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
The instant application is a 35 USC 371 National Stage entry of international application PCT/US2022/017312, filed April 23, 2021, which claims the benefit of an effective US filing date under 35 USC 119(e) from US Provisional Application 63/152,260, filed February 22, 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on August 21, 2023 and January 14, 2026 were in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the IDS documents were considered and signed copies of the 1449 forms are attached.
Election/Restrictions
Applicant's election of the compound species
PNG
media_image1.png
98
331
media_image1.png
Greyscale
in the reply filed January 14, 2026 is acknowledged. Applicant contends that claims 1-3, 5-11 and 13-31 read on the elected species.
In accordance with the MPEP, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended (see MPEP 803.02). If prior art is then found that anticipates or renders obvious the non-elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be reexamined. Id. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. Id. In the event prior art is found during reexamination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final. Id.
As indicated above, the examiner searched the compound based on the elected species above, wherein: the claims drawn to the elected species were not found to be allowable. Since this scope was not found to be allowable, the scope of the search and examination was not extended further.
Status of the Claims
Currently, claims 1-31 are pending in the instant application. Presently, claims 4 and 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a non-elected invention there being no allowable generic or linking claim.
Claim 1-3, 5-11 and 13-31 are under consideration in the instant application. It has been determined that the entire scope claimed is not patentable.
Claim Objections
Applicant is advised that should claim 8 be found allowable, claim 16 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Sequence Compliance
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Please note paragraph [0168] which contains two primer sequences not identified by Sequence ID’s and not include in any sequence listing. Appropriate correction, as noted above, is required.
Improper Markush Grouping Rejection
Claims 1, 5-6, 8-9, 13-14 and 16-31 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the compounds of instant formula I, “
PNG
media_image2.png
170
277
media_image2.png
Greyscale
”, is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons. The species of the Markush group of compounds of instant formula I do not share a “single structural similarity” because there are no required structural features within each variable definition such that each member of the group would have at least one structural feature, which feature is essential to the activity/function of the claimed compounds, in common. This rejection applies for the Markush groups used to define each of variables E, Y, C, D, X, B and A. The rejected claims encompass a wide variety of chemical species which are in different recognized physical classes, and would embrace different chemical compounds that do not share any single structural similarity between the species. Such is evidenced by the fact that each position in instant formula I encompassed by the claims is a variable (i.e., no single position in the chemical formula can be construed as being common among each member of the Markush group). The claims recite a Markush grouping for each position in claimed formula I. For the purposes of providing an example, it is noted that the A and B variables, for instance, in independent claim 1 encompasses a wide variety of fused cyclic skeletons such as: naphthalene, indole, benzofuran, quinoline, etc. as well as their hydrogenated forms. Each of these fused cyclic structures are distinctly classified. This demonstrates that not all members recited in this Markush group belong to the same recognized chemical class; i.e., the species fail to share a single structural similarity or any substantial structural feature.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 1-3, 5-11 and 13-31 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 COVID-19 or sequelae thereof, is not enabling for treatment of any and all viral infections as claimed, or treatment and prevention of any and all sequelae thereof. 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.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification 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, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc. 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. § 112, first paragraph, have been described. They are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack thereof in the art,
4. the amount of direction or guidance present,
5. the presence or absence of working examples,
6. the breadth of the claims,
7. the quantity of experimentation needed, and
8. the level of the skill in the art.
The nature of the invention
Applicant is claiming methods for treating all viral infections by administering a compound of the instant formula.
The state of the prior art and the predictability or lack thereof in the art
The state of the prior art is that the pharmacological art involves screening invitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. what compounds can treat which specific diseases by what mechanism). There is no absolute predictability even in view of the seemingly high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic regimen on its face.
The instantly claimed invention is highly unpredictable as discussed below: It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instantly claimed invention is highly unpredictable since one skilled in the art would recognize that in regards to therapeutic effects of the above listed diseases, whether or not the disease is affected by the instantly claimed compounds would be expected to differ greatly depending on the particular disease, its underlying mechanism, and the structure of the particular compound within the very chemically diverse Formula I.
With respect to the treatment of viral infections, the specification fails to enable the skilled artisan to use the compound of formula (I) to treat HIV, for example. In addition, there is no proof that the claimed compounds have ever been administered to a human. The obstacles to therapeutic approaches and vaccine development with regard to retroviruses associated with AIDS in humans are well documented in the literature. See, for example, Huff [J. Med. Chem. 34(8) 1991, p.2305-2314], on page 2314. These obstacles include, but are not limited to: 1) the extensive genomic diversity associated with HIV, particularly with respect to the gene encoding the envelope protein, 2) the fact that the modes of viral transmission include virus-infected mononuclear cells, which pass the infecting virus to other cells in a convert form, as well as via free virus transmission, 3) existence of a latent form of the virus, 4) the ability of the retrovirus to traverse the blood brain barrier, and 5) the complexity and variation of the elaboration of the disease. The existence of these obstacles established that the contemporary knowledge in the art would prevent a skilled artisan from accepting any therapeutic or preventative regimen on its face. In addition, there is no established correlation between in vitro activity and accomplishing treatment of viral infections, especially HIV infections, in vivo, and there is no description of an actual method where a viral infection in a host is treated.
