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 .
Withdrawn Rejections:
Applicant's amendments and arguments filed on 03/18/2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below is herein withdrawn.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Claims 1-5, 7-9, 11-14, 16-19, 23, 29 and 61-67 are pending, claims 1-5, 7-9, 11-14, 16-19, 23 and 29 are under examination.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1-5, 7-9, 11-14, 16-19, 23, 29 are rejected under 35 U.S.C. 103 as being unpatentable over Bastakoty et al. (“Inhibition of Wnt/β-catenin pathway promotes regenerative repair of cutaneous and cartilage injury”, FASEB J. 2015 Aug 12;29(12):4881–4892. doi: 10.1096/fj.15-275941; cited in IDS) in view of Holsworth (US20190105398).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Bastakoty et al. teaches Wound healing in mammals is a fibrotic process. The mechanisms driving fibrotic (as opposed to regenerative) repair are poorly understood. Herein we report that therapeutic Wnt inhibition with topical application of small-molecule Wnt inhibitors can reduce fibrosis and promote regenerative cutaneous wound repair. In the naturally stented model of ear punch injury, we found that Wnt/β-catenin pathway is activated most notably in the dermis of the wound bed early (d 2) after injury and subsides to baseline levels by d10. Topical application of either of 2 mechanistically distinct small-molecule Wnt pathway inhibitors (a tankyrase inhibitor, XAV-939, and the U.S. Food and Drug Administration–approved casein kinase activator, pyrvinium) in C57Bl/6J mice resulted in significantly increased rates of wound closure (72.3 ± 14.7% with XAV-939; and 52.1 ± 20.9% with pyrvinium) compared with contralateral controls (38.1 ± 23.0 and 40.4.±16.7%, respectively). Histologically, Wnt inhibition reduced fibrosis as measured by α-smooth muscle actin positive myofibroblasts and collagen type I α1 synthesis. Wnt inhibition also restored skin architecture including adnexal structures in ear wounds and dermal–epidermal junction with rete pegs in excisional wounds. Additionally, in ear punch injury Wnt inhibitor treatment enabled regeneration of auricular cartilage. Our study shows that pharmacologic Wnt inhibition holds therapeutic utility for regenerative repair of cutaneous wounds (abstract). To investigate the effect of Wnt pathway on wound healing, we treated ear punch wounds topically with small-molecule Wnt inhibitors (including XAV-939) every day after injury for 30 d. (page 4884, left column). A cutaneous wound healing response characterized by reduced fibrosis and regeneration of auricular cartilage and skin adnexa in response DMSO to inhibition of Wnt/b-catenin signaling has been demonstrated (page 4886, discussion section; page 4891, last paragraph).
Holsworth teaches a composition for treating a wound includes graphene oxide (GO) and hyaluronic acid (HA) that are covalently linked, XAV939, and water. The composition can also include a surfactant, such as PEG. The composition can be topically administered to a subject to treat a wound of the subject. Methods of treating a wound using the composition are also provided (abstract). XAV939 is a small molecule that selectively inhibits Wnt/β-catenin-mediated transcription through TNK 1 and 2 inhibition with an IC50 of 11 nM/4 nM in cell-free assays, regulates axin levels, and does not affect CRE, NF-κB, or TGF-β. Recently, topical application of XAV939 in a mouse ear punch assay demonstrated that XAV939 significantly increased rate of wound closure with reduced fibrosis (scarring). However, XAV939 was dissolved in DMSO and used only as a “research tool” compound due to its very low aqueous solubility (<1 mg/mL). The problem with this approach is that humans cannot tolerate the use of DMSO. A soluble form of XAV939 suitable for humans is required for practical and medical use ([0010]). In some embodiments, the linker linking the GO and HA includes 2-25 carbons. In some embodiments, the linker can be straight-chained (or linear). In other embodiments, the linker can be branched. In some embodiments, the linker comprises a linear alkylene —CmH2m— unit where m can be from 1 to 20. In some