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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 01/16/2026 is acknowledged. Claims 5,7,12-15,40-42 were cancelled. Claims 1,9-11,17 and 30 were amended. Claims 1,2,4,8-11,16,17,30 and 34 are pending.
Applicant elected Group I (claims 1,2,4,5,7-17,30 and 34) in the reply filed on 09/03/2025.
Claim 10 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim.
Applicant elected a PB2 promoter of SEQ ID NO: 3 (claim 5) and an inhibitory nucleic acid that targets SHN3 of SEQ ID NO: 9 (claim 11) as Species A, and soluble IL-1 Receptor Antagonist (claim 4). The elected species, SEQ ID NO: 3 and SEQ ID NO: 9, are free of the art, therefore the species are expanded to include those taught in WO 2019183605 and Glimcher et al. (US 20130202533).
Claims 1,2,4,8,9,11,16,17,30 and 34 are under examination.
Priority
This application is a 371 of PCT/US2021/046447 filed 08/18/2021 and which claims benefit of 63/067,581 filed 08/18/2020 as reflected on the most recent filing receipt.
Response to Arguments
Applicant’s arguments and amendments, see page 6, filed 01/16/2026, with respect to the objection to the misspelling in the specification have been fully considered and are persuasive due to the amendment correcting the abstract. The objection to the abstract has been withdrawn.
Applicant’s arguments and amendments, see page 11, filed 01/16/2026, with respect to the 35 U.S.C. 102(a)(1) rejection of claim 30 as anticipated by Gao et al. have been fully considered and are persuasive due to the amendment to claim 30 limiting the sequences to SEQ ID NO: 3 and SEQ ID NO: 9 which were not taught by Gao et al. and indicated as free of the art. The 35 U.S.C. 102(a)(1) rejection of claim 30 has been withdrawn.
Applicant's arguments and amendments, filed 01/16/2026 regarding the 35 U.S.C. 102(a)(1) and 102(a)(2) rejection of claims 1,2,5,8,9,11,16,17 and 34 as anticipated by WO 2019183605 have been fully considered and are partially persuasive regarding the amendment to claim 17, and therefore is partially withdrawn with regards to claim 17, as amended claim 17 now requires a PB2 promoter which is not taught by ‘605. However the rejection remains for claims 1,2,5,8,9,11,16 and 34. While applicant amended claim 1 to recite that the OC-specific promoter comprises an inflammation-inducible NF-kB promoter, and wherein the inflammation-inducible NF-kB promoter is a PB2 promoter, claim 1 still recites “comprising an osteoclast (OC)-specific promoter or an osteoblast (OB)-specific promoter. The rejection clearly states that ‘605 teaches a bone metabolism modulating agent which is an inhibitory nucleic acid that inhibits OB expression or activity and is an inhibitory nucleic acid targeting SHN3, and teaches a promoter operably linked to the transgene and the promoter is a bone tissue specific promoter including… osteocalcin… (page 6 of office action). Osteocalcin is an OB-specific promoter as seen on page 2 of the instant specification. Therefore, as amended claim 1 does not require the promoter to be an OC promoter, and allows the promoter to be an OB-specific promoter, the cited art still teaches the limitations of claims 1,2,8,9,11,16 and 34 and therefore the rejection is maintained for these claims.
Applicant’s arguments and amendments, see page 12, filed 01/16/2026 with respect to the 35 U.S.C. 103 rejection of claim 4 as unpatentable over ‘605 and further in view of Kay et al. has been fully considered but is not persuasive. As stated above, ‘605 still applies to claims 1,2,5,8,9,11,16,17 and 34 for the limitations pertaining to the OB-specific promoter, and therefore still applies to claim 4 which depends on claim 2 which depends on claim 1, further in view of Kay et al., and the rejection is maintained.
Applicant’s arguments and amendments, see pages 12-13, filed 01/16/2026, with respect to the rejection(s) of claim(s) 1,5,8 and 11 under 35 U.S.C. 103 as unpatentable over Glimcher et al. in view of Huizinga et al., claims 2,4 and 34 as unpatentable over Glimcher et al. in view of Huizinga et al. and further in view of Kay et al., and claims 9 and 16 as unpatentable over Glimcher et al. in view of Huizinga et al. and further in view of Calloni et al., have been fully considered and are persuasive, due to the amendments to the claim 1 requiring when the promoter is an OC-specific promoter, it is a PB2 promoter which is not taught by Glimcher et al. or Huizinga et al., as well as the cancellation of claim 5. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendments to claim 1 requiring the OC-specific promoter as an inflammation-inducible NF-kB promoter which is a PB2 promoter. See the new 103 rejections below which are necessitated by amendment.
Applicant’s arguments and amendments, see page 14, filed 01/16/2026, with respect to the rejection(s) of claim 17 under 35 U.S.C. 103 as unpatentable over Glimcher et al. in view of Calloni et al. have been fully considered and are persuasive due to the amendments to claim 17 to recite that the transgene further comprises a promoter operably linked to the first inhibitory nucleic acid or the second inhibitory nucleic acid, and the promoter is a PB2 promoter which is not taught by Glimcher or Calloni et al. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendment to claim 17 requiring the transgene further comprising a promoter operably linked to the first or second inhibitory nucleic acid and wherein the promoter is an inflammation-inducible promoter, comprising a PB2 promoter. See the new 103 rejection below which is necessitated by amendment.
Applicant’s arguments and amendments, see pages 6-10, filed 01/16/2026, with respect to the non-statutory double patenting rejections over claims 1-10 of U.S. Patent No. 12,194,108 and the provisional double-patenting rejections over claims 1-7 and 17-22 of co-pending Application 18/967,535 and claims 8-12 and 14-16 of co-pending Application 18/707,207 have been fully considered and are persuasive due to the amendments to claims 1 and 17 citing limitations of the promoter that are not taught by the cited references. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendments to claims 1 and 17 requiring when the promoter is an OC-specific promoter, it is a PB2 promoter. See the new NSDP rejections below, which are necessitated by amendment.
Maintained Rejections
Claim Rejections - 35 USC § 102
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 1,2,8,9,11,16 and 34 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by WO 2019183605 (‘605) (Published 26 Sept 2019, EFD 23 March 2018), cited on an IDS.
Regarding claims 1 and 11, ‘605 teaches an isolated nucleic acid encoding a region comprising a transgene encoding at least one bone metabolism modulating agent (page 2, lines 3-6), wherein the bone metabolism modulating agent is an inhibitory nucleic acid that inhibits OB expression or activity, and is an inhibitory nucleic acid targeting schnurri-3 (SHN3) (page 2, lines 10,11,15,16,19,20), and also teaches an isolated nucleic acid comprising a transgene encoding an artificial microRNA targeting the SHN3 gene (page 20, lines 23-24). ‘605 teaches an isolated nucleic acid further comprises at least one promoter operably linked to the transgene (page 3, lines 1-2), and wherein the promoter is a bone tissue-specific promoter including promoters of osterix, osteocalcin (an OB-specific promoter), type 1 collagen alpha1, DMP1, cathepsin K, Rank (page 26, lines 1-3). Therefore, ‘605 teaches an osteoblast-specific promoter (osteocalcin) operably linked to an inhibitory nucleic acid targeting SHN3.
Regarding claim 2, ‘605 teaches an isolated nucleic acid further comprising a transgene encoding a protein (page 26, lines 5-6).
Regarding claim 8, ‘605 teaches the inhibitory nucleic acid is selected from the group consisting of shRNA, miRNA and artificial miRNA (amiRNA) (page 2, lines 25-26, page 20, lines 23-24).
Regarding claim 9, ‘605 teaches the inhibitory nucleic acid is a miR-33-shn3 (Example 6, page 63, line 17).
Regarding claim 16, ‘605 teaches an isolated nucleic acid encoding a transgene encoding a bone metabolism modulating agent (page 2, line 5) and wherein the transgene encodes a bone formation promoting agent which is an inhibitory nucleic acid targeting schnurri-3 (page 2, lines 17-20). ‘605 teaches where a transgene encodes more than one miRNA, for example a nucleic acid encoding a first miRNA may be positioned in an intron of the transgene and a nucleic acid sequence encoding a second miRNA may be positioned in another untranslated region (page 23 lines 3-7).
Regarding claim 34, ‘605 teaches an AAV vector comprising the amiR-33-shn3 and AAV9 capsid (page 63, lines 16-24).
Therefore, claims 1,2,8,9,11,16 and 34 are anticipated by ‘605.
The applied reference has a common inventor(s) and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
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.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over ‘605 as applied to claims 1,2,8,9,11,16 and 34 above, and further in view of Kay et al. (J Gene Med. 2009 July; 11(7):605-614).
The teachings of ‘605 as applicable to claims 1,2,8,9,11,16 and 34 are described above.
