FINAL 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 .
Status of Claims
Claims 2-3, 5, 11-12, 14, 17, 22, 24-25 and 32 are cancelled.
Claims 1, 4, 6-10, 13, 15-16, 18, 20-21, 23, 26-31 and 33-34 are presented for examination herein.
Rejections Maintained
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, 6, 8-10, 15, 16, 18, 20, 21, 23, 26-31 and 33-34 are rejected under 35 U.S.C. 103 as being obvious over Lu et al. (US20130225655, published 09 May 2017), hereinafter Lu; in view of Anderson et al. (WO2017193084, published 09 November 2017), hereinafter Anderson; and VAN DE WATER et al. (US 2010/0292300 A1), hereafter Van De Water.
Lu is primarily directed towards compositions and method for treatment of including skin scaring (abstract).
Regarding claims 1, 15-16, 18, 20, 21, 23, and 26-30, Lu discloses "using combinations of TGFβ1 and Cox-2 inhibitors and TGFβ1 and Hoxb13 inhibitors for the treatment of various medical conditions, including skin scaring due to trauma wounds and surgery" (Abstract), and that "[p]referably, the carrier is suitable for topical administration" (Paragraph [0048]). The siRNA molecules (Claim 1) used to inhibit TGFβ1 expression are disclosed to be oligonucleotides (Paragraph [0040]). Lu discloses that "mRNA expression of TGFβ1 was reduced by 30% and 50%" (Paragraph [0107]). Lu discloses that “decreased and rapidly cleared TGFβ1 and TGFβ2 expression accompanied by increased and prolonged TGFβ3 levels in wounded E16 animals correlated with organized collagen deposition” (Paragraph [0005]). As such, it is known that topical administration of an oligonucleotide-comprising composition can affect TGFβ1 expression and scar formation. Lu teaches nanoparticle containing siRNA as an appropriate carrier (paragraph 48 and examples 4 and 5).
Lu does not disclose a spherical nucleic acid. Lu does not specifically teach administering to hypertrophic scar or a keloid scar. The deficiencies are made up for by the teachings of Anderson and Van De Water.
Regarding claim 31, Lu discloses an inhibitor of ALK5 (TGFβ type I receptor, TGF-βRI) (Example 5, paragraph [0118]). Anderson discloses antibodies (the checkpoint inhibitor may be "a monoclonal antibody, a humanized antibody, [or] a fully human antibody,” Claim 10). Because Lu discloses that TGFβ type I receptor inhibitors are useful for treating scars, and Lu discloses the use of antibodies with SNA delivery vehicles.
Anderson is primarily directed towards immuno stimulatory spherical nucleic acid (IS-SNA) for delivering immunostimulatory oligonucleotides (paragraph bridging pages 1 and 2).
Regarding claims 1, 4, 6-10, 18, 20, 23, 27-30 Anderson discloses an "immuno stimulatory spherical nucleic acid (IS-SNA), comprising a core having an oligonucleotide shell comprised of immuno stimulatory oligonucleotides positioned on the exterior of the core" (Claim 1). Anderson also discloses that “[the claimed SNA] structures exhibit the ability to enter cells without the need for auxiliary delivery vehicles or transfection reagents, by engaging scavenger receptors and lipid rafts” (page 12). Anderson discloses that the core of the SNA may be a liposomal core (Claim 5), and that the core may comprise sterols such as cholesterol (Claim 6). Anderson discloses that the core of the SNA may be a polymer (Claim 57), such as "amphiphilic block copolymers, hydrophobic polymers including polystyrene, poly(lactic acid), poly(lactic co-glycolic acid), poly(glycolic acid), poly(caprolactone) and other biocompatible polymers" (Claim 58). Anderson discloses that the SNA may comprise a “solid core comprised of noble metals, including gold and silver, transition metals including iron and cobalt, metal oxides” (Claim 3). Anderson discloses that the oligonucleotides may be antisense oligonucleotides or siRNA (page 37). Because Anderson provides for DNA (DNA synthesis and purification, page 49), it is construed to provide for antisense DNA. Anderson discloses that the liposomal cores were synthesizes via extrusion polycarbonate membranes with 50 nm pores (Liposome synthesis, page 32). As such, the liposomes are construed to have a diameter of 50 nm or less. Anderson discloses that the oligonucleotide shell has a density of 500-1000 oligonucleotides per SNA (Claim 72). Anderson discloses that the SNA may comprise a checkpoint inhibitor (Claim 1), that the checkpoint inhibitor may be "a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein or a combination thereof or a small molecule" (Claim 10), and that the checkpoint inhibitor may be incorporated into the liposomal core (Claim 9). Anderson discloses that the more may be polymeric (Claims 4 and 5), that the "solid core preferably is surrounded by a lipid bilayer" (page 23), and that the checkpoint inhibitor may be incorporated into the liposomal core" (Claim 9). Anderson teaches steroids (page 23, lines 3-5). As such, Anderson is construed to provide for a core that comprises a liposomal shell, a solid polymeric core (nanoparticle), and a checkpoint inhibitor within the liposome. Because the checkpoint inhibitor is unlikely to be incorporated within the polymeric core, it is construed to be conjugated to the surface to the nanoparticle.