The state of the prior art is that viral therapy, remains highly unpredictable. The above analysis focuses on one particularly difficult to treat virus, but there are countless types of viral infections.
Herpes viruses. The Herpes viruses are mostly assigned to three subfamilies. Subfamily Alphaherpesvirinae: Ateline herpesvirus 1, Bovine herpesvirus 2, Cercopithecine herpesvirus 1, Cercopithecine herpesvirus 2, Cercopithecine herpesvirus 16, Human herpesvirus 1, Human herpesvirus 2, Macropodid herpesvirus 1, Macropodid herpesvirus 2, Saimiriine herpesvirus 1, Bovine herpesvirus 1, Bovine herpesvirus 5, Bubaline herpesvirus 1, Canid herpesvirus 1, Caprine herpesvirus 1, Cercopithecine herpesvirus 9, Cervid herpesvirus 1, Cervid herpesvirus 2, Equid herpesvirus 1, Equid herpesvirus 3, Equid herpesvirus 4, Equid herpesvirus 8, Equid herpesvirus 9, Felid herpesvirus 1, Human herpesvirus 3, Phocid herpesvirus 1, Suid herpesvirus 1, Gallid herpesvirus 2, Gallid herpesvirus 3, Meleagrid herpesvirus 1, Gallid herpesvirus 1, and Psittacid herpesvirus 1. Subfamily Betaherpesvirinae: Cercopithecine herpesvirus 5, Cercopithecine herpesvirus 8, Human herpesvirus 5, Pongine herpesvirus 4, Murid herpesvirus 1, Murid herpesvirus 2, Human herpesvirus 6, Human herpesvirus 7, Caviid herpesvirus 2, and Tupaiid herpesvirus 1. Subfamily Gammaherpesvirinae: Callitrichine herpesvirus 3, Circopithecine herpesvirus 12, Cercopithecine herpesvirus 14, Cercopithecine herpesvirus 15, Human herpesvirus 4, Pongine herpesvirus 1, Pongine herpesvirus 2, Pongine herpesvirus 3, Alcelaphine herpesvirus 1, Alcelaphine herpesvirus 2, Ateline herpesvirus 2, Bovine herpesvirus 4, Cercopithecine herpesvirus 17, Equid herpesvirus 2, Equid herpesvirus 5, Equid herpesvirus 7, Hippotragine herpesvirus 1, Human herpesvirus 8, Murid herpesvirus 4, Mustelid herpesvirus 1, Ovine herpesvirus 2, Saimiriine herpesvirus 2 and Callitrichine herpesvirus 1. In addition, there are a number of Herpesviruses which have not been assigned to one of the three subfamilies: Ictalurid herpesvirus 1, Acipenserid herpesvirus 1, Acipenserid herpesvirus 2, Acciptrid herpesvirus 1, Anatid herpesvirus 1 and Anguillid herpesvirus 1.
The Herpes viruses show considerable diversity. For example, the Alphaherpesvirinae have a short reproductive cycle, and are neurotropic, whereas the Betaherpesvirinae have a long reproductive cycle and are lymphotropic. Herpes viruses are similar in terms of virion structure but are widely separated in terms of genomic sequence and proteins. They have no common antigens. Their shape is unusually complex.
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 devided into 9 genuses: 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, Saffold 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 genuses: 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.
Unlike in the bacterial area, broad based anti-virals are unknown. 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, Volume 5, Issue 9, pages 582-591, September 2009} state “There is currently no approved RSV vaccine, and the goal of preventing RSV-associated illness in the general population remains unmet.”
Hence, in the absence of showing a correlation between all the diseases claimed for the full scope of the instantly claimed formula, one of skill in the art is unable to predict possible results from the administration of the compounds of formula (I) due to the unpredictability of the role of the instantly claimed compounds.
The amount of direction or guidance present and the presence or absence of working examples
Applicant’s disclosure does not enable one of ordinary skill in the art to use the claimed invention within the entire scope of diseases, having provided evidence that only a single compound of the incredibly broadly claimed formula have efficacy against COVID-19. There is no compound, let alone an entire class of compounds which are as distinct as those encompassed by the instantly claimed formula, that can treat the various and divergent diseases as claimed.
A disclosure should contain representative examples which provide reasonable assurance to one skilled in the art that the compounds which fall within the scope of a claim will possess the alleged activity. Receptor activity is generally unpredictable and a highly structure specific area, and the data provided is insufficient for one of ordinary skill in the art to extrapolate.