‘605 does not teach wherein the transgene further comprises a nucleic acid encoding the soluble IL-1 Receptor Antagonist (sIL1R alpha).
However, before the effective filing date, Kay et al. teach AAV vectors for infecting lapine articular fibroblasts to determining transduction efficiency, transgene expression levels and nuclear trafficking, wherein the self-complementary AAV contains the cDNA for interleukin (IL)-1 receptor antagonist (Ra) delivered to joints of rabbits and those with IL-1-beta induced arthritis (Abstract). Kay et al. teach cDNA for human IL-1Ra was inserted into an scAAV vector and packaged into AAV serotype 2, and results showed lapine articular fibroblasts were amenable to transduction with the scAAV.nIL-1Ra (page 6, second paragraph). Kay et al. teach IL-1Ra is a secreted protein that serves as a competitive inhibitor of IL-1 by binding to available type IL-1 receptors and preventing subsequent interaction with IL-1 ligand and IL-1 receptor accessory protein (page 6, second paragraph). Kay et al. also teach intra-articular injection of the scAAV.IL-1Ra vector (page 6, fifth paragraph). Kay et al. teach after injection of approximately 5 × 1011 particles, sufficient levels of IL-1Ra transgene product were generated to cause a reduction in the leukocytic infiltration in joints inflamed by constitutive IL-1 production (page 8, first paragraph). Kay et al. teach the data obtained in the present study are among the first to report intra-articular transgene expression from an AAV vector in articular tissues on a clinically applicable scale. As shown by the ability of the IL-1Ra expression to alleviate leukocytosis in inflamed joints of the rabbits, the efficiency of scAAV-mediated gene delivery and ensuing expression is sufficient to induce a beneficial biological response in this context (page 8, second paragraph).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the SHN3 inhibitory nucleic acid molecule operably linked to the osteocalcin promoter of ‘605 and include a nucleic acid encoding soluble IL-1 Receptor Antagonist according to the teachings of Kay et al. with a reasonable expectation of success. There would be a reasonable expectation of success, as this would amount to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Kay et al. teach IL-1Ra is a secreted protein that serves as a competitive inhibitor of IL-1 by binding to available type IL-1 receptors and preventing subsequent interaction with IL-1 ligand and IL-1 receptor accessory protein (page 6, second paragraph), and that after injection of approximately 5 × 1011 particles, sufficient levels of IL-1Ra transgene product were generated to cause a reduction in the leukocytic infiltration in joints inflamed by constitutive IL-1 production (page 8, first paragraph), and the ability of the IL-1Ra expression to alleviate leukocytosis in inflamed joints of the rabbits (page 8, second paragraph).
Accordingly, the limitations of claim 4 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
The applied reference (‘605) has a common inventor(s) and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Claim Objections
Claims 1 and 17 are objected to because of the following informalities: Claims 1 and 17 recite “PB2 promoter”. Neither the claims nor the specification defines what “PB2” stands for. For clarity, the full name of the promoter should be recited in the claims. Appropriate correction is required.
New Rejections- Necessitated by Amendment
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 1,2,4,8,9,11,16,17,30 and 34 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.
Amended claim 1 recites “wherein the OC-specific promoter comprises an inflammation-inducible NF-kB promoter, and wherein the inflammation-inducible NF-kB promoter is a PB2 promoter”. Amended claim 17 recites “wherein the promoter is an inflammation-inducible promoter, comprising a PB2 promoter”. Previously, claim 5 which is now cancelled, recited “optionally wherein the NF-kB promoter is a PB2 promoter (SEQ ID NO: 3). The examiner indicated SEQ ID NO: 3 was free of the art, but when claims 1 and 17 were amended, the limitation requiring the PB2 promoter of SEQ ID NO: 3 was not incorporated into the claims. The specification does not have a definition of what PB2 stands for or what is encompassed by the PB2 promoter. Therefore, claims 1 and 17 are indefinite, as the metes and bounds of what is encompassed by “PB2 promoter” is not clear.
Claims 2,4,8,9,11,16 and 34 depend on claim 1, and are therefore included in the rejection as they do not correct the issue.
Regarding amended claim 30, the claim now recites “An isolated nucleic acid comprising or encoding a sequence set forth in SEQ ID NO: 3 and SEQ ID NO: 9”. The scope of the claim is not clear as to whether the isolated nucleic acid requires both SEQ ID NO: 3 and 9, or if the claim is supposed to be in the alternative. Prior to the amendment, the claim recited “any one of SEQ ID NOs: 1-40” and therefore only needed to be one of the sequences, but the removal of “any one of” and reciting “SEQ ID NO: 3 and SEQ ID NO: 9” makes the scope of what is required by the claim unclear.
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.
Instant claims 1,2,4,8,9,11,16,17 and 34 encompass that the OC-specific promoter comprises an inflammation-inducible NF-kB promoter which is a PB2 promoter.
The instant specification discloses in FIG. 14A a PB2 promoter-driven expression cassette cloned in an AAV genome vector, and shows the sequence of the PB2 promoter as SEQ ID NO: 3 (FIG. 14A, and page 9). Page 25 of the instant specification discloses that In some embodiments, an inflammation-induced promoter comprises a NF-kappa B (NFKB) promoter. In some embodiments, a NF-kappa B (NFKB) promoter is a PB2 promoter. In some embodiments, a NF-kappa B (NFKB) promoter (e.g., a PB2 promoter) comprises the nucleic acid sequence that is at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity, or are 100% identical, including all values in between to SEQ ID NO: 3. In some embodiments, a NF-kappa B (NFKB) promoter (e.g., a PB2 promoter) comprises the nucleic acid sequence set forth in SEQ ID NO: 3.
Therefore, the specification does not disclose what PB2 stands for and does not structurally identify what it is other than citing at least 70% identity to SEQ ID NO: 3 or that it comprises the nucleic acid sequence set forth in SEQ ID NO: 3.
The specification discloses a PB2 promoter of SEQ ID NO: 3 which meet the written description and enablement provisions of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. However, claims 1,2,4,8,9,11,16,17 and 34 are directed to encompass any inflammation-inducible NF-kB promoter which is a PB2 promoter as the OC-specific promoter which only correspond in some undefined way to the specifically instantly disclosed PB2 promoter of SEQ ID NO: 3. “PB2 promoter” does not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, due to lacking chemical structural information for what they are and chemical structures are highly variant and encompass a myriad of possibilities. The specification provides insufficient written description to support the genus encompassed by the claim. Note: MPEP 2163.
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 the above specifically disclosed chemical structure of SEQ ID NO: 3, the skilled artisan cannot envision the detailed chemical structure of the encompassed PB2 promoter, regardless of the complexity or simplicity of the method of isolation. 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 the above chemically structurally defined PB2 promoter of SEQ ID NO: 3, 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.)
Claim Interpretation
It is noted that applicant amended both claims 1 and 17 to incorporate “wherein the OC-specific promoter comprises an inflammation-inducible NF-kB promoter, and wherein the inflammation-inducible NF-kB promoter is a PB2 promoter” but did not incorporate that the PB2 promoter is SEQ ID NO: 3 which was indicated as free of the art. Therefore, the examiner is interpretating these claims as not requiring a PB2 promoter of SEQ ID NO: 3 as this is not a required limitation of claims 1 and 17 as amended, and is broader than previously claimed. The specification does not have a definition of what PB2 stands for or what is encompassed by the PB2 promoter. Therefore, the examiner is interpreting the recited inflammation inducible NF-kB promoter which is a PB2 promoter, to be any promoter for NF-kB2 (p52).
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 1,8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Glimcher et al. (US 20130202533, Published 8 Aug 2013) in view of Maruyama et al. (JBMR, Vol. 25, No. 5, May 2010, pp 1058-1067) and Abu-Amer (Osteoporos Int 2013 Sept; 24(9).
Regarding claims 1 and 11, Glimcher et al. teach Shn3 or schnurri 3 is a member of the ZAS DNA binding family of proteins and has been identified as a key regulator of osteoblast function, and that Shn3 -/- mice exhibit a pronounced high-bone mass phenotype that arises through augmentation of osteoblast synthetic activity (paragraphs 0005,0008). Glimcher et al. teach that Shn3 also regulates osteoclasts in calvarie and diaphyseal bone, and that reduction in Shn3 reduces osteoclast numbers and/or activity in these types of bone but not in metaphyseal regions, and that Shn3 associates with RANKL gene regulatory elements (paragraph 0010). Glimcher et al. teach a nucleic acid molecule that is antisense to a Shn3 molecule or a Shn3 siRNA (paragraphs 0047-0049,0075), as well as RNA interfering agents include, but are not limited to, nucleic acid molecules including RNA molecules which are homologous to the target gene or genomic sequence, e.g., Shn2, Shn3, or a fragment thereof, “short interfering RNA” (siRNA), “short hairpin” or “small hairpin RNA” (shRNA), and small molecules which interfere with or inhibit expression of a target gene by RNA interference (RNAi) (paragraph 0238). Glimcher et al. teach the nucleic acid molecule that is antisense to Shn3 or Shn3 siRNA may treat a disease, condition or injury associated with osteoclastic bone destruction in calvariae or diaphyseal bone (paragraph 0075), and that inhibition of Shn3 activity is desirable in situations in which Schn3 is abnormally upregulated and/or in which decreased Shn3 activity is likely to have a beneficial effect including osteoporosis, osteomalacia, skeletal changes of hyperparathyroidism and chronic renal failure (renal osteodystrophy) and osteitis deformans (Paget's disease of bone), osteopenia, osteoarthritis and inflammatory arthritis characterized by bone loss or excess bone formation including for example rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis (paragraph 0220). Glimcher et al. teach since inhibition of Shn3 activity is associated with increased bone formation and mineralization, to increase bone formation and mineralization (e.g., osteoblasts or osteoclasts) are contacted with an agent that inhibits Shn3 activity (paragraph 0232).
