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 the Claims
Claims 1-19 are pending. Acknowledgment is made of Applicant’s amendments filed on 12/29/2023, amendment of claims 2 and 10-12, and addition of claims 14-19.
Priority
This application claims priority to US Provisional Patent Application 63/202,907, filed on 06/29/2021, and to PCT/US22/73268, filed on 06/29/2022.
Claim Rejections - 35 USC § 112
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 9, 14-15, and 18-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of SARS-COV-2 infection comprising administering the compounds from claim 1, does not reasonably provide enablement for the treatment of all viruses. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, state and predictability of the art, and relative skill of those in the art
The invention is drawn to the use of compounds in claim 1 to treat inflammation and immune responses in a subject infected with a virus.
The relative skill of those in the art is high, generally that of a M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain).
At the time the instant application was filed, the state of the art of treating a viral infection as recited in claims 9, 14-15, and 18-19 embraces treatment of the following unrelated diseases and/or infections caused by the following viruses (without limitation, because the claim is open-ended and embraces any infection caused by any virus):
Adenoviruses. The adenoviruses are divided into four genera: Mastadenovirus: Bovine adenovirus A, Bovine adenovirus B, Bovine adenovirus C, Canine adenovirus, Equine adenovirus A, Equine adenovirus B, Human adenovirus A, Human adenovirus B, Human adenovirus C, Human adenovirus D, Human adenovirus E, Human adenovirus F, Murine adenovirus A, Ovine adenovirus A, Ovine adenovirus B, Porcine adenovirus A, Porcine adenovirus B, Porcine adenovirus C, and Tree shrew adenovirus; Aviadenovirus: Fowl adenovirus A, Fowl adenovirus B, Fowl adenovirus C, Fowl adenovirus D, Fowl adenovirus E, and Goose adenovirus; Atadenovirus: Bovine adenovirus D, Duck adenovirus A, Ovine adenovirus D, and Possum adenovirus; and Siadenovirus: Frog adenovirus, Turkey adenovirus A.
In addition, there are further adenovirus serotypes. Thus, while there are 6 species of human adenovirus (Human adenovirus A-F), there are 51 immunologically distinct human adenovirus serotypes that can cause human infections ranging from respiratory disease, to conjunctivitis to gastroenteritis and possibly, obesity.
Hepadnaviruses. The hepadnaviruses consist of Ground squirrel hepatitis virus, Hepatitis B virus, Woodchuck hepatitis virus, Woolly monkey hepatitis B virus, Duck hepatitis B virus and Heron hepatitis B virus.
Flavivirus. The human Flavivirus (Positive Stranded ssRNA Virus) are a diverse lot, including the Pestiviruses (such as Classical swine fever (CSF) and Bovine viral diarrhoea / Mucosal disease (BVD/MD) ), Hepatitis C, Yellow fever virus, Gadgets Gully virus, Kadam virus, Kyasanur Forest disease virus, Langat virus, Omsk hemorrhagic fever virus, Powassan virus, Royal Farm virus, Tick-borne encephalitis virus, Meaban virus, Tyuleniy virus, Aroa virus, Dengue virus, Kedougou virus, Cacipacore virus, Koutango virus, Japanese encephalitis virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Usutu virus, West Nile virus, Kunjin virus, Ntaya virus, Uganda S virus, Apoi virus, Montana myotis leukoencephalitis virus, and many, many more.
