises an inflammation inducible NF-kB promoter, and wherein the inflammation inducible Nf-KB promoter is a PB2 promoter”, and by reciting “a promoter comprising the sequence set forth in SEQ ID NO: 3”. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made regarding the genus of inhibitory nucleic acids recited in the claims. See the new written description rejection below.
Applicant’s arguments and amendments, see page 8, filed 07/17/2026, with respect to the 35 U.S.C. 102(a)(1) and 102(a)(2) rejection of claims 1,2,8,9,11,16 and 34 as anticipated by WO 2019183605 have been fully considered and are persuasive due to the amendment to claim 1 reciting the promoter comprises SEQ ID NO: 3 which was indicated as free of the art. The 35 U.S.C. 102(a)(1) and 102(a)(2) rejection of claims 1,2,8,9,11,16 and 34 has been withdrawn.
Applicant’s arguments and amendments, see page 8, filed 07/17/2026, with respect to the 35 U.S.C. 103 rejections of claim 4 as unpatentable over ‘605 and further in view of Kay et al.; claims 1,8 and 11 as unpatentable over Glimcher et al. in view of Maruyama et al. and Abu-Amer; claims 2,4 and 34 as unpatentable over Glimcher et al. in view of Maruyama et al. and Abu-Amer and further in view of Kay et al.; claims 9 and 16 as unpatentable over Glimcher et al. and Maruyama et al. and Abu-Amer and further in view of Calloni et al.; Claim 17 as unpatentable over Glimcher et al. in view of Maruyama et al., Abu-Amer and Calloni et al. have been fully considered and are persuasive due to the amendment to claim 1 reciting the promoter comprises SEQ ID NO: 3 which was indicated as free of the art. The above 35 U.S.C. 103 rejections have been withdrawn.
The following rejections and/or objections are newly applied. They constitute the complete set presently being applied to the instant application.
Claim Objections
Claim 1 is objected to because of the following informalities: line 5 of claim 1 recites “ receptor activator of NF-kB, (RANK)” and therefore has a comma between NF-kB and (RANK) which should be removed since (RANK) is the abbreviation for that gene. Appropriate correction is required.
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 16 and 17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 16 and 17 recite, “targeting a gene selected from SHN3, CTSK, SOST, RANK and RANKL”. It is not clear if Applicant is trying to recite a Markush grouping or if this includes mixtures or not, or a closed group. See MPEP 2173.05(h). Regarding a Markush grouping, alternatives may be set forth as "a material selected from the group consisting of A, B, and C" or "wherein the material is A, B, or C"). In this case, the claim is missing “the group consisting of”, or could recite “targeting a gene which is SHN3, CTSK, SOST, RANK or RANKL”.
Written Description Rejection
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 1,2,4,8,9,11,16,17 and 34 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A3.(a).(i) states the following:
“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 inventor was in possession of the claimed genus.”
“Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).”
Claims 1,2,4,8,9,11,16,17 and 34 encompass a large genus of one or more inhibitory nucleic acids targeting sclerostin (SOST), schnurri-3 (SHN3), cathepsin K (CTSK), receptor activator of NF-kB (RANK) and/or receptor activator of NF-kB ligand (RANKL), which includes but is not limited to antisense oligonucleotides, splice-switching oligonucleotides, siRNA, shRNA, aptamers, miRNAs, amiRNAs which inhibit the recited target genes SOST, SHN3, CTSK, RANK, and/or RANKL. The target genes encompass both human and mammalian species, and the inhibitory nucleic acids can target any portion of the recited target genes, and therefore the number of species encompassed by the inhibitory nucleic acids is millions of possible species.
The instant specification discloses sequences of amiRNAs targeting mouse SHN3 of SEQ ID NO: 8 and amiRNAs targeting human SHN3 of SEQ ID NOs: 9-11 (pages 62-63), amiRNAs targeting mouse RankL of SEQ ID NO: 12-15 (pages 63-64), amiRNAs targeting human RankL of SEQ ID NOs:16-19 (pages 64-65), amiRNAs targeting mouse Cathepsin K of SEQ ID NO: 20-21 (page 65) and amiRNAs targeting human Cathepsin K of SEQ ID NOs: 22-25 (page 65-66), amiRNAs targeting mouse SOST of SEQ ID NOs: 26-27 (page 66) and amiRNAs targeting human SOST of SEQ ID NOs: 28-31 (page 67).