Glimcher et al. teach recombinant expression vectors of the invention comprise a nucleic acid molecule in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression and the level of expression desired, which is operatively linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, “operably linked” is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner which allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). The term “regulatory sequence” includes promoters, enhancers and other expression control elements (paragraph 0175).
Glimcher et al. do not explicitly recite an osteoclast (OC)-specific promoter operably linked to a nucleic acid encoding the inhibitory nucleic acid targeting SHN3, wherein the OC-specific promoter comprising an inflammation inducible NF-kB promoter which is a PB2 promoter.
However, before the effective filing date, Maruyama et al. taught osteoclasts play a critical role in bone resorption, and taught a new member of the tumor necrosis factor (TNF) ligand family, receptor activator of nuclear factor-kB ligand (RANKL) (Introduction). Maruyama et al. taught a critical signaling mechanism triggered by RANKL following ligation of RANK is activation of the inducible transcription factor NF-kB, implicating this pathway as a key regulator of osteoclast differentiation (Introduction). Maruyama et al. taught this central role for NF-kB is further supported by the demonstration that gene-specific deletion of the NF-kB subunits p50 and p52 causes severe osteoporosis through the absences of osteoclasts, and that studies strongly suggest that osteoclast differentiation depends on RANKL-induced NF-kB activity in osteoclast precursors (Introduction).
Abu-Amer also taught that NF-kB signaling mediates RANK ligand-induced osteoclastogenesis and NF-kB activity has been described as the centerpiece of inflammatory responses and is considered a potent mediator of inflammatory osteolysis (Abstract). Abu-Amer taught the transcription factor family, nuclear factor kB (NF-kB), consists of several factors capable of crossing the nuclear membrane, binding to specific promoters and regulating expression of numerous genes involved in normal and pathological functions. The founding members of this family were NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB, and c-Rel (Introduction, first paragraph). Abu-Amer taught prominent activators of NF-kB include receptor activator of NF-kB ligand (RANKL), TNF alpha, lymphotoxin, bacterial endotoxins, Toll-like receptor ligands, CD40L, IL-1 (Introduction, second paragraph).
Abu-Amer taught the role of NF-κB in bone homeostasis was first unintentionally realized following combined deletion of NF-κB1/p50 and NF-κB2/p52 subunits. These mice displayed severe osteopetrosis owing to complete deficiency of osteoclasts. Further analysis of these double knockout mice established that NF-κB1 and NF-κB2 are crucial for osteoclast precursor differentiation into osteoclasts rather than survival, a hallmark of NF-κB activity. It was further established that none of the well-known osteoclastogenic cytokines, including RANKL and TNF, is capable of inducing differentiation of the NF-κB-null precursor cells into osteoclasts. This realization was instrumental to establish new paradigm in osteoclast biology, namely NF-κB is required for osteoclast formation and activity (page 2, third paragraph). Abu-Amer taught NF-κB is considered a central culprit in the pathogenesis of osteolysis in inflammatory diseases, including rheumatoid arthritis, periprosthetic osteolysis, periodontitis, low-grade systemic inflammation, Paget's disease of bone (PDB), and other bacterial infections (page 6, 2nd paragraph).
Regarding claim 8, Glimcher et al. teach nucleic acid molecules including RNA molecules which are homologous to the target gene or genomic sequence, e.g., Shn2, Shn3, or a fragment thereof, “short hairpin” or “small hairpin RNA” (paragraph 0238).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified the SHN3 inhibitory nucleic acid molecule of Glimcher et al. by operably linking an osteoclast-specific promoter, which is an inflammation inducible NF-kB promoter for NF-κB2 (p52), to the SHN3 inhibitory nucleic acid molecule according to the teachings of Maruyama et al. and Abu-Amer with a reasonable expectation of success. There would be a reasonable expectation of success because Glimcher et al. teaches a recombinant expression molecule with regulatory sequence(s) operably linked and that regulatory sequence includes promoters and Glimcher et al. teach that Shn3 regulates osteoclasts and Shn3 associates with RANKL gene regulatory elements (paragraph 0010), and Maruyama et al. taught a critical signaling mechanism triggered by RANKL following ligation of RANK is activation of the inducible transcription factor NF-kB, and Abu-Amer taught NF-κB1 and NF-κB2 are crucial for osteoclast precursor differentiation into osteoclasts. One of ordinary skill in the art would have been motivated to modify the SHN3 inhibitory nucleic acid molecule of Glimcher et al. by operably linking an osteoclast-specific promoter which is an inflammation inducible NF-kB promoter for NF-κB2 (p52), to the SHN3 inhibitory nucleic acid molecule according to the teachings of Maruyama et al. and Abu-Amer, to the SHN3 inhibitory nucleic acid molecule because Maruyama et al. taught a critical signaling mechanism triggered by RANKL following ligation of RANK is activation of the inducible transcription factor NF-kB, implicating this pathway as a key regulator of osteoclast differentiation and taught this central role for NF-kB is further supported by the demonstration that gene-specific deletion of the NF-kB subunits p50 and p52 causes severe osteoporosis through the absences of osteoclasts, and that studies strongly suggest that osteoclast differentiation depends on RANKL-induced NF-kB activity in osteoclast precursors, and because Abu-Amer also taught that that NF-kB signaling mediates RANK ligand-induced osteoclastogenesis and NF-kB activity has been described as the centerpiece of inflammatory responses and is considered a potent mediator of inflammatory osteolysis. One of ordinary skill in the art would have been motivated by the teachings of Abu-Amer that the transcription factor family, nuclear factor kB (NF-kB), consists of several factors capable of crossing the nuclear membrane, binding to specific promoters and that the founding members of this family were NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB, and c-Rel (Introduction, first paragraph). Abu-Amer taught that NF-κB1 and NF-κB2 are crucial for osteoclast precursor differentiation into osteoclasts rather than survival, a hallmark of NF-κB activity, and that NF-κB is required for osteoclast formation and activity, and NF-κB is considered a central culprit in the pathogenesis of osteolysis in inflammatory diseases, including rheumatoid arthritis, periprosthetic osteolysis, periodontitis, low-grade systemic inflammation, Paget's disease of bone (PDB).
Accordingly, the limitations of claims 1,8 and 11 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 2,4 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Glimcher et al. in view of Maruyama et al. and Abu-Amer as applied to claims 1,8 and 11 above, and further in view of Kay et al. (J Gene Med. 2009 July; 11(7):605-614).
The teachings of Glimcher et al., Maruyama et al. and Abu-Amer as applicable to claims 1,8 and 11 are described above.
Additionally, Glimcher et al. teach adeno-associated virus vectors, and that a variety of nucleic acids have been introduced into different cells types using AAV vectors, and has high frequency of stable integration (paragraph 0285).
Glimcher et al., Maruyama et al. and Abu-Amer do not teach wherein the transgene further comprises a nucleic acid encoding a protein, wherein the protein comprises a soluble IL-1 Receptor Antagonist (sIL1Ralpha), or wherein the rAAV comprises an AAV capsid protein.