Van De Water is primarily directed towards compositions and methods for inhibiting or reversing fibrotic disorders (abstract).
Regarding claim 1, Van De Water teaches it has been shown that TGFβ1 is the major cytokine responsible for the onset of fibrotic disorders including keloids and hypertrophic scars (paragraph [0005]).
One of ordinary skill in the art at the time of instant filing would be motivated to combine the teachings of Lu, Anderson and Van De Water, as Lu teaches topical oligonucleotide nanoparticle formulations for the treatments of scars/scarring, Anderson teaches an enhanced delivery nanoparticle vehicle for oligonucleotides and Van De Water teaches inhibiting or reversing fibrotic disorders which includes keloid and hypertrophic scars which TGFβ1 has been shown to be a major cytokine responsible for the onset of fibrotic disorders including keloid and hypertrophic scars. Such a combination would result in a method of treating scars including keloid and hypertrophic scars, wherein the oligonucleotide actives of Lu are better able to penetrate cells, and are therefore more effective delivery and effectiveness.
Regarding the recitation “reduces elevation of the abnormal scar relative to elevation of an abnormal scar in a subject that was not administered the SNA” (e.g., claim 1) and claims 33-34, it light of the disclosure of Lu and the teachings of Anderson, it would have been prima facie obvious for one of ordinary skill in the art at the time of instant filing to treat including skin scaring due to trauma wounds and surgery by administering topically a composition comprising SNA comprising nanoparticle core and siRNA (e.g., oligonucleotide) that silences TGFβ1 expression, wherein the siRNA that silences TGFβ1 expression are positioned on the exterior of the nanoparticle core (described above). Thus, the method, which is prima facie obvious it light of the disclosure of Lu and the teachings of Anderson, is the same as the instantly claimed method and would necessarily provide the same characteristics, e.g., reduces elevation of the abnormal scar relative to elevation of an abnormal scar in a subject that was not administered the SNA, wherein the elevation of the abnormal scar is reduced by at least about 5%, especially in the absence of evidence to the contrary.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Lu in view of Anderson and Van De Water, as applied to claims 1, 4, 6, 8-10, 15-16, 18, 20-21, 23, 26-31 and 33-34 above, and further in view of Banga et al. (DOI: 10.1021/jacs.6b13359, published 16 February 2017), hereinafter Banga.
Lu, Anderson and Van De Water render obvious the claims discussed above. They do not disclose an SNA comprising a micellar center.
Regarding claim 7, Banga discloses "micellar spherical nucleic acid (SNA) nanostructures" (Abstract, page 4278), and that these SNAs could be used to deliver fluorescent proteins (Fig. 3). The SNAs comprise a micelle core and are surrounded by oligonucleotides (Scheme 1). The liposomal SNA core of Anderson and micellar SNA core of Banga are construed to be equivalents known in the art to be useful for encapsulating biological actives for controlled delivery via an SNA. As such, it is obvious to substitute the liposome of Anderson for the micelle of Banga.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Lu in view of Anderson and Van De Water, as applied to claim 1, 4, 6, 8-10, 15-16, 18, 20-21, 23, 26-31 and 33-34 above, and further in view of Tan et al. (DOI: 10.1021/jacs.6b07554, published 15 August 2016), hereinafter Tan.