other embodiments, the linker can comprise one or more heteroatoms. For example, the linker can include one or more —CH2CH2O— units. In certain embodiments, the linker comprises —Rx—RS—Ry—, wherein Rx and Ry are each independently selected from the group consisting of —CO—, —COO—, —NH—, —NH—NH—, —NH—NH—CO—, —CS—, —S—, —O—, and wherein RS is an unsubstituted or substituted linear alkylene group having 1-40, or 2-20 backbone carbons. In specific embodiments, Rx and Ry are each —NH—NH—CO— ([0014]). In some embodiments, the weight ratio of XAV939 to GO-HA can be from about 1:100 to about 100:1, for example, from about 1:2 to about 2:1. In some embodiments, XAV939 constitutes from about 0.001 wt % to about 5 wt % of the total composition. In certain embodiments, the GO-HA constitutes from 0.001 wt % to about 5 wt % of the total composition ([0015]). In one aspect of the invention, a composition for treating a wound is provided, which includes: a matrix component comprising a conjugate of graphene oxide (GO) and hyaluronic acid (HA) where GO and HA are covalently linked via a linker; XAV939; and water. The covalently-linked GO and HA is also referred to herein as GO-HA conjugate or simply GO-HA. XAV939 is a potent tankyrase inhibitor, with a chemical name 3,5,7,8-Tetrahydro-2-[4-(trifluoromethyl)phenyl]-4H-thiopyrano[4,3-d]pyrimidin-4-one ([0021-0022]). In the composition of present invention, the GO and HA are covalently linked to form a matrix component (or a carrier), which can serve to solubilize XAV939 as well as providing other simultaneous benefits to wound healing ([0025]). In general, the composition overall can appear as a slightly dark or black viscous liquid. XAV939 is evenly dispersed in the viscous suspension, which is stable at room temperature for months. In some embodiments, the composition further comprises a surfactant that enhances mixability or solubility of hydrophobic substances in water. In some examples, the surfactant can be a non-ionic hydrophilic material such as polyethylene glycol (PEG). In some embodiments, the PEG can be present in the composition in an amount of from about 0.1 to about 20 wt % of that of the total composition ([0029]). In some embodiments, the composition of the invention further comprises a thickener for desired viscosity of the composition for skin delivery. For example, the thickener can include hydroxypropyl cellulose (HPC) ([0033]). The composition(s) of the present invention described herein can be administered by applying the composition(s) topically on the wound site. In some embodiments, the method of treatment can include delivering a second wound medication or therapeutic agent to the subject ([0038-0039]). The present invention provides a wound treatment strategy that simultaneously addresses several facets of wound healing by synergistically combining a multi-functional scaffold (GO) conjugated to a highly hygroscopic material (HA) traditionally beneficial in wound healing, and aqueous solubilization of a potent Wnt pathway inhibitor (XAV939) for improved healing of cutaneous wounds with reduced scarring ([0043]). Additional benefits of the topical composition and topical administration of embodiments of the present invention is low toxicity and high bioavailability of the beneficial components to the site of injury/wound ([0044]). A specifical example of GO-HA is prepared ([0052, Scheme 3).
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While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, composition, device, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, compositions, devices, systems, articles, materials, kits, and/or methods, if such features, compositions, devices, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure ([0091]).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02)
The difference between the instant application and Bastakoty et al. is that Bastakoty et al. do not expressly teach GO-HA conjugate, surfactant PEG and thickener hydroxypropyl cellulose. This deficiency in Bastakoty et al. is cured by the teachings of Holsworth.
Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Bastakoty et al., as suggested by Holsworth, and produce the instant invention.