However, before the effective filing date, Kay et al. taught AAV vectors for infecting lapine articular fibroblasts to determining transduction efficiency, transgene expression levels and nuclear trafficking, wherein the self-complementary AAV contains the cDNA for interleukin (IL)-1 receptor antagonist (Ra) delivered to joints of rabbits and those with IL-1-beta induced arthritis (Abstract). Kay et al. taught AAV has characteristics that may make it more suitable for gene delivery to joint tissues and it can achieve significant levels of cellular transduction after delivery in vivo, and advancements in AAV technology including the capacity to cross-package the vector in alternate capsid serotypes and methods for generating large-scale, high-titer, adenovirus free preparations have brought wider interest to the use of this system, including the use for treating the arthritides (page 2, introduction, third paragraph). Kay et al. taught cDNA for human IL-1Ra was inserted into an scAAV vector and packaged into AAV serotype 2, and results showed lapine articular fibroblasts were amenable to transduction with the scAAV.nIL-1Ra (page 6, second paragraph). Kay et al. taught IL-1Ra is a secreted protein that serves as a competitive inhibitor of IL-1 by binding to available type IL-1 receptors and preventing subsequent interaction with IL-1 ligand and IL-1 receptor accessory protein (page 6, second paragraph). Kay et al. also taught intra-articular injection of the scAAV.IL-1Ra vector (page 6, fifth paragraph). Kay et al. taught after injection of approximately 5 × 1011 particles, sufficient levels of IL-1Ra transgene product were generated to cause a reduction in the leukocytic infiltration in joints inflamed by constitutive IL-1 production (page 8, first paragraph). Kay et al. taught the data obtained in the present study are among the first to report intra-articular transgene expression from an AAV vector in articular tissues on a clinically applicable scale. As shown by the ability of the IL-1Ra expression to alleviate leukocytosis in inflamed joints of the rabbits, the efficiency of scAAV-mediated gene delivery and ensuing expression is sufficient to induce a beneficial biological response in this context (page 8, second paragraph). Kay et al. taught in attempting to improve the efficiency of AAV transduction, the development of methods to cross-package vector genomes in alternate capsid serotypes has dramatically expanded the host cell range of the widely used, AAV serotype 2-based vectors (page 9, first paragraph).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the SHN3 inhibitory nucleic acid molecule of Glimcher et al. operably linked to the OC-specific inflammation inducible NF-kB promoter for NF-κB2 (p52), according to the teachings of Maruyama et al. and Abu-Amer, and include a nucleic acid encoding soluble IL-1 Receptor Antagonist according to the teachings of Kay et al. with a reasonable expectation of success. There would be a reasonable expectation of success, as this would amount to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Kay et al. teach IL-1Ra is a secreted protein that serves as a competitive inhibitor of IL-1 by binding to available type IL-1 receptors and preventing subsequent interaction with IL-1 ligand and IL-1 receptor accessory protein (page 6, second paragraph), and that after injection of approximately 5 × 1011 particles, sufficient levels of IL-1Ra transgene product were generated to cause a reduction in the leukocytic infiltration in joints inflamed by constitutive IL-1 production (page 8, first paragraph), and the ability of the IL-1Ra expression to alleviate leukocytosis in inflamed joints of the rabbits (page 8, second paragraph).
Accordingly, the limitations of claims 2 and 4 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date to provide the SHN3 inhibitory nucleic acid molecule of Glimcher et al. that is operably linked to the OC-specific inflammation inducible NF-kB promoter for NF-κB2 (p52), according to the teachings of Maruyama et al. and Abu-Amer, with an AAV capsid protein to provide a recombinant AAV of Kay et al. with a reasonable expectation of success. There would be a reasonable expectation of success, because Glimcher et al. teaches adeno-associated virus vectors, and that a variety of nucleic acids have been introduced into different cells types using AAV vectors, and has high frequency of stable integration (paragraph 0285), and would amount to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Kay et al. teach AAV has characteristics that may make it more suitable for gene delivery to joint tissues and it can achieve significant levels of cellular transduction after delivery in vivo, and advancements in AAV technology including the capacity to cross-package the vector in alternate capsid serotypes and that the data obtained in the present study are among the first to report intra-articular transgene expression from an AAV vector in articular tissues on a clinically applicable scale (page 8, second paragraph).
Accordingly, the limitations of claim 34 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 9 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Glimcher et al. and Maruyama et al. and Abu-Amer as applied to claims 1,8 and 11 above, and further in view of Calloni et al. (Human Gene Therapy Methods, Vol. 26, No. 5, 2015, pages 162-173).
The teachings of Glimcher et al., Maruyama et al. and Abu-Amer as applicable to claims 1,8 and 11 are described above.
Glimcher et al., Maruyama et al. and Abu-Amer do not teach wherein the inhibitory nucleic acid is an ami-RNA comprising a human miRNA backbone. Glimcher et al. does not teach a second inhibitory nucleic acid targeting SHN3 gene.
Calloni et al. taught gene silencing using synthetic molecules that mimic miRNAs, and that the basic principle of this approach is to replace in the pre-miRNA stem-loop the sequence of the mature miRNA with a sequence targeting the gene of interest, which allows the artificial hairpin to be processed by the same pathway as natural miRNAs (Intro, right column). Calloni et al. taught this technique goes by different denominations in literature including “second generation hairpin”, “shRNA-miR”, “synthetic miRNA”, “miR-shRNA”, “artificial miRNAs” and “shRNAmiR”, but that the article uses “artificial miRNAs” (amiRNAs) as it is the most common nomenclature found in literature (page 162, right column to page 163, left column).
Calloni et al. taught advantages of amiRNAs over traditional silencing approaches include co-expression with a reporter gene, the constructs are generally under control of RNA polymerase II responsive promoters which enables their expression to be regulated using induces or cell-specific promoters, and also several design layouts of possible including that amiRNAs can be placed inside introns, can be co-expressed with a nonmarker gene, and can be grouped to form clusters (page 163, left column). Additionally, amiRNAs are a safer silencing approach, as shRNAs cause side effects to cells including disrupting the endogenous miRNA pathways, impairing miRNA biogenesis and reducing cell viability in vivo and in vitro, and may trigger cellular immune responses (Page 163, left column). Calloni et al. taught amiRNAs are as efficient as shRNAs at silencing genes, but do not affect miRNA processing and do not elicit and interferon response (Page 163, left column).
Calloni et al. taught the miR-26a miRNA has already been identified in human cells and is the first miRNA whose scaffold was applied to induce amiRNA-based gene knockdown, and also the miR-30 family has been documented to exist in humans and the human miR-30a stem-loop is the most widely used scaffold for construction of amiRNA vectors (page 163, right column). Calloni et al. taught variations of the human miR-30 scaffold structures were tested for potential knockdown, and those with major structural similarity to the original miR-30 hairpin were the most effective in silencing and had the highest expression levels (page 164, left column).
Calloni et al. taught using gene silencing to study gene function is the primary application of amiRNAs, but studies applying amiRNAs for use as a potential alternative therapy have also been conducted (page 169, left column).
Calloni et al. taught software for designing amiRNAs is available, AmiRzyn, which analyzes user input of the target DNA sequence to predict possible siRNA sequences, off-target verification is then performed through a BLAST facility, then miRNA backbone and restriction sites can be chosen among five options. The AmiRzyn output includes the amiRNA sequence organized in the 5’-3’ direction a sense restriction site, sense miRNA backbone, sense siRNA, loop, antisense siRNA, antisense miRNA backbone and antisense restriction site (page 170, right column).
Regarding the limitation in claim 16 regarding a second inhibitory nucleic acid targeting SHN3, Calloni et al. taught an miR-30 based polycistronic approach, where amiRNAs are concatenated to improve knockdown of a single target or designed to silence either two or three different mRNAs, and that in the case of a single target, the inclusion of a second amiRNA led to a large increase in small RNA levels and consistent reduction in target protein levels (page 165, right column). Calloni et al. taught the multi-hairpin design can be applied to target two or three different mRNAs and the silencing efficiency can be equal to or higher than that observed for the single-hairpin vectors and the order of the amiRNAs does not seem to affect the silencing rates (page 165, right column).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to replace the inhibitory nucleic acids targeting SHN3 of Glimcher et al. modified with the OC-specific inflammation inducible NF-kB promoter for NF-κB2 (p52), according to the teachings of Maruyama et al. and Abu-Amer, with the amiRNA comprising the human miR-30 backbone of Calloni et al. with a reasonable expectation of success. There would be a reasonable expectation of success because this would amount to simple substitution of one known element for another to obtain predictable results (substitution of inhibitory nucleic acids including antisense, siRNA or shRNA of Glimcher et al. for the inhibitory nucleic acid amiRNA of Calloni et al.). One of ordinary skill in the art would have been motivated to provide an amiRNA targeting SNH3 because Calloni et al. teach advantages of amiRNAs over traditional silencing approaches including that amiRNAs are a safer silencing approach, as shRNAs cause side effects to cells including disrupting the endogenous miRNA pathways, impairing miRNA biogenesis and reducing cell viability in vivo and in vitro, and may trigger cellular immune responses (Page 163, left column), and amiRNAs are as efficient as shRNAs at silencing genes, but do not affect miRNA processing and do not elicit and interferon response (Page 163, left column). An ordinary artisan could design an amiRNA targeting a specific target gene (SHN3) using the software for designing amiRNAs, AmiRzyn, taught by Calloni et al. One of ordinary skill in the art would have been motivated to use a human miRNA backbone because Calloni et al. teach the human miR-30a stem-loop is the most widely used scaffold for construction of amiRNA vectors (page 163, right column) and that human miR-30 scaffold structures with major structural similarity to the original miR-30 hairpin were the most effective in silencing and had the highest expression levels (page 164, left column).