Retroviruses. The retroviruses (ssRNA RT-Viruses) fall into seven different genuses. The first is Alpharetrovirus. These include the Avian leukosis virus (ALV) (which comes in two strains), Rous sarcoma virus (RSV), which has 3 strains, Avian carcinoma Mill Hill virus 2, Avian myeloblastosis virus, Avian myelocytomatosis virus 29, Avian sarcoma virus CT10, Fujinami sarcoma virus, UR2 sarcoma virus (also known as University of Rochester virus 2 and Avian sarcoma virus UR-2), and the Y73 sarcoma virus. The second genus is the Betaretrovirus. This include the Langur virus (LNGV), Mason-Pfizer monkey virus (which comes in 3 strains), Mouse mammary tumor virus, Ovine pulmonary adenocarcinoma virus, Jaagsiekte sheep retrovirus, and the Squirrel monkey retrovirus. The third genus is the Gammaretrovirus. This includes the Feline leukemia virus, Gibbon ape leukemia virus, Guinea pig type C oncovirus, Murine leukemia virus (which exists in at least 6 strains and isolates), Porcine type C oncovirus, Finkel-Biskis-Jinkins murine sarcoma, Gardner-Arnstein feline sarcoma virus, Hardy-Zuckerman feline sarcoma virus, Harvey murine sarcoma virus, Kirsten murine sarcoma virus, Moloney murine sarcoma virus, Snyder-Theilen feline sarcoma virus, Woolly monkey sarcoma virus, Viper retrovirus, Chick syncytial virus, Reticuloendotheliosis virus, and the Trager duck spleen necrosis virus. The fourth genus is the Deltaretrovirus. This includes the Bovine leukemia virus, Primate T-lymphotropic virus 1, Human T-lymphotropic virus 1 (HTLV-1), Simian T-lymphotropic virus 1 (STLV-1), Primate T-lymphotropic virus 2 (PTLV-2), Human T-lymphotropic virus 2 (HTLV-2), Simian T-lymphotropic virus 2 (STLV-2), and the Primate T-lymphotropic virus-3. The fifth genus is the Epsilonretrovirus. These include the Walleye dermal sarcoma virus, Walleye epidermal hyperplasia virus type 1, Walleye epidermal hyperplasia virus type 2, Perch hyperplasia virus, and the Snakehead retrovirus. The sixth Genus is the Lentivirus. This includes Bovine immunodeficiency virus, Equine infectious anemia virus, Feline immunodeficiency virus, Feline immunodeficiency virus (Oma), Puma lentivirus, Caprine arthritis encephalitis virus, Visna/maedi virus (which comes in 3 strains), Human immunodeficiency virus 1 (HIV-1, which comes is many strains), HIV-2, HIV-3, and Simian immunodeficiency virus (SIV) which comes in many strains, including African green monkey, chimpanzee SIV, mandrill SIV and others. The seventh genus is the Spumavirus. This includes Bovine foamy virus, Chimpanzee foamy virus, Feline foamy virus, Simian foamy virus 1 and Simian foamy virus 3.
Filovirus. The Filoviridae (Negative Stranded ssRNA) consists of the Marburg virus (which has 6 different strains), and the Ebola virus (which has 4 different strains).
Papovirus. The papillomaviruses are divided in to 16 genera: Alphapapillomavirus (Human papillomavirus 2, Human papillomavirus 6, Human papillomavirus 7, Human papillomavirus 10, Human papillomavirus 16, Human papillomavirus 18, Human papillomavirus 26, Human papillomavirus 32, Human papillomavirus 34, Human papillomavirus 53, Human papillomavirus 54, Human papillomavirus 61, Human papillomavirus 71, Human papillomavirus cand90, Rhesus monkey papillomavirus 1); Betapapillomavirus (Human papillomavirus 5, Human papillomavirus 9, Human papillomavirus 49, Human papillomavirus cand92, Human papillomavirus cand96); Gammapapillomavirus (Human papillomavirus 4, Human papillomavirus 48, Human papillomavirus 50, Human papillomavirus 60, Human papillomavirus 88); Deltapapillomavirus (Bovine papillomavirus 1, Deer papillomavirus, European elk papillomavirus, Ovine papillomavirus 1); Epsilonpapillomavirus (Bovine papillomavirus 5); Zetapapillomavirus (Equine papillomavirus 1); Etapapillomavirus (Fringilla coelebs papillomavirus); Thetapapillomavirus (Psittacus erithacus timneh papillomavirus); Iotapapillomavirus (Mastomys natalensis papillomavirus); Kappapapillomavirus (Cottontail rabbit papillomavirus, Rabbit oral papillomavirus); Lambdapapillomavirus (Canine oral papillomavirus, (Feline papillomavirus); Mupapillomavirus (Human papillomavirus 1, Human papillomavirus 63); Nupapillomavirus (Human papillomavirus 41); Xipapillomavirus(Bovine papillomavirus 3); Omicronpapillomavirus (Phocoena spinipinnis papillomavirus); and Pipapillomavirus (Hamster oral papillomavirus).
The Coronaviruses (positive-sense single-stranded) are sorted into three groups. Group 1: Canine coronavirus, Feline coronavirus, Feline infectious peritonitis virus, Human coronavirus 229E, Porcine epidemic diarrhea virus,Transmissible gastroenteritis virus, and Human Coronavirus NL63. Group 2: Bovine coronavirus, Canine respiratory coronavirus, Human coronavirus OC43, Human enteric coronavirus, Mouse hepatitis virus, Murine hepatitis virus, Puffinosis coronavirus, Porcine hemagglutinating encephalomyelitis virus, Rat coronavirus, Sialodacryoadenitis virus, and Severe Acute Respiratory Syndrome Coronavirus (SARS). Group 3 Avian infectious bronchitis virus, Rabbit coronavirus, Infectious bronchitis virus, and Turkey coronavirus (Bluecomb disease virus).
