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 .
Priority
This application is a national stage entry of PCT/CN2022/095861 filed on 05/30/2022. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in China on 05/31/2021.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 5, 7 and 11-13) drawn to a method for preventing or treating human papillomavirus comprising administering 5-nitro-8-hydroxyquinoline, or a salt, crystal, solvate, isotope, or prodrug thereof; HPV16 as a species of an HPV type and 5-nitro-8-hydroxyquinoline as a species of a compound in the reply filed on February 11, 2026 is acknowledged.
Claims 6, 8-10, and 13-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group or species, there being no allowable generic or linking claim.
Claims 5, 7, 11 and 12 are being examined as they read on the elected species.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 5, 7, 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Zeligs WO 2004/071425 A2 in view of Sobke et al. (Antimicrobial Agents and Chemotherapy, November 2012, Volume 56 Number 11, pages 6021–6025).
Claims 5, 7, 11 and 12 claim a method for preventing or treating a viral infection, comprising administering a prophylactically effective or therapeutically effective amount of 5-nitro-8-hydroxyquinoline, to a subject in need thereof; wherein the virus is human papillomavirus, specifically HPV16.
Zeligs teaches synergistic compositions and methods for using cruciferous indoles with iron/zinc chelators in the treatment of papillomavirus-related conditions (abstract). Zeligs teaches synergistic compositions of diindolylymethane (DIM), related trimeric derivatives, and related indole derivatives in combinations with iron/zinc chelators as effective therapies for common cutaneous warts (verrucae) and related dysplasias of the oropharynx, genitalia, and uterine cervix (abstract).
Zeligs teaches that the present invention includes compositions and methods for the treatment and prevention of papillomavirus-related disease, including occult infection, pre-cancerous epithelial dysplasias, and papillomavirus-related epithelial cancers (page 1 lines 9-13). Zeligs teaches that the methods include systemic and topical combinations, result in synergistic amplification of apoptosis, and include combined compositions of indole phytochemicals, chemical iron/zinc chelators, and optionally, one or more of the iron-displacing trace element, gallium, a zinc-binding histone deacetylase inhibitor and an Epidermal Growth Factor Receptor (EGFR) antagonist (page 1 lines 16-23). Zeligs teaches that the induced promotion of apoptosis results in elimination of abnormal epithelial cells infected with papillomavirus, and causes resolution of papillomavirus- related lesions of skin and epithelial surfaces (page 1 lines 25-30).
Zeligs teaches that epidemic papillomavirus infections lead to cancer (page 2 lines 2-3). Zeligs teaches that papillomaviruses are small DNA viruses infecting stratified cutaneous or mucosal epithelial tissue that are prevalent in humans and animals, and they are responsible for a spectrum of diseases ranging from benign warts (veruccae) to malignant neoplasms (page 2 lines 4-8). Zeligs teaches that papillomavirus infection often results in oral-genital manifestations, including oropharyngeal papillomas and dysplasia, peri-anal verrucae, virus-related papillomas and dysplasia, vaginal papillomas and dysplasia, and uterine cervical papilloma virus-related papilloma and dysplasia (page 2 lines 17-23). Papillomavirus induced dysplasia progresses unpredictably to intra-epithelial neoplasia and subsequently to a number of types of cancer including non-melanoma skin cancer, squamous cell head and neck cancer, esophageal cancer, anal cancer, cervical cancer, and prostate cancer (page 2 lines 23-33).
Zeligs teaches that iron and zinc chelators can act to promote apoptosis and have been shown to have antiviral activity (pages 7-10). Zeligs teaches that examples of iron and zinc chelators include desferrioxamine (deferoxamine), EDTA, silybin, deferiprone, picolinic acid, and dipyridine (bipyridine 2,2’-bypyridyl) (page 14 and Table 1 pages 26-27). Thus, Zeligs teaches methods of treating papillomavirus-related conditions by administering one or more cruciferous indoles and one or more metal chelators (page 14 lines 16-18 and page 16 lines 19-23). In a particular embodiment, the papillomavirus-related condition is common cutaneous warts (verrucae) often involving the hands and the feet (page 15 lines 4-6). In addition, Zeligs teaches methods for the treatment of papillomavirus-related oral-genital papillomavirus infections, and for uterine cervical papillomavirus-related conditions, including cervical dysplasia and papillomavirus-related cancer (page 15 lines 6-11 and page 17 line 23-page 17 line 4).
Zeligs teaches that the subject, or patient, to be treated using the methods of the invention is an animal, e.g., a mammal, and is preferably human, and can be male or female, child, or adult (page 45 lines 4-7).