Accordingly, the limitations of claim 9 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the nucleic acid targeting SHN3 of Glimcher et al. modified by the OC-specific inflammation inducible NF-kB promoter for NF-κB2 (p52), according to the teachings of Maruyama et al. and Abu-Amer, and provide a second inhibitory nucleic acid targeting SHN3 based on the teachings of Calloni et al. with a reasonable expectation of success. There would be a reasonable expectation of success as this amounts to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to provide a nucleic acid encoding a first inhibitory nucleic acid targeting SHN3 and a second inhibitory nucleic acid targeting SHN3 in order to increase SHN3 target knockdown as Calloni et al. teach an miR-30 based polycistronic approach, where amiRNAs are concatenated to improve knockdown of a single target or designed to silence either two or three different mRNAs, and that in the case of a single target, the inclusion of a second amiRNA led to a large increase in small RNA levels and consistent reduction in target protein levels (page 165, right column) as well as a multi-hairpin design can be applied to target two or three different mRNAs and the silencing efficiency can be equal to or higher than that observed for the single-hairpin vectors (page 165, right column).
Accordingly, the limitations of claim 16 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Glimcher et al. (US 20130202533, Published 8 Aug 2013) in view of Maruyama et al. (JBMR, Vol. 25, No. 5, May 2010, pp 1058-1067), Abu-Amer (Osteoporos Int 2013 Sept; 24(9), and Calloni et al. (Human Gene Therapy Methods, Vol. 26, No. 5, 2015, pages 162-173).
Regarding claim 17, Glimcher et al. teach a nucleic acid molecule that is antisense to a Shn3 molecule or a Shn3 siRNA (paragraphs 0047-0049,0075), as well as RNA interfering agents include, but are not limited to, nucleic acid molecules including RNA molecules which are homologous to the target gene or genomic sequence, e.g., Shn2, Shn3, or a fragment thereof, “short interfering RNA” (siRNA), “short hairpin” or “small hairpin RNA” (shRNA), and small molecules which interfere with or inhibit expression of a target gene by RNA interference (RNAi) (paragraph 0238). Glimcher et al. teach the nucleic acid molecule that is antisense to Shn3 or Shn3 siRNA may treat a disease, condition or injury associated with osteoclastic bone destruction in calvariae or diaphyseal bone (paragraph 0075), and that inhibition of Shn3 activity is desirable in situations in which Schn3 is abnormally upregulated and/or in which decreased Shn3 activity is likely to have a beneficial effect including osteoporosis, osteomalacia, skeletal changes of hyperparathyroidism and chronic renal failure (renal osteodystrophy) and osteitis deformans (Paget's disease of bone), osteopenia, osteoarthritis and inflammatory arthritis characterized by bone loss or excess bone formation including for example rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis (paragraph 0220). Glimcher et al. teach since inhibition of Shn3 activity is associated with increased bone formation and mineralization, to increase bone formation and mineralization (e.g., osteoblasts or osteoclasts) are contacted with an agent that inhibits Shn3 activity (paragraph 0232).
Glimcher et al. does not teach a second inhibitory nucleic acid targeting SHN3 gene. Glimcher et al. does not teach an osteoclast (OC)-specific promoter operably linked to a nucleic acid encoding the inhibitory nucleic acid targeting SHN3, wherein the OC-specific promoter comprising an inflammation inducible NF-kB promoter which is a PB2 promoter.
However, before the effective filing date, Maruyama et al. taught osteoclasts play a critical role in bone resorption, and taught a new member of the tumor necrosis factor (TNF) ligand family, receptor activator of nuclear factor-kB ligand (RANKL) (Introduction). Maruyama et al. taught a critical signaling mechanism triggered by RANKL following ligation of RANK is activation of the inducible transcription factor NF-kB, implicating this pathway as a key regulator of osteoclast differentiation (Introduction). Maruyama et al. taught this central role for NF-kB is further supported by the demonstration that gene-specific deletion of the NF-kB subunits p50 and p52 causes severe osteoporosis through the absences of osteoclasts, and that studies strongly suggest that osteoclast differentiation depends on RANKL-induced NF-kB activity in osteoclast precursors (Introduction).
Abu-Amer also taught that NF-kB signaling mediates RANK ligand-induced osteoclastogenesis and NF-kB activity has been described as the centerpiece of inflammatory responses and is considered a potent mediator of inflammatory osteolysis (Abstract). Abu-Amer taught the transcription factor family, nuclear factor kB (NF-kB), consists of several factors capable of crossing the nuclear membrane, binding to specific promoters and regulating expression of numerous genes involved in normal and pathological functions. The founding members of this family were NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB, and c-Rel (Introduction, first paragraph). Abu-Amer taught prominent activators of NF-kB include receptor activator of NF-kB ligand (RANKL), TNF alpha, lymphotoxin, bacterial endotoxins, Toll-like receptor ligands, CD40L, IL-1 (Introduction, second paragraph).
Abu-Amer taught the role of NF-κB in bone homeostasis was first unintentionally realized following combined deletion of NF-κB1/p50 and NF-κB2/p52 subunits. These mice displayed severe osteopetrosis owing to complete deficiency of osteoclasts. Further analysis of these double knockout mice established that NF-κB1 and NF-κB2 are crucial for osteoclast precursor differentiation into osteoclasts rather than survival, a hallmark of NF-κB activity. It was further established that none of the well-known osteoclastogenic cytokines, including RANKL and TNF, is capable of inducing differentiation of the NF-κB-null precursor cells into osteoclasts. This realization was instrumental to establish new paradigm in osteoclast biology, namely NF-κB is required for osteoclast formation and activity (page 2, third paragraph). Abu-Amer taught NF-κB is considered a central culprit in the pathogenesis of osteolysis in inflammatory diseases, including rheumatoid arthritis, periprosthetic osteolysis, periodontitis, low-grade systemic inflammation, Paget's disease of bone (PDB), and other bacterial infections (page 6, 2nd paragraph).
Calloni et al. taught gene silencing using synthetic molecules that mimic miRNAs, and that the basic principle of this approach is to replace in the pre-miRNA stem-loop the sequence of the mature miRNA with a sequence targeting the gene of interest, which allows the artificial hairpin to be processed by the same pathway as natural miRNAs (Intro, right column). Calloni et al. taught this technique goes by different denominations in literature including “second generation hairpin”, “shRNA-miR”, “synthetic miRNA”, “miR-shRNA”, “artificial miRNAs” and “shRNAmiR”, but that the article uses “artificial miRNAs” (amiRNAs) as it is the most common nomenclature found in literature (page 162, right column to page 163, left column).
Calloni et al. taught advantages of amiRNAs over traditional silencing approaches include co-expression with a reporter gene, the constructs are generally under control of RNA polymerase II responsive promoters which enables their expression to be regulated using induces or cell-specific promoters, and also several design layouts of possible including that amiRNAs can be placed inside introns, can be co-expressed with a nonmarker gene, and can be grouped to form clusters (page 163, left column). Additionally, amiRNAs are a safer silencing approach, as shRNAs cause side effects to cells including disrupting the endogenous miRNA pathways, impairing miRNA biogenesis and reducing cell viability in vivo and in vitro, and may trigger cellular immune responses (Page 163, left column). Calloni et al. taught amiRNAs are as efficient as shRNAs at silencing genes, but do not affect miRNA processing and do not elicit and interferon response (Page 163, left column).
Calloni et al. taught using gene silencing to study gene function is the primary application of amiRNAs, but studies applying amiRNAs for use as a potential alternative therapy have also been conducted (page 169, left column).
Calloni et al. taught software for designing amiRNAs is available, AmiRzyn, which analyzes user input of the target DNA sequence to predict possible siRNA sequences, off-target verification is then performed through a BLAST facility, then miRNA backbone and restriction sites can be chosen among five options. The AmiRzyn output includes the amiRNA sequence organized in the 5’-3’ direction a sense restriction site, sense miRNA backbone, sense siRNA, loop, antisense siRNA, antisense miRNA backbone and antisense restriction site (page 170, right column).
Regarding the limitation of a second inhibitory nucleic acid targeting SHN3, Calloni et al. taught an miR-30 based polycistronic approach, where amiRNAs are concatenated to improve knockdown of a single target or designed to silence either two or three different mRNAs, and that in the case of a single target, the inclusion of a second amiRNA led to a large increase in small RNA levels and consistent reduction in target protein levels (page 165, right column). Calloni et al. taught the multi-hairpin design can be applied to target two or three different mRNAs and the silencing efficiency can be equal to or higher than that observed for the single-hairpin vectors and the order of the amiRNAs does not seem to affect the silencing rates (page 165, right column).