One of ordinary skill in the art would have been motivated to include GO-HA conjugate in the topical composition comprising XAC939 for treating cartilage injury because GO-HA conjugate can serve to solubilize XAV939 as well as providing other simultaneous benefits to wound healing as suggested by Holsworth. Since it is advantage to do so, it is obvious for one of ordinary skill in the art to include GO-HA conjugate in the topical composition comprising XAC939 for treating cartilage injury and produce instant claimed invention with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to include surfactant PEG and thickener hydroxypropyl cellulose because surfactant PEG can enhance mixability or solubility of hydrophobic substances in water and thickener can provide desired viscosity of the topical composition. Since it is advantage to do so, it is obvious for one of ordinary skill in the art to include surfactant PEG and thickener hydroxypropyl cellulose and produce instant claimed invention with reasonable expectation of success.
Regarding claims 1, prior art teaches a method of treating ear punch injury to enable regeneration of auricular cartilage by topically administration to cartilage of a composition comprising GO-HA and XAV939.
Regarding claims 2-3 and 17-18, since this is ear punch injury, it is considered as acute and elastic.
Regarding claim 7, prior art teaches 0.1 to about 20 wt % of PEG.
Regarding claims 11-13, Holsworth teaches the linker can include one or more —CH2CH2O— units. In certain embodiments, the linker comprises —Rx—RS—Ry—, wherein Rx and Ry are each independently selected from the group consisting of —CO—, —COO—, —NH—, —NH—NH—, —NH—NH—CO—, —CS—, —S—, —O—, and wherein RS is an unsubstituted or substituted linear alkylene group having 1-40, or 2-20 backbone carbons. In specific embodiments, Rx and Ry are each —NH—NH—CO—.
Regarding claims 14 and 29, Holsworth teaches the weight ratio of XAV939 to GO-HA can be from about 1:100 to about 100:1, for example, from about 1:2 to about 2:1.
Regarding claim 16, prior art teaches administration daily instead of every 48h (2d), it is within skill of one artisan in the art to adjust and optimize the frequency of administration through routing experimentation and have administration every 48h, especially in the absence of showing criticality of claimed range. MPEP 2144.05.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Argument:
Applicants argue that hindsight and one artisan in the art would not get guidance from Holsworth. All related arguments are incorporated herein by reference.
In response to this argument: this is not percussive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As discussed in the above 103 rejection, Holsworth teaches GO-HA conjugate can serve to solubilize XAV939 as well as providing other simultaneous benefits to wound healing, Holsworth teaching can be relied on whether Holsworth teaching is clinical acceptable or not, and it is advantage to include GO-HA conjugate to solubilize XAV939 (poor aqueous solubility) as well as providing other simultaneous benefits to wound healing. Regarding argument that no teaching of claimed administration, it is argued that claim 1 only requires contacting of cartilage with the composition, and Bastakoty et al. teaches topical application of composition comprising XAV939 to cartilage, this procedure will result in contacting composition comprising XAV939 to cartilage, and the limitation of claimed administration is met. Finally, for the same rational, it is advantage to include surfactant PEG and thickener hydroxypropyl cellulose because surfactant PEG can enhance mixability or solubility of hydrophobic substances in water and thickener can provide desired viscosity of the topical composition. Therefore, the 103 rejection is till proper.
Applicants argue about unexpected results regarding better performance and shorter during of treatment.
In response to this argument: this is not persuasive. MPEP 716.02, Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). MPEP 716.02(c) II, "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). As discussed in the above, Holsworth teaches XAV939 was dissolved in DMSO and used only as a “research tool” compound due to its very low aqueous solubility (<1 mg/mL). The problem with this approach is that humans cannot tolerate the use of DMSO; and XAV939 has practically extremely low solubility, thus, since GO-HA conjugate can serve to solubilize XAV939 (poor aqueous solubility) as well as providing other simultaneous benefits to wound healing, thus the composition comprising XAV939 and GO-HA conjugate is expected to have better performance than composition comprising XAV939 in DMSO or saline. Since the results are expected, the 103 rejection is still proper.