The Picornaviruses (single stranded, positive sense) are divided into 9 genera: 1. Enteroviruses (Bovine enterovirus, Human enterovirus A (21 types, including some coxsackie A viruses), Human enterovirus B (57 types, including assorted enteroviruses, coxsackie B viruses, echoviruses, and swine vesicular disease virus), Human enterovirus C (14 types including some coxsackie A viruses and enteroviruses), Human enterovirus D (2 types), Human enterovirus E Poliovirus (3 types), Porcine enterovirus A Porcine enterovirus B, and Simian enterovirus A(20 types). 2. Rhinoviruses (Human rhinovirus A, Human rhinovirus B). 3. Cardiovirus (Theiler's murine encephalomyellitis virus (TMEV), Vilyuisk human encephalomyelitis virus (VHEV), Theiler-like virus (TLV) of rats, Scaffold virus (SAFV-1 and SAFV-2), Columbia SK virus, Maus Elberfeld virus and Mengovirus). 4. Aphthovirus (Foot-and-mouth disease virus (in 10 forms) and Equine rhinitis A virus) 5. Hepatovirus (Hepatitis A virus, avian encephalomyelitis virus). 6. Parechovirus (Human parechovirus (HPeV) 1, HPeV-2, HPeV-3, HPeV-4, HPeV-5, HPeV-6 and Ljungan virus) 7. Erbovirus (equine rhinitis B virus (ERBV) 1, ERBV-2, ERBV-3) 8. Kobuvirus (Aichi virus, bovine kobuvirus) 9. Teschovirus (porcine teschovirus in 11 serotypes). In addition, there are numerous unassigned viruses that are normally placed with the Picronaviruses, including Acid-stable equine picornaviruses, Avian entero-like virus 2, Avian entero-like virus 3, Avian entero-like virus 4, Avian nephritis virus 3, Barramundi virus-1+, Cockatoo entero-like virus, Duck hepatitis virus 1, Duck hepatitis virus 3, Equine rhinovirus 3, Guineafowl transmissible enteritis virus, Harbour seal picorna-like virus, Sea-bass virus-1+, Sikhote-Alyn virus, Smelt virus-1+, Smelt virus-2+, Syr-Daria Valley fever virus, Taura syndrome virus of marine penaeid shrimp, Turbot virus-1, Turkey entero-like virus, Turkey hepatitis virus, Turkey pseudo enterovirus 1, and Turkey pseudo enterovirus 2.
Poxviruses are very large viruses about the size of small bacteria. They have a complex internal structure - a large double-stranded DNA genome (about 200 kbp in size) is enclosed within a "core" that is flanked by 2 "lateral bodies". The scope of pox viruses is quite extensive, in part because there are 11 genera: 1. Orthopoxvirus: Camelpox virus, Cowpox virus, Ectromelia virus, Monkeypox virus, Raccoonpox virus, Taterapox virus, Vaccinia virus (Vaccinia virus Ankara, Vaccinia virus Copenhagen, Vaccinia virus Tian Tan, Vaccinia virus WR, Buffalopox virus, Rabbitpox virus Utrecht, Cantagalo virus), Variola virus (Variola major virus Bangladesh-1975, Variola major virus India-1967, Variola virus minor Garcia-1966), Volepox virus. 2. Parapoxvirus: Bovine papular stomatitis virus, Orf virus, Parapoxvirus of red deer in New Zealand, Pseudocowpox virus, Squirrel parapoxvirus. 3. Avipoxvirus: Canarypox virus, Fowlpox virus, Juncopox virus, Mynahpox virus, Pigeonpox virus, Psittacinepox virus, Quailpox virus, Sparrowpox virus, Starlingpox virus, Turkeypox virus. 4. Capripoxvirus: Goatpox virus, Lumpy skin disease virus, Sheeppox virus. 5. Leporipoxvirus: Hare fibroma virus, Myxoma virus, Rabbit fibroma virus, Squirrel fibroma virus. 6. Suipoxvirus: Swinepox virus. 7. Molluscipoxvirus: Molluscum contagiosum virus. 8. Yatapoxvirus:Tanapox virus, Yaba monkey tumor virus. 