FIG. 10B and page 8 of the specification shows that amiR-SHN3 reduced SHN3 mRNA levels in the tibia. Page 54 of the specification also says this amiR-SHN3 resulted in ~40% reduction of SHN3 mRNA levels in the tibial bone as shown in FIG. 10B. However, it is not clear what the amiR-SHN3 sequence was that resulted in this since several amiR-SHN3 sequences are disclosed and the drawings and description thereof do not specify which.
Page 8 of the specification discloses that mice were injected with bone targeting DSS.rAAV9 carrying amiR-ctrl or amiR-CTSK and that FIG. 11A shows trabecular bone mass and cortical bone thickness in the femur, FIG. 11C shows joint inflammation was not altered by treatment with the vectors. Again, it is not clear what amiR-CTSK sequence was used.
Therefore, while the specification discloses a few sequences of amiRNAs that are either mouse or human derived sequences that target the recited genes, the specification is not clear what sequences of amiRNAs result in inhibiting the mRNA of the target genes. In addition, the specification does not disclose any other species of the genus of inhibitory nucleic acids (no shRNAs, siRNAs, antisense oligonucleotides, aptamers, splice-switching oligonucleotides, miRs).
Regarding the state of the art for the genus of antisense oligonucleotides, Freier et al. (Antisense Drug Technology, Second Edition, 2007, Chapter 5, pages 117-138) teach screening results for 57 ASOs targeted to a single gene showed typical results in that about one third of the ASOs tested reduced target mRNA below 40% control, 12% reduced it below 25% control, and 7 reduced it below 20% control, and therefore an active ASO that reduced target by 60% or more could likely have been identified by testing three to six ASOs at random from this set (Section 5.2.8, page 127). Freier et al. teach target validation is easier with the most potent and most active ASO, and that typically 78 candidate ASOs for one target or 37 ASOs for each of two targets are screened and typically results in two to eight lead compounds for subsequent evaluation (page 128).
Regarding siRNA and shRNA, Reynolds et al. (Nature Biotechnology, Vol. 22, No. 3, March 2004, pages 326-330) teach that potent siRNAs can be rationally designed and tested. Reynolds et al. taught to identify siRNA-specific features likely
to contribute to efficient processing at each step, a systematic analysis of 180 siRNAs targeting the mRNA of two genes and eight characteristics associated with siRNA functionality were identified: low G/C content, a bias towards low internal stability at the sense strand 3′-terminus, lack of inverted repeats, and sense strand base preferences (positions 3, 10, 13 and 19). Further analyses revealed that application of an algorithm incorporating all eight criteria significantly improves potent siRNA selection (Abstract). Reynolds et al. taught all duplexes of this validation set were assayed for gene silencing (Fig. 3), and of 30 rationally designed siRNAs, 29 were functional. The algorithm improved the average probability of selecting an F50 siRNA from 46.5% (random selection) to 96.6% in this validation set. Furthermore, approximately 56.7% of the rationally selected siRNAs were F80, compared to 16.3% for randomly selected siRNAs (Fig. 3f). Thus, on average, the algorithm ensured functional duplex selection for all six genes with over a 3.5-fold improvement in achieving 80% knockdown (page 327).
Therefore, both Freier et al. and Reynolds et al. show there is predictability in design and activity of antisense oligonucleotides, siRNA and shRNA.
However, the prior art teaches unpredictability regarding aptamers, splice-switching oligonucleotides, miRs and amiRs.
Regarding aptamers, Emami (Emami et al., 2020, Journal of Theoretical Biology, 497 (2020), pg. 1-14) teaches that SELEX “success rates are relatively low,” and “often fails to enrich high-affinity aptamers,” and that despite the use of various computational tools, the skilled artisan cannot yet predict the structures of aptamers which will selectively bind to a target (Abstract, pg. 1; Introduction, pg. 2; Conclusion, pg. 12).
Regarding the genus of miRNA as inhibitory nucleic acids, Liang et al. (Journal of Biomedicine and Biotechnology, 2012, pg. 1-8) teach that the seed sequence of a miRNA dictates its target(s) and biological role(s) (Abstract) but despite well-conserved sequences, miRNAs show evolutionary stable “seed shifting” events across different animal species, especially toward the 3′ ends (page 2). The prior art teaches that targets of miRNAs can be predicted based on sequence (Liang, pg. 2-4), but also provides that the biological networks downstream of miR-548 family members are complex and remain uncharacterized functionally (“it is quite necessary to further study its evolutionary and functional relationship by systematic analysis,” pg. 2, left col.; “the primate-specific gene family might contribute to dynamic expression profiles and regulatory networks,” Abstract).