It would have been obvious to one of ordinary skill in the art, to modify the nucleic acid targeting SHN3 of Glimcher et al. by operably linking an inflammation inducible NF-kB promoter for NF-κB2 (p52), to the SHN3 inhibitory nucleic acid molecule according to the teachings of Maruyama et al. and Abu-Amer and provide a second inhibitory nucleic acid targeting SHN3 based on the teachings of Calloni et al. with a reasonable expectation of success. There would be a reasonable expectation of success as this amounts to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to modify the SHN3 inhibitory nucleic acid molecule of Glimcher et al. by operably linking an osteoclast-specific promoter which is an inflammation inducible NF-kB promoter for NF-κB2 (p52), to the SHN3 inhibitory nucleic acid molecule according to the teachings of Maruyama et al. and Abu-Amer, to the SHN3 inhibitory nucleic acid molecule because Maruyama et al. taught a critical signaling mechanism triggered by RANKL following ligation of RANK is activation of the inducible transcription factor NF-kB, implicating this pathway as a key regulator of osteoclast differentiation and taught this central role for NF-kB is further supported by the demonstration that gene-specific deletion of the NF-kB subunits p50 and p52 causes severe osteoporosis through the absences of osteoclasts, and that studies strongly suggest that osteoclast differentiation depends on RANKL-induced NF-kB activity in osteoclast precursors, and because Abu-Amer also taught that that NF-kB signaling mediates RANK ligand-induced osteoclastogenesis and NF-kB activity has been described as the centerpiece of inflammatory responses and is considered a potent mediator of inflammatory osteolysis. One of ordinary skill in the art would have been motivated by the teachings of Abu-Amer that the transcription factor family, nuclear factor kB (NF-kB), consists of several factors capable of crossing the nuclear membrane, binding to specific promoters and that the founding members of this family were NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB, and c-Rel (Introduction, first paragraph). Abu-Amer taught that NF-κB1 and NF-κB2 are crucial for osteoclast precursor differentiation into osteoclasts rather than survival, a hallmark of NF-κB activity, and that NF-κB is required for osteoclast formation and activity, and NF-κB is considered a central culprit in the pathogenesis of osteolysis in inflammatory diseases, including rheumatoid arthritis, periprosthetic osteolysis, periodontitis, low-grade systemic inflammation, Paget's disease of bone (PDB).
One of ordinary skill in the art would have been motivated to provide a nucleic acid encoding a first inhibitory nucleic acid targeting SHN3 and a second inhibitory nucleic acid targeting SHN3 in order to increase SHN3 target knockdown. An ordinary artisan could design an amiRNA targeting a specific target gene (SHN3) using the software for designing amiRNAs, AmiRzyn, taught by Calloni et al. (page 170, right column). Calloni et al. teach an miR-30 based polycistronic approach, where amiRNAs are concatenated to improve knockdown of a single target or designed to silence either two or three different mRNAs, and that in the case of a single target, the inclusion of a second amiRNA led to a large increase in small RNA levels and consistent reduction in target protein levels (page 165, right column) as well as a multi-hairpin design can be applied to target two or three different mRNAs and the silencing efficiency can be equal to or higher than that observed for the single-hairpin vectors (page 165, right column).
Accordingly, the limitations of claim 17 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
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).
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Claims 1,8,9,11 and 34 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12,194,108, (‘108) Issued 14 Jan 2025, in view of in view of Maruyama et al. (JBMR, Vol. 25, No. 5, May 2010, pp 1058-1067) and Abu-Amer (Osteoporos Int 2013 Sept; 24(9).
Instant claims 1 and 11 recite an isolated nucleic acid comprising a transgene encoding an osteoclast specific promoter or an osteoblast specific promoter operably linked to a nucleic acid sequence encoding one or more inhibitory nucleic acids targeting schnurri-3 (SHN3), wherein the OC-specific promoter comprises an inflammation inducible promoter which is a PB2 promoter. Instant claim 8 recites the inhibitory nucleic acid is shRNA, miRNA or artificial miRNA. Instant claim 9 recites wherein the ami-RNA comprises a human miRNA backbone, optionally a human miR-33 backbone. Instant claim 34 recites a recombinant adeno-associated virus comprising the isolated nucleic acid of claim 1 and at least one AAV capsid protein.
Claims 1,3-6 and 10 of ‘108 recite an isolated nucleic acid encoding a first region comprising a first AAV ITR or variant thereof, and a second region comprising a transgene encoding at least one bone metabolism modulating agent, wherein the transgene comprises the sequence set forth in any one of SEQ ID NOs: 1-15 and 55-56. SEQ ID NOs: 1-3 of ‘108 are amiR-33mSHN3 (column 54), which are species of the inhibitory nucleic acid targeting SHN3 of instant claims. Claim 2 recites further comprising at least one promoter that is operably linked to the transgene. Claims 7-9 recite an isolated nucleic acid encoding a second region comprising a transgene encoding at least one bone formation promoting agent which is an inhibitory nucleic acid targeting schnurri-3 (SHN3). Claims 6-9 recite an rAAV comprising a capsid protein and an isolated nucleic acid of claim 1 or an isolated nucleic acid comprising a transgene encoding at least one bone formation promoting agent which is an inhibitory nucleic acid targeting schnurri-3 (SHN3).
‘108 does not teach wherein the promoter is an osteoclast specific promoter, specifically wherein it is an inflammation-inducible NF-kB promoter which is a PB2 promoter.
The teachings of Maruyama et al. and Abu-Amer have been described above in the 103 rejection.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified the isolated inhibitory nucleic acid targeting SHN3 of ‘108 by operably linking an osteoclast-specific promoter, which is an inflammation inducible NF-kB promoter which is a PB2 promoter to the SHN3 inhibitory nucleic acid molecule (amiR-33mSHN3) according to the teachings of Maruyama et al. and Abu-Amer with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the SHN3 inhibitory nucleic acid molecule of ‘108 by operably linking an inflammation inducible NF-kB promoter which is a PB2 promoter, to the SHN3 inhibitory nucleic acid molecule because Maruyama et al. taught a critical signaling mechanism triggered by RANKL following ligation of RANK is activation of the inducible transcription factor NF-kB, implicating this pathway as a key regulator of osteoclast differentiation and taught this central role for NF-kB is further supported by the demonstration that gene-specific deletion of the NF-kB subunits p50 and p52 causes severe osteoporosis through the absences of osteoclasts, and that studies strongly suggest that osteoclast differentiation depends on RANKL-induced NF-kB activity in osteoclast precursors, and because Abu-Amer also taught that that NF-kB signaling mediates RANK ligand-induced osteoclastogenesis and NF-kB activity has been described as the centerpiece of inflammatory responses and is considered a potent mediator of inflammatory osteolysis. One of ordinary skill in the art would have been motivated by the teachings of Abu-Amer that the transcription factor family, nuclear factor kB (NF-kB), consists of several factors capable of crossing the nuclear membrane, binding to specific promoters and that the founding members of this family were NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB, and c-Rel (Introduction, first paragraph). Abu-Amer taught that NF-κB1 and NF-κB2 are crucial for osteoclast precursor differentiation into osteoclasts rather than survival, a hallmark of NF-κB activity, and that NF-κB is required for osteoclast formation and activity, and NF-κB is considered a central culprit in the pathogenesis of osteolysis in inflammatory diseases, including rheumatoid arthritis, periprosthetic osteolysis, periodontitis, low-grade systemic inflammation, Paget's disease of bone (PDB).
Accordingly, the limitations of claims 1,8,9,11 and 34 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 2 and 4 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12,194,108, (‘108) Issued 14 Jan 2025, in view of Maruyama et al. and Abu-Amer as applied to claims 1,8,9,11 and 34 above and further in view of Kay et al. (J Gene Med. 2009 July; 11(7):605-614).
The teachings of ‘108, Maruyama et al. and Abu-Amer as applicable to claims 1,8,9,11 and 34 are described above.
‘108, Maruyama et al. and Abu-Amer do not teach wherein the transgene further comprises a nucleic acid encoding a protein, wherein the protein comprises a soluble IL-1 Receptor Antagonist (sIL1Ralpha).
However, Kay et al. cures these deficiencies. The teachings of Maruyama et al., Abu-Amer and Kay et al. is described above in the 103 rejections.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the SHN3 inhibitory nucleic acid molecule of ‘108 operably linked to the OC-specific inflammation inducible NF-kB promoter for NF-κB2 (p52) as taught by Maruyama et al., Abu-Amer and include a nucleic acid encoding soluble IL-1 Receptor Antagonist according to the teachings of Kay et al. with a reasonable expectation of success. There would be a reasonable expectation of success, as this would amount to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Kay et al. teach IL-1Ra is a secreted protein that serves as a competitive inhibitor of IL-1 by binding to available type IL-1 receptors and preventing subsequent interaction with IL-1 ligand and IL-1 receptor accessory protein (page 6, second paragraph), and that after injection of approximately 5 × 1011 particles, sufficient levels of IL-1Ra transgene product were generated to cause a reduction in the leukocytic infiltration in joints inflamed by constitutive IL-1 production (page 8, first paragraph), and the ability of the IL-1Ra expression to alleviate leukocytosis in inflamed joints of the rabbits (page 8, second paragraph).