9. Alphaentomopoxvirus: Anomala cuprea entomopoxvirus, Aphodius tasmaniae entomopoxvirus, Demodema boranensis entomopoxvirus, Dermolepida albohirtum entomopoxvirus, Figulus subleavis entomopoxvirus, Geotrupes sylvaticus entomopoxvirus, Melolontha entomopoxvirus, 10. Betaentomopoxvirus: Acrobasis zelleri entomopoxvirus 'L', Amsacta moorei entomopoxvirus 'L', Arphia conspersa entomopoxvirus 'O', Choristoneura biennis entomopoxvirus 'L', Choristoneura conflicta entomopoxvirus 'L', Choristoneura diversuma entomopoxvirus 'L', Choristoneura fumiferana entomopoxvirus ‘L’, Chorizagrotis auxiliars entomopoxvirus 'L’, Heliothis armigera entomopoxvirus ‘L’, Locusta migratoria entomopoxvirus 'O', Oedaleus senigalensis entomopoxvirus 'O', Operophtera brumata entomopoxvirus 'L', Schistocera gregaria entomopoxvirus 'O'. 11. Gammaentomopoxvirus: Aedes aegypti entomopoxvirus, Camptochironomus tentans entomopoxvirus, Chironomus attenuatus entomopoxvirus, Chironomus luridus entomopoxvirus, Chironomus plumosus entomopoxvirus, Goeldichironomus haloprasimus entomopoxvirus. There are many other poxviruses which are not assigned to a particular genus: Diachasmimorpha entomopoxvirus, Skunkpox virus, Uasin Gishu disease virus, Auzduk disease virus, Camel contagious ecthyma virus, Chamois contagious ecthyma virus, Sealpox virus, Crowpox virus, Peacockpox virus, Penguinpox virus, California harbor seal poxvirus, Cotia virus, Dolphin poxvirus, Embu virus, Grey kangaroo poxvirus, Marmosetpox virus, Molluscum-like poxvirus, Mule deer poxvirus, Nile crocodile poxvirus, Quokka poxvirus, Red kangaroo poxvirus, Salanga poxvirus, Spectacled caiman poxvirus, and Yoka poxvirus.
The paramyxoviruses (single stranded, negative sense) are divided into 7 genera: 1. Rubulavirus: Human parainfluenza virus 2, Human parainfluenza virus 4 (includes several different strains), Mapuera virus, Mumps virus, Porcine rubulavirus, Simian virus 5, Simian virus 41. 2. Avulavirus: Avian paramyxovirus 2, Avian paramyxovirus 3, Avian paramyxovirus 4, Avian paramyxovirus 5, Avian paramyxovirus 6, Avian paramyxovirus 7, Avian paramyxovirus 8, Avian paramyxovirus 9, Newcastle disease virus. 3. Respirovirus: Bovine parainfluenza virus 3, Human parainfluenza virus 1, Human parainfluenza virus 3, Sendai virus, Simian virus 10. 4. Henipavirus: Hendra virus, Nipah virus. 5. Morbillivirus: Canine distemper virus, Cetacean morbillivirus virus, Measles virus, Peste-des-petits-ruminants virus, Phocine distemper virus, Rinderpest virus. 6. Pneumovirus: Bovine respiratory syncytial virus, Human respiratory syncytial virus, Murine pneumonia virus. 7. Metapneumovirus: Avian metapneumovirus, Human metapneumovirus. There are also some unassigned viruses in this family: Tupaia paramyxovirus, Fer-de-Lance virus, Menangle virus, Nariva virus and Tioman virus.
Even a viral agent against a family such as the Arenaviridae or the Bunyaviridae is unknown; these viruses are simply too diverse. Because of the great diversity of these viruses, which arises in part due to the wide range of mammals and birds that these infect, for a compound to work generally against these is contrary to present medical knowledge. Indeed, there is presently no agent which is effective against even a modest range of pox viruses. Currently, the only marketed antiviral that has inhibitory effects on any poxvirus is Cidofovir, which, however, as of yet has not been established as effective for the treatment of any pox disease. The vast majority of both DNA and RNA viruses have no effective antiviral treatment. Schickli et al. (Human Vaccines, 5:9, 582-591) state “There is currently no approved RSV vaccine, and the goal of preventing RSV-associated illness in the general population remains unmet.”
Thus, the art of developing and testing drugs, particularly for use in treating any viral infection, is extremely unpredictable.