Zeligs specifically exemplifies treatment of HPV16 which is an HPV type causing cervical cancer (page 66 lines 17-18), with the synergistic combination of DIM and iron/zinc chelators (pages 66-69). Claim 1 of Zeligs claims a method of treating a papillomavirus related epithelial disorder comprising administering to a subject in need thereof a therapeutically effective amount of one or more iron/zinc chelators and one or more cruciferous indoles.
Zeligs does not teach the administration of 5-nitro-8-hydroxyquinoline.
Sobke et al. teaches that the antimicrobial effects of the urinary antibiotic 5-Nitro-8-Hydroxyquinoline (nitroxoline) have long been known to depend on its ability to chelate bivalent and trivalent cations (page 6021). Sobke et al. demonstrates that the effects of nitroxoline is due to iron chelation and to a lesser degree zinc chelation (pages 6022-6023).
Sobke et al. teaches that nitroxoline, which has been in clinical use in Europe for half a century has activity comparable to that reported for EDTA, but it is orally applicable, and less toxic (page 6024). Sobke et al. further teaches that in contrast to lactoferrin and the related egg white-derived conalbumin, it is a synthetic, relatively cheap compound, without additional immunomodulating functions and far lesser allergenic potential (page 6024). Sobke et al. further teaches that nitroxoline activity was found superior to that reported for pure iron chelators like 2,2’-dipyridyl, deferoxamine mesylate, or diethylenetriamine pentaacetic acid (pages 6024-6025).
Accordingly, prior to the effective filing date of the claimed invention it would have been obvious to a person of ordinary skill in the art to combine the teachings of Zeligs which teaches a method of treating a papillomavirus related epithelial disorder wherein the papillomavirus may be selected as human papillomavirus 16 (HPV16) which cause cervical cancer comprising administering to a subject in need thereof a therapeutically effective amount of one or more iron/zinc chelators and one or more cruciferous indoles, wherein suitable iron/zinc chelators include desferrioxamine (deferoxamine), EDTA, silybin, deferiprone, picolinic acid, and dipyridine (bipyridine, 2,2’-bypyridyl); with the teachings of Sobke et al. which teaches that 5-Nitro-8-Hydroxyquinoline (nitroxoline) is an antimicrobial antibiotic known to chelate bivalent and trivalent cations including iron chelation and zinc chelation with superior activity as compared to 2,2’-dipyridyl and deferoxamine and less toxicity as compared to EDTA. Thus, an ordinary skilled artisan would have been motivated to substitute nitroxoline as an iron/zinc chelator useful in the method of Zeligs for the specific iron/zinc chelators taught in Zeligs based on the teachings of Sobke et al. which teaches that nitroxoline has improved activity and is less toxic than the specific iron/zinc chelators taught in Zeligs. An ordinary skilled artisan practicing the invention of Zeligs would have had a reasonable expectation of success in the substitution and would have been motivated to do so since said substitution would have been expected to yield predictable results in view of the teachings of Sobke et al.
In the alternative, an ordinary skilled artisan would have been motivated to add nitroxoline to the method of Zeligs as an additional iron/zinc chelator with a reasonable expectation of improved results in the treatment of viral infections related to human papillomavirus. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980).
Thus, the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Claims 5, 7, 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Hoppe et al. WO 2019-101897 A1 in view of Sobke et al. (Antimicrobial Agents and Chemotherapy, November 2012, Volume 56 Number 11, pages 6021–6025).
Claims 5, 7, 11 and 12 claim a method for preventing or treating a viral infection, comprising administering a prophylactically effective or therapeutically effective amount of 5-nitro-8-hydroxyquinoline, to a subject in need thereof; wherein the virus is human papillomavirus, specifically HPV16.
Hoppe et al. teaches a pharmaceutically compatible iron chelator or a prodrug thereof for use in treatment and/or prevention of a human papillomavirus (HPV) related lesion (abstract). Hoppe et al. teaches that Human Papillomaviruses (HPVs) are known to be associated with 4.5% of all cancers worldwide including cancers of the cervix and other cancers within the anogenital region as well as head and neck cancers, and the causative role of HPV is best characterized in cervical cancer (page 1 lines 27-30).
Hoppe et al. teaches that preferably, the pharmaceutically compatible iron chelator is an iron chelator comprising a chemical compound in clinical use, preferably approved for clinical use by at least one of the Food and Drug Administration (FDA), the European Medicines Agency (EMEA), and the Bundesinstitut fur Arzneimittel und Medizinprodukte (BfArM) (page 5 lines 4-9). Preferable iron chelators include ciclopirox, Deferoxamine or hydroxycarbamide, 3-aminopyridine-2-carboxaldehyde, Thiosemicarbazone or 5-Hydroxypyridine-2-carboxaldehyde, Deferasirox, Deferiprone, or N,NN"-tris(2-pyridylmethyl)-cis,cis-l,3,5-triaminocyclohexane (Tachpyr) (page 5 lines 12-18).