Accordingly, the limitations of claims 2 and 4 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 16 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12,194,108, (‘108) Issued 14 Jan 2025, in view of Maruyama et al. and Abu-Amer as applied to claims 1,8,9,11 and 34 above and further in view of Calloni et al. (Human Gene Therapy Methods, Vol. 26, No. 5, 2015, pages 162-173).
The teachings of ‘108, Maruyama et al. and Abu-Amer as applicable to claims 1,8,9,11 and 34 are described above.
‘108, Maruyama et al. and Abu-Amer do not teach a second inhibitory nucleic acid targeting the SHN3 gene.
Calloni et al. cures these deficiencies. The teachings of Calloni et al. is described above in the 103 rejections.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to combine the nucleic acid targeting SHN3 of ‘108 modified by the OC-specific inflammation inducible NF-kB promoter for NF-κB2 (p52) as taught by Maruyama et al., Abu-Amer with a second inhibitory nucleic acid targeting SHN3 based on the teachings of Calloni et al. with a reasonable expectation of success. There would be a reasonable expectation of success as this amounts to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so as Calloni et al. teach an miR-30 based polycistronic approach, where amiRNAs are concatenated to improve knockdown of a single target or designed to silence either two or three different mRNAs, and that in the case of a single target, the inclusion of a second amiRNA led to a large increase in small RNA levels and consistent reduction in target protein levels (page 165, right column) as well as a multi-hairpin design can be applied to target two or three different mRNAs and the silencing efficiency can be equal to or higher than that observed for the single-hairpin vectors (page 165, right column).
Accordingly, the limitations of claim 16 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 17 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12,194,108, (‘108) Issued 14 Jan 2025, in view of Maruyama et al., Abu-Amer and Calloni et al. (Human Gene Therapy Methods, Vol. 26, No. 5, 2015, pages 162-173).
Instant claim 17 recites an isolated nucleic acid comprising a transgene encoding a first inhibitory nucleic acid targeting an SHN3 gene and a second inhibitory nucleic acid targeting an SHN3 gene, wherein the transgene further comprises a promoter operably linked to the first or second inhibitory nucleic acid, wherein the promoter is an inflammation-inducible promoter, comprising a PB2 promoter.
Claims 1-6 and 10 of ‘108 recite an isolated nucleic acid encoding a second region comprising a transgene encoding at least one bone metabolism modulating agent, wherein the transgene comprises the sequence set forth in any one of SEQ ID NOs: 1-15 and 55-56. SEQ ID NOs: 1-3 of ‘108 are amiR-33mSHN3 (column 54), which are species of the instant claim. Claims 7-9 recite an isolated nucleic acid encoding a second region comprising a transgene encoding at least one bone formation promoting agent which is an inhibitory nucleic acid targeting schnurri-3 (SHN3).
‘108 does not teach a second inhibitory nucleic acid targeting SHN3 gene, or wherein the transgene further comprises a promoter operably linked to the first or second inhibitory nucleic acid, wherein the promoter is an inflammation-inducible promoter, comprising a PB2 promoter.
The teachings of Maruyama et al., Abu-Amer and Calloni et al. have been described above in the 103 rejections.
It would have been obvious to one of ordinary skill in the art, to combine the nucleic acid targeting SHN3 of ‘108 with a second inhibitory nucleic acid targeting SHN3 based on the teachings of Calloni et al., and to provide a promoter operably linked to the first or second inhibitory nucleic acid, which promoter is a PB2 promoter according to the teachings of Maruyama et al. and Abu-Amer with a reasonable expectation of success. There would be a reasonable expectation of success as this amounts to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so in order to increase SHN3 target knockdown, and because Maruyama et al. taught a critical signaling mechanism triggered by RANKL following ligation of RANK is activation of the inducible transcription factor NF-kB, implicating this pathway as a key regulator of osteoclast differentiation and taught this central role for NF-kB is further supported by the demonstration that gene-specific deletion of the NF-kB subunits p50 and p52 causes severe osteoporosis through the absences of osteoclasts, and that studies strongly suggest that osteoclast differentiation depends on RANKL-induced NF-kB activity in osteoclast precursors, and because Abu-Amer also taught that that NF-kB signaling mediates RANK ligand-induced osteoclastogenesis and NF-kB activity has been described as the centerpiece of inflammatory responses and is considered a potent mediator of inflammatory osteolysis. One of ordinary skill in the art would have been motivated by the teachings of Abu-Amer that the transcription factor family, nuclear factor kB (NF-kB), consists of several factors capable of crossing the nuclear membrane, binding to specific promoters and that the founding members of this family were NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB, and c-Rel (Introduction, first paragraph). Abu-Amer taught that NF-κB1 and NF-κB2 are crucial for osteoclast precursor differentiation into osteoclasts rather than survival, a hallmark of NF-κB activity, and that NF-κB is required for osteoclast formation and activity, and NF-κB is considered a central culprit in the pathogenesis of osteolysis in inflammatory diseases, including rheumatoid arthritis, periprosthetic osteolysis, periodontitis, low-grade systemic inflammation, Paget's disease of bone (PDB). An ordinary artisan could design an amiRNA targeting a specific target gene (SHN3) using the software for designing amiRNAs, AmiRzyn, taught by Calloni et al. (page 170, right column). Calloni et al. teach an miR-30 based polycistronic approach, where amiRNAs are concatenated to improve knockdown of a single target or designed to silence either two or three different mRNAs, and that in the case of a single target, the inclusion of a second amiRNA led to a large increase in small RNA levels and consistent reduction in target protein levels (page 165, right column) as well as a multi-hairpin design can be applied to target two or three different mRNAs and the silencing efficiency can be equal to or higher than that observed for the single-hairpin vectors (page 165, right column).
Accordingly, the limitations of claim 17 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 1,8,9,11 and 34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 17-22 of copending Application No. 18/967,535 (‘535) (reference application) or claims 8-12 and 14-16 of copending Application No. 18/707,207 (‘207) in view of Maruyama et al. and Abu-Amer (cited above).
Instant claims 1 and 11 recite an isolated nucleic acid comprising a transgene encoding an osteoclast specific promoter or an osteoblast specific promoter operably linked to a nucleic acid sequence encoding one or more inhibitory nucleic acids targeting schnurri-3 (SHN3), wherein the OC-specific promoter comprises an inflammation inducible promoter which is a PB2 promoter. Instant claim 8 recites the inhibitory nucleic acid is shRNA, miRNA or artificial miRNA. Instant claim 9 recites wherein the ami-RNA comprises a human miRNA backbone, optionally a human miR-33 backbone. Instant claim 34 recites a recombinant adeno-associated virus comprising the isolated nucleic acid of claim 1 and at least one AAV capsid protein.
Claim 1 of ‘535 recites an isolated nucleic acid encoding a first region comprising a first AAV ITR or variant thereof, and a second region comprising a transgene encoding at least one bone metabolism modulating agent. Claims 2-3 of ‘535 recite the bone metabolism modulating agent is an inhibitory nucleic acid that inhibits osteoclast or osteoblast activity or expression, and claims 4-5 recite the transgene encodes an inhibitory nucleic acid targeting schnurri-3 (SHN3). Claims 6-7 of ‘535 recite the inhibitory nucleic acid is dsRNA, siRNA, shRNA, miRNA and amiRNA. Claims 17-22 of ‘535 recite an rAAV comprising a capsid protein and an isolated nucleic acid of claim 1.
Claims 8,12 and 14-16 of ‘207 recite an isolated nucleic acid comprising a transgene comprising a chicken B-actin promoter operably linked to an inhibitory nucleic acid targeting schnurri-3; claim 9 recites the inhibitory nucleic acid is selected from dsRNA, siRNA, shRNA, miRNA and amiRNA; claim 10 recites the inhibitory nucleic acid is amiRNA comprising a human miRNA backbone, optionally a human miR-33 backbone.
‘535 and ‘207 do not teach wherein the promoter is an osteoclast specific promoter, specifically wherein it is an inflammation-inducible NF-kB promoter which is a PB2 promoter.