Lu, Anderson and Van De Water render obvious the claims discussed above. They do not disclose an SNA comprising a sulfur linkage.
Regarding claim 13, Tan discloses drug-delivery SNAs comprising a disulfide bond linking the SNA core to the DNA, wherein the “bioreductively activated, self-immolative disulfide linker is used to tether the drug, allowing free drug to be released upon cell uptake” (Abstract, page 10834). Tan discloses that “oligonucleotides are an efficient carrier system for improving the water solubility of hydrophobic drugs and facilitating their intracellular delivery” and that the delivery vehicle “bypasses the need for a complex carrier system that often give rise to additional cytotoxic or immunogenic challenges” (page 10837). One of ordinary skill in the art at the time of instant filing would be motivated to combine the teachings of Lu, Anderson, Van De Water and Tan, as Lu teaches topical oligonucleotide formulations for the treatments of scars/scarring, Anderson teaches an enhanced delivery vehicle for oligonucleotides, and Tan teaches the benefits of disulfide linkages connecting the core of the SNA and a drug intended to be delivered. Such a combination would result in a scar-affecting drug delivery vehicle that more effectively penetrates cells and more efficiently delivers drugs.
Response to Arguments
Applicant’s first argument is that it would not have been obvious from the cited prior art to topically administer an SNA according to the instant claim 1 with a reasonable expectation of success. Applicant argues that it was unpredictable in view of the cited prior art that a composition as recited in the instant claims could penetrate an abnormal scar, which are scar comprising excessive collagen deposition, and retain the ability to inhibit expression of transforming growth factor beta 1 (TGF-β1). Applicant argues that Van De Water references “transdermal” or “topical” administration in boilerplate laundry lists relating generally to administration. Applicant argues that Examples 3 and 4 of Van De Water administers Hic-5 antagonist by intradermal or intrawound injection to inhibit expression of TGF-β1. Applicant argues that from the teachings and Examples of Van De Water, the person of ordinary skill in the art would have understood that topical administration of an agent would not achieve penetration of the agent to an abnormal scar, let alone sufficient penetration to inhibit expression of TGF-β1.
Applicant's arguments filed on 19 August 2025 have been fully considered but they are not persuasive. In response, it would have been prima facie obvious for one of ordinary skill in the art at the time of instant filing to treat scarring including keloid and hypertrophic scars (e.g., abnormal scar) with a method comprising topical administration of a composition comprising SNA comprising nanoparticle core and siRNA (e.g., oligonucleotide) that silences TGFβ1 expression, wherein the siRNA that silences TGFβ1 expression are positioned on the exterior of the nanoparticle core. The person of ordinary skill in the art would have been motivated to make those modifications in order to: 1) obtain a method with more efficient delivery of oligonucleotides to a cell, resulting in enhanced therapeutic response, by presenting the siRNA (e.g., oligonucleotide) that silences TGFβ1 expression on the exterior of SNA as taught by Anderson; and 2) to treat scarring issues including keloid and hypertrophic scars (e.g., abnormal scar) which TGFβ1 has been shown to be a major cytokine responsible for the onset thereof. The person of ordinary skill in the art would have reasonably expected success because , Lu discloses "using combinations of TGFβ1 and Cox-2 inhibitors and TGFβ1 and Hoxb13 inhibitors for the treatment of various medical conditions, including skin scaring due to trauma wounds and surgery" (Abstract), and that "[p]referably, the carrier is suitable for topical administration" (Paragraph [0048]). The siRNA molecules (Claim 1) used to inhibit TGFβ1 expression are disclosed to be oligonucleotides (Paragraph [0040]). Lu teaches nanoparticle containing siRNA as an appropriate carrier (paragraph 48 and examples 4 and 5). Anderson discloses an "immuno stimulatory spherical nucleic acid (IS-SNA), comprising a core having an oligonucleotide shell comprised of immuno stimulatory oligonucleotides positioned on the exterior of the core" (Claim 1). Anderson also discloses that “[the claimed SNA] structures exhibit the ability to enter cells without the need for auxiliary delivery vehicles or transfection reagents, by engaging scavenger receptors and lipid rafts” (page 12). Anderson teaches that SNA allows efficient delivery of oligonucleotides, resulting in enhanced therapeutic responses (page 21, lines 26-31). Van De Water teaches it has been shown that TGFβ1 is the major cytokine responsible for the onset of fibrotic disorders including keloids and hypertrophic scars (paragraph [0005]). Van De Water teaches administration of a Hic-5 antagonist that inhibits TGF- β1 signaling pathway (paragraphs [0075] and [0080]).