Hoppe et al. teaches a pharmaceutically compatible iron chelator for use in treatment and/or prevention of a human papillomavirus (HPV) related lesion, wherein the term "papillomavirus" (PV) relates to a DNA virus from the papillomaviridae family of viruses that infects the skin and mucous membranes of mammals, preferably livestock, more preferably cattle and horses, most preferably humans (page 15 lines 28-33).
Hoppe et al. teaches that for human PV (HPV), more than 110 HPV genotypes have been described and approximately 50 HPV genotypes are known to infect the mucosa and are classified into three different groups based on their epidemiological association with cancer: “low-risk” human papillomaviruses (LR- HPV), “high-risk” human papillomaviruses (HR-HPV) and “putative high-risk” human papillomaviruses (pHR-HPV) (page 15 line 33-page 16 line 6). It is also known that HR-HPVs can cause vulvar, anal, vaginal, penile, and oropharyngeal cancer, as well as vaginal intraepithelial neoplasia, anal intraepithelial neoplasia, vulvar intraepithelial neoplasia, and penile intraepithelial neoplasia (page 16 lines 6-8). Preferably, HPVs are mucosal HPVs; more preferably, HPVs of the current invention are High-risk HPV genotypes (HR-HPVs), which are the main cause for the development of cervical cancer, most preferably at least one of HPV 6, 16, 18, 31, 33, 35, 51 and 59 (page 16 lines 9-13).
Hoppe et al. teaches that the subject is an animal, preferably a vertebrate, more preferably a mammal, and most preferably, the subject is a human (page 12 lines 30-33).
Thus, Hoppe et al. teaches the use of a pharmaceutically compatible iron chelator for the treatment and/or prevention of a human papillomavirus (HPV) related lesion, preferably, the HPVs are mucosal HPVs; more preferably, HPVs are High-risk HPV genotypes (HR-HPVs), which are the main cause for the development of cervical cancer, including HPV16.
Hoppe et al. does not teach the administration of 5-nitro-8-hydroxyquinoline.
Sobke et al. teaches that the antimicrobial effects of the urinary antibiotic 5-Nitro-8-Hydroxyquinoline (nitroxoline) have long been known to depend on its ability to chelate bivalent and trivalent cations (page 6021). Sobke et al. demonstrates that the effects of nitroxoline is due to iron chelation and to a lesser degree zinc chelation (pages 6022-6023).
Sobke et al. teaches that nitroxoline, which has been in clinical use in Europe for half a century has activity comparable to that reported for EDTA, but it is orally applicable, and less toxic (page 6024). Sobke et al. further teaches that in contrast to lactoferrin and the related egg white-derived conalbumin, it is a synthetic, relatively cheap compound, without additional immunomodulating functions and far lesser allergenic potential (page 6024). Sobke et al. further teaches that nitroxoline activity was found superior to that reported for pure iron chelators like 2,2’-dipyridyl, deferoxamine mesylate, or diethylenetriamine pentaacetic acid (pages 6024-6025).
Accordingly, prior to the effective filing date of the claimed invention it would have been obvious to a person of ordinary skill in the art to combine the teachings of Hoppe et al. which teaches the use of a pharmaceutically compatible iron chelator for the treatment and/or prevention of a human papillomavirus (HPV) related lesion, preferably, the HPVs are mucosal HPVs; more preferably, HPVs are High-risk HPV genotypes (HR-HPVs), which are the main cause for the development of cervical cancer, including HPV16; with the teachings of Sobke et al. which teaches that 5-Nitro-8-Hydroxyquinoline (nitroxoline) is an antimicrobial antibiotic known to chelate bivalent and trivalent cations including iron chelation with superior activity as compared to 2,2’-dipyridyl and deferoxamine and less toxicity as compared to EDTA. Thus, an ordinary skilled artisan would have been motivated to substitute nitroxoline as an iron chelator useful in the method of Hoppe et al. for the specific iron chelators taught in Hoppe et al. based on the teachings of Sobke et al. which teaches that nitroxoline has improved activity and is less toxic than the specific iron chelators taught in Hoppe et al. An ordinary skilled artisan practicing the invention of Hoppe et al. would have had a reasonable expectation of success in the substitution and would have been motivated to do so since said substitution would have been expected to yield predictable results in view of the teachings of Sobke et al.
In the alternative, an ordinary skilled artisan would have been motivated to add nitroxoline to the method of Hoppe et al. as an additional iron chelator with a reasonable expectation of improved results in the treatment of human papillomavirus lesions. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980).
Thus, the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 5, 7, 11 and 12 are rejected. Claims 1-4 are canceled. Claims 6, 8, 9, 10 and 13-15 are withdrawn. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA R. MCMILLIAN whose telephone number is (571)270-5236. The examiner can normally be reached Tuesday-Friday 12:00 PM-6:00 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571)270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM
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