The disclosure does not provide how this provided data correlates to the treatment of the entirety of assorted diseases claimed over the entire scope of Formula (I). The instant specification is short of any examples or data in regards to the supposed treating of the aforementioned diseases. Applicants have not provided any competent evidence or disclosed tests that are highly predictive for the pharmaceutical use of the instant compounds. Pharmacological activity in general is a very predictable area. Note that cases involving physiological activity such as the instant case, “the scope of enablement obviously caries inversely with the degree of predictability of the factors involved." See In re Fisher, 427 F. 2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The breadth of the claims
The breadth of the claims is treating of all viruses as well as treating or preventing all sequelae thereof, comprising administration of an incredible breadth of compounds.
The quantity of experimentation needed
The nature of the pharmaceutical arts is that it involves screening in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities for each of the diseases and disorders instantly claimed. The quantity of experimentation needed would be undue when faced with the lack of direction and guidance present in the instant specification in regards to testing all of the viruses generically embraced in the claim language, and when faced with the unpredictability of the pharmaceutical art. Thus, factors such as “sufficient working examples”, “the level of skill in the art” and predictability, etc. have been demonstrated to be sufficiently lacking in the instant case for the instant method claims.
The level of the skill in the art
Even though the level of skill in the pharmaceutical art is very high, based on the unpredictable nature of the invention and state of the prior art and lack of guidance and direction, one skilled in the art could not use the claimed invention without undue experimentation.
MPEP 2164.01(a) states, "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562,
27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." That conclusion is clearly justified here. The examiner recommends limiting the compounds and viruses claimed to a scope which could be reasonably extrapolated from the anti-viral data provided.
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.
Claim(s) 1-3, 5-11 and 13-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/001572 (“the ‘572 publication”).
Determining the scope and contents of the prior art
The ‘572 publication discloses compounds of the formula
PNG
media_image3.png
113
154
media_image3.png
Greyscale
as inhibitors of Rho-associated protein kinase (ROCK), preferably ROCK2 (paragraph [0006]). The prior art teaches numerous compounds which anticipate instant Formula I. For example, as it pertains to the instantly elected species, the prior art teaches TDI01470 (paragraph [0177]) has an IC50 of 33nM with respect to ROCK2 and >10000 with respect to ROCK1, thus establishing that the compound is particularly selective for ROCK2 over ROCK1. As disclosed by the prior art, the prior art compounds are administered for the treatment of diseases, where viral infection is disclosed (paragraph [0200], claim 13).
Ascertaining the differences between the prior art and the claims at issue
The difference between the instant invention and the prior art is that the prior art does not teach a specific example where viral infection is treated.
Resolving the level of ordinary skill in the pertinent art
To this end, it is noted that MPEP 2141 states, "The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit. The Court quoting In re Kahn, 441 F.3d 977, 988, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006), stated that "[R]ejections on obviousness cannot be sustained by mere conclusatory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.’" KSR, 550 U.S. at ___, 82 USPQ2d at 1396. Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) " Obvious to try " - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
The ‘572 publication discloses that viral infections are treatable by the compounds disclosed therein. Accordingly, it would not have been considered inventive for the skilled artisan to follow the explicit suggestion of the prior art to treat diseases known in the art to be associated with ROCK inhibition, and in particular the ROCK2 selectivity demonstrated by the instantly elected species. Doing so would have been obvious because a person of ordinary skill in the art would be implementing the explicit suggestion of the ‘572 publication.
With respect to the dosages in claims 22-31, the art describes that 0.7 mg to about 700 mg/day should be administered (paragraph [0208]), where the dosage of the compound is each of which overlaps with the ranges recited by the instantly claimed methods. Further, dosage regimens may be adjusted such that a single bolus or several divided doses may be administered over time (paragraph [0207]). Regardless, “specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition” (paragraph [0207]). MPEP 2144.05(I) provides that "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003). See also In re Harris, 409 F.3d 1339, 74 USPQ2d 1951 (Fed. Cir. 2005) (claimed alloy held obvious over prior art alloy that taught ranges of weight percentages overlapping, and in most instances completely encompassing, claimed ranges; furthermore, narrower ranges taught by reference overlapped all but one range in claimed invention). Thus, the prior art ranges render the dosages of the instant claims obvious.
Accordingly, based on the teachings of the MPEP and KSR above, by employing the rationale in (B), (D), (E) or (G) above, it would have been obvious for one of ordinary skill in the art to treat viral infections in view of the teachings of the ‘572 publication. There would have been a reasonable expectation of success in treating these diseases since the same Compound was specifically disclosed as a selective ROCK2 inhibitor and the art describes the use for treating viral infections. The instantly claimed invention would have therefore been obvious to a person of ordinary skill before the filing of the instantly claimed invention.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alicia L. Otton whose telephone number is (571)270-7683. The examiner can normally be reached on Monday - Thursday, 8:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mr. Fereydoun Sajjadi can be reached on 571-272-0699. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALICIA L OTTON/Primary Examiner, Art Unit 1699
Prosecution Insights