Regarding Applicant’s argument of unexpected results, Applicant has not provided clear evidence to show that SNA are not expected to penetrate hypertropic scar or keloid scar. From the teachings of Anderson, SNA are expected to improve the uptake of oligonucleotide and when incorporated with the oligonucleotide that inhibits TGFβ1 of Lu, would be expected to provide enhanced therapeutic responses. Applicant is remined that arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Lu discloses "using combinations of TGFβ1 and Cox-2 inhibitors and TGFβ1 and Hoxb13 inhibitors for the treatment of various medical conditions, including skin scaring due to trauma wounds and surgery" (Abstract), and that "[p]referably, the carrier is suitable for topical administration" (Paragraph [0048]). Anderson teaches that SNA allows efficient delivery of oligonucleotides, resulting in enhanced therapeutic responses (page 21, lines 26-31). Van De Water teaches it has been shown that TGFβ1 is the major cytokine responsible for the onset of fibrotic disorders including keloids and hypertrophic scars (paragraph [0005]). Van De Water teaches administration for including topically (paragraph [0128]). Thus, one of ordinary skill in the art would be motivated to administer oligonucleotide that inhibit TGFβ1 of Lu on the exterior of SNA of Anderson and administered to scars including keloids and hypertrophic scars, in light of the disclosure of Lu and the teachings of Anderson and Van De Water (described above).
Applicant is remined that “[t]he fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) (Claims were directed to grooved carbon disc brakes wherein the grooves were provided to vent steam or vapor during a braking action. A prior art reference taught noncarbon disc brakes which were grooved for the purpose of cooling the faces of the braking members and eliminating dust. The court held the prior art references when combined would overcome the problems of dust and overheating solved by the prior art and would inherently overcome the steam or vapor cause of the problem relied upon for patentability by applicants. Granting a patent on the discovery of an unknown but inherent function (here venting steam or vapor) “would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art.” 596 F.2d at 1022, 201 USPQ at 661.); In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991). In the instant case, it would have been prima facie obvious for one of ordinary skill in the art at the time of instant filing to treat scarring including keloid and hypertrophic scars (e.g., abnormal scar) with a method comprising topical administration of a composition comprising SNA comprising nanoparticle core and siRNA (e.g., oligonucleotide) that silences TGFβ1 expression, wherein the siRNA that silences TGFβ1 expression are positioned on the exterior of the nanoparticle core (described above). The person of ordinary skill in the art would have been motivated to make those modifications in order to: 1) obtain a method with more efficient delivery of oligonucleotides to a cell, resulting in enhanced therapeutic response, by presenting the siRNA (e.g., oligonucleotide) that silences TGFβ1 expression on the exterior of SNA as taught by Anderson; and 2) to treat scarring issues including keloid and hypertrophic scars (e.g., abnormal scar) which TGFβ1 has been shown to be a major cytokine responsible for the onset thereof.
Thus, for the reasons of record and for the reasons presented above claims 1, 4, 6-10, 13, 15-16, 18, 20-21, 23, 26-31 and 33-34 are rejected under 35 U.S.C. 103(a).
Conclusion and Correspondence
No claims are allowed.
THIS ACTION IS MADE FINAL.
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 extension fee 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 date of this final action.
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/JOHN P NGUYEN/
Examiner, Art Unit 1619
/BENNETT M CELSA/Quality Assurance Specialist , Art Unit 1600