The teachings of Maruyama et al. and Abu-Amer have been described above in the 103 rejection.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified the isolated inhibitory nucleic acid targeting SHN3 of ‘535 or ‘207 by operably linking an osteoclast-specific promoter, which is an inflammation inducible NF-kB promoter which is a PB2 promoter to the SHN3 inhibitory nucleic acid molecule according to the teachings of Maruyama et al. and Abu-Amer with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to do so because Maruyama et al. taught a critical signaling mechanism triggered by RANKL following ligation of RANK is activation of the inducible transcription factor NF-kB, implicating this pathway as a key regulator of osteoclast differentiation and taught this central role for NF-kB is further supported by the demonstration that gene-specific deletion of the NF-kB subunits p50 and p52 causes severe osteoporosis through the absences of osteoclasts, and that studies strongly suggest that osteoclast differentiation depends on RANKL-induced NF-kB activity in osteoclast precursors, and because Abu-Amer also taught that that NF-kB signaling mediates RANK ligand-induced osteoclastogenesis and NF-kB activity has been described as the centerpiece of inflammatory responses and is considered a potent mediator of inflammatory osteolysis. One of ordinary skill in the art would have been motivated by the teachings of Abu-Amer that the transcription factor family, nuclear factor kB (NF-kB), consists of several factors capable of crossing the nuclear membrane, binding to specific promoters and that the founding members of this family were NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB, and c-Rel (Introduction, first paragraph). Abu-Amer taught that NF-κB1 and NF-κB2 are crucial for osteoclast precursor differentiation into osteoclasts rather than survival, a hallmark of NF-κB activity, and that NF-κB is required for osteoclast formation and activity, and NF-κB is considered a central culprit in the pathogenesis of osteolysis in inflammatory diseases, including rheumatoid arthritis, periprosthetic osteolysis, periodontitis, low-grade systemic inflammation, Paget's disease of bone (PDB).
Accordingly, the limitations of claims 1,8,9,11 and 34 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 2 and 4 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 17-22 of copending Application No. 18/967,535 (‘535) (reference application) or claims 8-12 and 14-16 of copending Application No. 18/707,207 (‘207) in view of Maruyama et al. and Abu-Amer as applied to claims 1,8,9,11 and 34 above and further in view of Kay et al. (J Gene Med. 2009 July; 11(7):605-614).
The teachings of ‘535, ‘207, Maruyama et al. and Abu-Amer as applicable to claims 1,8,9,11 and 34 are described above.
‘535, ‘207, Maruyama et al. and Abu-Amer do not teach wherein the transgene further comprises a nucleic acid encoding a protein, wherein the protein comprises a soluble IL-1 Receptor Antagonist (sIL1Ralpha).
However, Kay et al. cures these deficiencies. The teachings of Kay et al. is described above in the 103 rejections.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the SHN3 inhibitory nucleic acid molecule of ‘535 or ‘207 operably linked to the OC-specific inflammation inducible NF-kB promoter for NF-κB2 (p52) as taught by Maruyama et al., Abu-Amer, and include a nucleic acid encoding soluble IL-1 Receptor Antagonist according to the teachings of Kay et al. with a reasonable expectation of success. There would be a reasonable expectation of success, as this would amount to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Kay et al. teach IL-1Ra is a secreted protein that serves as a competitive inhibitor of IL-1 by binding to available type IL-1 receptors and preventing subsequent interaction with IL-1 ligand and IL-1 receptor accessory protein (page 6, second paragraph), and that after injection of approximately 5 × 1011 particles, sufficient levels of IL-1Ra transgene product were generated to cause a reduction in the leukocytic infiltration in joints inflamed by constitutive IL-1 production (page 8, first paragraph), and the ability of the IL-1Ra expression to alleviate leukocytosis in inflamed joints of the rabbits (page 8, second paragraph).
Accordingly, the limitations of claims 2 and 4 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 16 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 17-22 of copending Application No. 18/967,535 (‘535) (reference application) or claims 8-12 and 14-16 of copending Application No. 18/707,207 (‘207) in view of Maruyama et al. and Abu-Amer as applied to claims 1,8,9,11 and 34 above and further in view of Calloni et al. (Human Gene Therapy Methods, Vol. 26, No. 5, 2015, pages 162-173).
The teachings of ‘535, ‘207 and Huizinga et al. as applicable to claims 1,5,8,9,11 and 34 are described above.
‘535, ‘207 and Huizinga et al. do not teach a second inhibitory nucleic acid targeting the SHN3 gene.
Calloni et al. cures these deficiencies. The teachings of Calloni et al. is described above in the 103 rejections.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to combine the nucleic acid targeting SHN3 of ‘535 or ‘207 modified by the OC-specific inflammation inducible NF-kB promoter for NF-κB2 (p52) as taught by Maruyama et al., Abu-Amer, with a second inhibitory nucleic acid targeting SHN3 based on the teachings of Calloni et al. with a reasonable expectation of success. There would be a reasonable expectation of success as this amounts to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Calloni et al. teach an miR-30 based polycistronic approach, where amiRNAs are concatenated to improve knockdown of a single target or designed to silence either two or three different mRNAs, and that in the case of a single target, the inclusion of a second amiRNA led to a large increase in small RNA levels and consistent reduction in target protein levels (page 165, right column) as well as a multi-hairpin design can be applied to target two or three different mRNAs and the silencing efficiency can be equal to or higher than that observed for the single-hairpin vectors (page 165, right column).
Accordingly, the limitations of claim 16 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 17 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 17-22 of copending Application No. 18/967,535 (‘535) (reference application) or claims 8-12 and 14-16 of copending Application No. 18/707,207 (‘207) in view of Maruyama et al., Abu-Amer and Calloni et al. (Human Gene Therapy Methods, Vol. 26, No. 5, 2015, pages 162-173).
Instant claim 17 recites an isolated nucleic acid comprising a transgene encoding a first inhibitory nucleic acid targeting an SHN3 gene and a second inhibitory nucleic acid targeting an SHN3 gene, wherein the transgene further comprises a promoter operably linked to the first or second inhibitory nucleic acid, wherein the promoter is an inflammation-inducible promoter, comprising a PB2 promoter.
‘535 and ‘207 have been described above.
‘535 and ‘207 do not teach a second inhibitory nucleic acid targeting SHN3 gene, or wherein the transgene further comprises a promoter operably linked to the first or second inhibitory nucleic acid, wherein the promoter is an inflammation-inducible promoter, comprising a PB2 promoter.
The teachings of Maruyama et al., Abu-Amer and Calloni et al. have been described above in the 103 rejections.
It would have been obvious to one of ordinary skill in the art, to combine the nucleic acid targeting SHN3 of ‘535 or ‘207 with a second inhibitory nucleic acid targeting SHN3 based on the teachings of Calloni et al. and to provide a promoter operably linked to the first or second inhibitory nucleic acid, which promoter is a PB2 promoter according to the teachings of Maruyama et al. and Abu-Amer with a reasonable expectation of success. There would be a reasonable expectation of success as this amounts to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so in order to increase SHN3 target knockdown, and because Maruyama et al. taught a critical signaling mechanism triggered by RANKL following ligation of RANK is activation of the inducible transcription factor NF-kB, implicating this pathway as a key regulator of osteoclast differentiation and taught this central role for NF-kB is further supported by the demonstration that gene-specific deletion of the NF-kB subunits p50 and p52 causes severe osteoporosis through the absences of osteoclasts, and that studies strongly suggest that osteoclast differentiation depends on RANKL-induced NF-kB activity in osteoclast precursors, and because Abu-Amer also taught that that NF-kB signaling mediates RANK ligand-induced osteoclastogenesis and NF-kB activity has been described as the centerpiece of inflammatory responses and is considered a potent mediator of inflammatory osteolysis. One of ordinary skill in the art would have been motivated by the teachings of Abu-Amer that the transcription factor family, nuclear factor kB (NF-kB), consists of several factors capable of crossing the nuclear membrane, binding to specific promoters and that the founding members of this family were NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB, and c-Rel (Introduction, first paragraph). Abu-Amer taught that NF-κB1 and NF-κB2 are crucial for osteoclast precursor differentiation into osteoclasts rather than survival, a hallmark of NF-κB activity, and that NF-κB is required for osteoclast formation and activity, and NF-κB is considered a central culprit in the pathogenesis of osteolysis in inflammatory diseases, including rheumatoid arthritis, periprosthetic osteolysis, periodontitis, low-grade systemic inflammation, Paget's disease of bone (PDB).
An ordinary artisan could design an amiRNA targeting a specific target gene (SHN3) using the software for designing amiRNAs, AmiRzyn, taught by Calloni et al. (page 170, right column). Calloni et al. teach an miR-30 based polycistronic approach, where amiRNAs are concatenated to improve knockdown of a single target or designed to silence either two or three different mRNAs, and that in the case of a single target, the inclusion of a second amiRNA led to a large increase in small RNA levels and consistent reduction in target protein levels (page 165, right column) as well as a multi-hairpin design can be applied to target two or three different mRNAs and the silencing efficiency can be equal to or higher than that observed for the single-hairpin vectors (page 165, right column).
Accordingly, the limitations of claim 17 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1,2,4,8,9,11,16,17,30 and 34 are rejected.
As previously indicated, SEQ ID NOs: 3 and 9 are free of the prior art.
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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/STEPHANIE L SULLIVAN/ Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636