Regarding artificial miRNAs, Bhagwat et al. (Biotechnology of Plant Secondary Metabolism: Methods and Protocols, Methods in Molecular Biology, Vol. 1405, Chapter 14, 2016, pages 149-162) teach that artificial microRNA (amiRNA) technology uses microRNA biogenesis pathway to produce artificially selected small RNAs using miRNA gene backbone, and provides a feasible strategy for inducing loss of gene function. However, a big challenge in amiRNA applications is the unpredictability of silencing efficacy of the designed amiRNAs (Abstract). Bhagwat et al. taught a recent study found that silencing efficacy of designed amiRNAs was generally less potent than that of the endogenous miRNA even though the amiRNAs and the miRNA showed analogous target complementarities (page 150).
Regarding the genus of splice-switching oligonucleotides, Aartsma-Rus (Aartsma-Rus, 2012, Exon Skipping: Methods and Protocols, Methods in Molecular Biology, 867, Chapter 8, pg. 117-129) teaches “generalizable” guidelines to design antisense oligomers that interfere with splicing, i.e., guidelines which Aartsma-Rus teaches apply to multiple gene targets (pg. 118). In addition to having sufficient affinity to the target, Aartsma-Rus teaches that the antisense oligomer must be designed to bind at an accessible target site (pg. 121). Aartsma-Rus teaches that pre-mRNAs form dynamic secondary structures (pg. 121), and that effective antisense oligomers likely severely disrupt the pre-mRNA secondary structure (pg. 123). Such folding can be estimated using available software (e.g., “m-fold software”) (pg. 122-123).
While Aartsma-Rus provides guidance as to the general factors influencing splice modulation by antisense oligomers, and a method to design splice modulating oligomers, Aartsma-Rus also strongly suggests that there is a level of unpredictability in producing an effective splice-modulating antisense oligomer, describing the process as involving “trial and error” (“there are also effective AONs that do not fulfill these criteria and similarly there are AONs that fulfill all criteria and are ineffective”, pg. 126; “there is also a trial and error aspect involved. Generally, at least one AON is effective when two AONs are tested for a single exon”, pg. 127).
Therefore, the prior art provides uncertainty and unpredictability regarding the species within the large genus of miRNAs, amiRNAs, splice-switching oligonucleotides, and aptamers as inhibiting the recited target genes.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, (Fed. Cir. 1991), makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Univ. of Rochester v. G.D. Searle, 69 USPQ2d 1886, 1892 (CAFC 2004), further supports this by stating that:
The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. A description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) described even in terms of its functioning of lessening inflammation of tissues fails to distinguish any steroid from others having the same activity or function. A description of what a material does, rather than of what it is, usually does not suffice…. The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described. (Emphasis added).
With the exception of antisense oligonucleotides, siRNA and shRNA as the inhibitory nucleic acids targeting SOST, SHN3, CTSK, RANK and/or RANKL, which are taught as predictable by the state of the art, the skilled artisan cannot envision the detailed chemical structure of the encompassed inhibitory nucleic acids targeting SOST, SHN3, CTSK, RANK and/or RANKL. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The chemical structure itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Circ. 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016, (Fed. Cir. 1991). In Fiddes v. Baird, 30 USPQ2d 1481, 1483, (Bd. Pat. App. & Int. 1993), claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 (Fed. Cir. 1997) held that:
...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Furthermore, to the extent that a functional description can meet the requirement for an adequate written description, it can do so only in accordance with PTO guidelines stating that the requirement can be met by disclosing “sufficiently detailed, relevant identifying characteristics,” including “functional characteristics when coupled with a known or disclosed correlation between function and structure.” Univ. of Rochester v. G.D. Searle, 68 USPQ2d 1424, 1432 (DC WNY 2003).
Therefore, only antisense oligonucleotides, siRNA and shRNA as the inhibitory nucleic acids targeting SOST, SHN3, CTSK, RANK and/or RANKL, but not the full breadth of the claim(s) meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC § 112 is severable from its enablement provision. (See page 1115.)
Conclusion
Claims 1,2,4,8,9,11,16,17 and 34 are rejected.
Claims 30 and 52 are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram R Shukla can be reached at 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