The breadth of the claims
Claims 9, 14-15, and 18-19 are very broad in terms of the type of diseases being treated: all types of viral infections are claimed to be treated with the compounds of claim 1.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides examples for treating SARS-CoV-2 in vitro by administering the compounds of claim 1 to activate NRF2. However, the specification does not provide any data that shows that these compounds are useful for treating any viral infection.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that the compounds of claim 1 could be predictably used as prevention or treatment for all viral infections other than SARS-CoV-2 virus.
Determining if a particular compound will treat any particular disease state would require formulation into a dosage form, and subjecting into clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the limited guidance and direction provided by Applicant.
Accordingly, the inventions of claims 9, 14-15, and 18-19 do not comply with the scope of enablement requirement of 35 U.S.C 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation with no assurance of success.
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.
Claims 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over Sun (Sig. Transduct. Target Ther. (2021) 6:212, cited in the IDS filed 03/22/2024) in view of Kazantsev (US 9,737,525, cited in the IDS filed 03/22/2024).
Regarding claims 1-2 and 5, Sun teaches that bardoxolone and bardoxolone methyl, two NRF2 activators, inhibit SARS-CoV-2 replication (Title). Sun teaches “it was reported that the Nrf2 pathway was suppressed in lung biopsies from COVID-19 patients and the induction of Nrf2 by 4-octyl-itaconate and dimethyl fumarate limited the host inflammatory response and inhibited the replication of SARS-CoV-2”) (p. 1, right column, para. 3) and “recommends testing their activities as anti-COVID-19 agents”. Sun teaches anti-SARS-CoV-2 activity and cytotoxicity of bardoxolone methyl and bardoxolone was tested in Calu-3 cells (Fig 1 caption). Calu-3 cells read on lung cells. Thus, Sun teaches a method of inhibiting SARS-CoV-2 and a method of treating SARS-CoV-2 comprising administering an Nrf2 activator to a lung cell. Sun does not teach the Nrf2 activator is one of the compounds of instant claims 1 and 2.
Kazantsev (col. 38) teaches the following compounds recited in instant claim 1:
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Kazantsev (col. 41) further teaches the following two compounds, also recited in instant claim 1.
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MIND4-17 is the compound specified in claim 2.
Kazantsev teaches that the compounds of the disclosure, including MIND4, MIND4A, MIND4-17, MIND4-17C, MIND4-17-3, and MIND4-17-33, are activators of the NRF2 pathway (abstract).
Thus, regarding claims 1-2 and 5, it would have been obvious to one of ordinary skill in the art prior to the filing of the instant application to modify the method of administering NRF2 activators to inhibit SARS-CoV-2 viral replication in lung cells as taught by Sun with the NRF2 activators as taught by Kazantsev. One would have been motivated and had a reasonable expectation of success to do so given the teaching by Sun that NRF2 activators (“induction of NRF2”) inhibited SARS-CoV-2 viral replication in lung biopsies along with the teaching by Kazantsev that their disclosed compounds, which are recited in instant claims 1-2, are NRF2 activators. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to for a person of ordinary skill in the art to substitute one functional equivalence (any NRF2 activators) for another (MIND4, MIND4-A MIND4-17, MIND4-17C, MIND4-17-3, MIND4-17-33) with an expectation of success, since the prior art establishes that both function in similar manner.
Thus, claims 1-2, drawn to inhibiting SARS-CoV-2 replication in a cell by administering certain NRF2 inhibitors; and claim 5, drawn to inhibiting SARS-CoV-2 replication in a lung cell; are rejected.
Regarding claims 3-4, Sun does not explicitly teach that the cell is a neuron or that the cell is in the central nervous system of a subject. However, Sun does teach anti-SARS-CoV-2 activity and cytotoxicity of bardoxolone methyl and bardoxolone was tested in Vero cells or Calu-3 cells (Fig 1 caption). Vero cells read on kidney cells and Calu-3 cells read on lung cells. Thus, Sun teaches inhibiting anti-SARS-CoV-2 activity in different organ cells. Moreover, Kazantsev teaches MIND4 and MIND4-17 are effective in activating NRF2 in neurons (col. 43, lines 41-45, “Given the NRF2 activating properties of MIND4 and MIND4-17, the effects of these compounds on neuronal NRF2 activation responses were tested and demonstrated in primary cortical neurons (DIVE) derived from wild type mice”) and that MIND4 is safe and effective to administer in mice and mice brains (Example 10: col. 36, lines 53-58, “Wild type mice (N=3) were subjected to MIND4 treatment at escalated dosing from 50 mg/kg up to a final dose of 275 mg/kg administered daily by intraperitoneal (i.p.) injection. No weight loss or sudden death were observed suggesting lack of acute toxicity of MIND4 in that dose range.”; also col. 37, lines 9-11, “HPLC analysis detected MIND4 presence in wild type mouse cortices at estimated 0.5 μM concentration, providing preliminary evidence for compound brain permeability”).