MPEP 2141 III states: “The proper analysis is whether the claimed invention would have been obvious to one of ordinary skill in the art after consideration of all the facts.” Respectfully, after weighing all the evidence, the Examiner has reached a determination that the instant claims are not patentable in view of the preponderance of evidence and consideration of all the facts which is more convincing than the evidence which has been offered in opposition to it.
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).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5, 7-9, 11-14, 16-19, 23 and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11291730 in view of Bastakoty et al. (“Inhibition of Wnt/β-catenin pathway promotes regenerative repair of cutaneous and cartilage injury”, FASEB J. 2015 Aug 12;29(12):4881–4892. doi: 10.1096/fj.15-275941; cited in IDS). The reference patent teaches a topical composition comprising GO-HA and XAV939 for treating wound, in view of Bastakoty et al. teaching a topical composition comprising XAV939 treating cartilage injury for regeneration of cartilage, it is obvious for one of ordinary skill in the art to administer a topical composition comprising GO-HA and XAV939 for treating cartilage injury for regeneration of cartilage and produce applicant’s claimed invention with reasonable expectation of success.
Claims 1-5, 7-9, 11-14, 16-19, 23 and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11369685 in view of Bastakoty et al. (“Inhibition of Wnt/β-catenin pathway promotes regenerative repair of cutaneous and cartilage injury”, FASEB J. 2015 Aug 12;29(12):4881–4892. doi: 10.1096/fj.15-275941; cited in IDS). The reference patent teaches a topical composition comprising GO-HA and XAV939 for treating wound, in view of Bastakoty et al. teaching a topical composition comprising XAV939 treating cartilage injury for regeneration of cartilage, it is obvious for one of ordinary skill in the art to administer a topical composition comprising GO-HA and XAV939 for treating cartilage injury for regeneration of cartilage and produce applicant’s claimed invention with reasonable expectation of success.
Claims 1-5, 7-9, 11-14, 16-19, 23 and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12059469 in view of Bastakoty et al. (“Inhibition of Wnt/β-catenin pathway promotes regenerative repair of cutaneous and cartilage injury”, FASEB J. 2015 Aug 12;29(12):4881–4892. doi: 10.1096/fj.15-275941; cited in IDS). The reference patent teaches a topical composition comprising GO-HA and XAV939 for treating wound, in view of Bastakoty et al. teaching a topical composition comprising XAV939 treating cartilage injury for regeneration of cartilage, it is obvious for one of ordinary skill in the art to administer a topical composition comprising GO-HA and XAV939 for treating cartilage injury for regeneration of cartilage and produce applicant’s claimed invention with reasonable expectation of success.
Claims 1-5, 7-9, 11-14, 16-19, 23 and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13, 15-20, 22-24 and 27-28 of copending Application No. 18776025 in view in view of Bastakoty et al. (“Inhibition of Wnt/β-catenin pathway promotes regenerative repair of cutaneous and cartilage injury”, FASEB J. 2015 Aug 12;29(12):4881–4892. doi: 10.1096/fj.15-275941; cited in IDS). The reference application teaches a topical composition comprising GO-HA and XAV939 for treating wound, in view of Bastakoty et al. teaching a topical composition comprising XAV939 treating cartilage injury for regeneration of cartilage, it is obvious for one of ordinary skill in the art to administer a topical composition comprising GO-HA and XAV939 for treating cartilage injury for regeneration of cartilage and produce applicant’s claimed invention with reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Response to Argument:
Applicants argued about US’398.
In response to this argument: this is no persuasive. US’398 is not relied on in the above double patenting rejection and thus applicant’s arguments are moot.
Conclusion
No claim is 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 nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JIANFENG SONG. Ph.D. whose telephone number is (571)270-1978. The examiner can normally be reached M-F 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian-Yong Kwon can be reached at (571)272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JIANFENG SONG/Primary Examiner, Art Unit 1613
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