It would have been prima facie obvious to one of ordinary skill in the art prior before the effective filing date of the instant application to administer MIND4 to inhibit SARS-CoV-2 viral replication in neurons in the central nervous system of a subject because Sun teaches that activating Nrf2 is useful for inhibiting SARS-CoV-2 viral replication and because Kazantsev teaches that MIND4 activates Nrf2 in neuronal cells and is safe to administer to the brain of a subject.
Regarding claim 7, administering MIND4 to inhibit SARS-CoV-2 viral replication in neurons in the central nervous system of a mouse as suggested by the cited art reads on wherein the cell is in vivo.
Thus, claims 3-4 and 7 are all rejected.
Regarding claim 6, Kazantsev teaches that MIND4-17 inhibits inflammation in response to LPS and IFN-g stimulation in primary monocytes (col. 55, lines 22-25), noting that ex vivo peripheral immune cells from Huntington’s disease patients also produce inflammatory cytokines in response to LPS and IFN-g stimulation. In other words, one of ordinary skill in the art would have been motivated and had reasonable expectation of success to administer MIND4-17 to inhibit inflammation in an ex vivo cell.
Thus, it would have been prima facie obvious to administer MIND4-17 to an ex vivo cell to inhibit SARS-CoV-2 viral replication since the art teaches that activating NRF2 is useful for inhibiting SARS-CoV-2 viral replication, and because MIND4-17 activates NRF2 and one would be motivated to administer MIND4-17 to an ex vivo cell.
Regarding claims 8 and 9, Kazantsev further teaches administering MIND4, MIND4-17, and other claimed NRF2 inhibitors to a subject (claim 1 of Kazantsev), defined as “humans and other animals, particularly mammals” (col. 25, lines 48-49).
Thus, it would have been obvious to one of ordinary skill in the art prior to the filing of the instant application to administer the compounds in the instant disclosure to treat a SARS-CoV-2 infection in a subject and to ameliorate the inflammatory response in a subject infected thereof. One would have been motivated and had a reasonable expectation of success to do so given the teaching by Sun that NRF2 activators limit the host inflammatory response in COVID-19 infection and inhibited the replication of SARS-CoV-2 virus and the recommendation to test NRF2 activators as anti-COVID 19 agents; and the teaching by Kazantsev that the compounds of the disclosure are NFR2 activators that can be safely and effectively administered to a subject.
Thus claim 8, drawn to treating a SARS-CoV-2 infection in a subject by administering a compound of claim 1; and claim 9, drawn to ameliorating inflammatory or immune reactions associated with viral infection; are rejected.
Regarding claims 10, 11, 14, and 15, Kazantsev teaches the disclosed compounds are formulated in a pharmaceutical composition and it is typically formulated to be compatible with its intended route of administration including intravenous and oral (e.g., inhalation) (col 22, lines 31-35). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to administer the compounds by intravenous administration or by inhalation in view of the teachings of Kazantsev, since Kazantsev teaches these are suitable routes of administration for the disclosed compounds.
Regarding claims 12, 13, and 16-19, Kazantsev teaches a dosage of 60 mg/kg of MIND4 is effective for activating NRF2 (col. 48, lines 13-16) and safe to administer in mice. It would have been prima facie obvious to one of ordinary skill in the art to utilize the amounts of MIND4 taught by Kazantsev as a starting point for optimizing the amount of MIND4 utilized to treat SARS-CoV-2 infection since Kazantsev teaches this amount is useful for activating NRF2 and Sun teaches activating NRF2 is useful for treating SAR2-CoV-2 infection and because dosage and treatment regimen are result-effective variables, i.e. a variable that achieves a recognized result. In addition, Kazantsev notes that “it is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data” (col. 24, lines 28-32). Therefore, the determination of the optimum or workable dosages to treat SARS-CoV-2 would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Taken together, all this would result in the methods of claims 12, 13, and 16-19 with a reasonable expectation of success.
Conclusion
No claims are allowed.
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/OLIVER D HEES/Examiner, Art Unit 1628
/Rayna Rodriguez/Primary Examiner, Art Unit 1628