DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-6, 8, 10-17, 19 and 20 are examined herein.
Claims 21-25, and 30 are withdrawn (see restriction/election below).
Priority
This application is filed 02/24/2023 and claims the benefit of domestic priority as below:
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Information Disclosure Statements
One IDS(s) received 2/28/2023, and all references from IDS(s) have been considered unless marked with a strikethrough.
Election/Restrictions
Applicant elects group I with SARS-CoV-2 as the species of RNA virus infection, merafloxacin as the species of Formula (I) or Formula (II), and remdesivir as the as the species of the additional pharmaceutically active compound with traverse in the reply filed on 10/1/2025 is acknowledged.
Applicant cites MPEP 803 and argues that all claims must be examined on the merits. Applicants reason for traversal includes MPEP 803 and a limited number of claims can be searched and examined together without serious burden. This is not found persuasive because MPEP 803 states that restriction is not required only when the search and examination of all claims can be conducted without serious burden. Conversely, when the claims require separate searches or distinct lines of examination, restriction and species election is appropriate.
In the present application, the claims are directed to distinct groups of inventions that differ in structural feature, mechanisms of action, and scopes of application. Examination of these claims would require multiple, independent search strategies and review of different prior arts, which cannot be reasonably accomplished through a single comprehensive search.
While it is acknowledged that restriction requirements in applications entering the U.S. national phase under 35 USC § 371 do not require a showing of search burden, the present claims nevertheless present issues that would also be applicable under standard U.S. examination practice. Specifically, the claims recite a broad genus encompassing multiple structurally distinct species, and examination of all species would impose a serious burden on the examiner.
The requirement is deemed proper and is therefore made FINAL.
The elected specie reads on the following claims 1-6, 8, 10-17, 19, and 20.
Although no anticipatory art was found of the elected species, the Examiner expandesd the search pursuant to MPEP 803.0. See 35 USC § 112 and § 103 rejections below.
Abstract
The abstract of the disclosure is objected to because the abstract should be in narrative form and
generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length.
The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details. The current submitted abstract is the front pages of PCT application. Examiner requests to bring in narrative form to satisfy the abstract requirement.
Correction is required. See MPEP § 608.01(b).
Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because:
The lines, numbers and lettering are not clean, well-defined, sufficiently dense and dark, and uniformly thick and well defined in Figure(s) 1C, 1G, 2C, 2E, 2G, 4, and 6A-F. See 37 CFR 1.84(l) and (q).
Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Claim Objections
Claims 1, and 13 are objected to because of the following informalities:
The term “stereoisomers” encompasses compounds have the same atomic connectivity but differing in the spatial arrangement, and “geometric isomers” are a subset of stereoisomers.
Appropriate correction is required.
Claim Rejections - 35 USC § 112, Enablement
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 1-6, 8, 10-17, 19 and 20 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while providing experimental data demonstrating modulation of programmed ribosomal frameshifting (PRF), and antiviral activity in cell culture for merafloxacin and certain analogs, does not reasonably enable the full scope of the claimed methods of treating all RNA virus infections without undue experimentation. The specification is not intended to enable a person skilled in the art to use the invention to the extent consistent with the claims, or to use the invention to the extent consistent with the claims, even if the person skilled in the art to which this specification pertains is skilled in the art to the extent consistent with the claims.
The instant claims are drawn to a method of treating, ameliorating, and/or preventing an RNA virus infection in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or Formula (II), including a salt, solvate, isotopically labelled derivative, stereoisomer, tautomer, or geometric isomer thereof, and any mixtures thereof. The claims broadly encompass treatment of infections caused by a wide range of RNA viruses without limitation to a specific virus, while also encompassing broad Markush genera of compounds defined by numerous alternative substituents. In the view of this breadth, the specification fails to provide sufficient expiations, data, or examples to enable a person of ordinary skill in the art to practice the claimed methods across the full scope of claims without undue experimentation.
To be enabling, the specification of the patent 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 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
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 the 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).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 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 level
The invention relates to a method for treating, ameliorating, and/or preventing an RNA virus infection through modulation of PRF. Although the level of ordinary skill in the art is advanced, antiviral drug development is highly unpredictable, especially targeting pseudoknots using Formula (I) or Formula (II). For example, the review of principles for targeting RNA with drug like small molecules from Warner et al. (Nature Reviews Drug Discovery, 2018, 17, 547–558, pub’d 07/06/2018) mentions that the overarching challenge of identifying appropriate RNA target structures with druggable binding pockets and observe that only limited class of RNA binding small molecules have reached clinical use, suggesting inherent difficulties in predicting small molecule activity against RNA targets. (abstract and the sections of provocative guidelines, and perspective)
The specification recites that “no existing antiviral therapeutics act by inhibiting this process” (page 2, line 4). While this may support novelty, it further underscores that PRF targeted antiviral therapy is not an established or clinically validated, or predictable therapeutic modality at the time of filing. The specification does not provide the prior art or guidance for predicting antiviral efficacy based solely on PRF modulation, nor does it establish a consensus regarding the relationship between PRF modulation and therapeutic outcomes across divers claimed RNA viruses. While the specification provides that merafloxacin inhibits PRF in SARS-CoV-2, and certain other beta coronaviruses and reduces viral replication in infected cell cultures, such disclosure is limited in scope and does not support the broad generalization of therapeutic efficacy to the treatment, amelioration, and/or prevention of RNA virus infections as broadly claimed. At most, the specification provides experimental support directed to the treatment of SARS-CoV-2 infection using specific exemplified compounds, and does not reasonably enable that claimed methods to that extent as they encompass other RNA viruses, preventative uses, or structurally diverse compounds within the broad Markush genera recited in the claims, without undue experimentations.
However, the same disclosure indicates that merafloxacin has limited or no activity against alphacoronaviruses, human immunodeficiency virus (HIV), West Nile virus (WNV), equine arteritis virus (EAV), and other virus tested (page 58 line 17 – page 59 line 9). These results indicates that responsiveness to PRF modulation depends on specific SARS-CoV-2 FSE sequence. As recognized in the review article from Atkins et al. (Nucleic Acids Research, 2016, 44, 7007-7078, pub’d 07/19/2016), ribosomal frameshifting is not a uniform or conserved mechanism across RNA viruses, but instead varies substantially with respect to genome organization, frameshift signal structure, and functional reliance on PRF (introduction section, and framing fidelity section).
RNA viruses shows substantial diversity in genome organization, secondary structures, replication, and reliance on PRF. Accordingly, therapeutic outcomes based on PRF modulation cannot be reliably predicted across the broad category of “RNA virus infections”, particularly where differences in frameshift efficiency and regulatory mechanisms are well documented in the art from Atkins et al. (occurrence and function in mobile elements, derivatives and secondary genomes section). Moreover, due to the structural variation of RNA virus and their utilization of distinction or dependence PRF, results are highly unpredictable.
The Examiner contends that RNA virus infections are mechanistically distinct. As can be inferred from Warner et al., and Atkins et al., any inference made for one type of RNA viruses cannot be assigned to other RNA virus infections as their mechanism and/or etiology are contrastingly different. Given that applicant has yet to provide any data demonstrating treatment, amelioration, and/or prevention of actual RNA virus infections, the Examiner maintains that Applicant has yet to enable the full breadth of the claims.
The breadth of the claims
The claims are thus very broad insofar as they recite the “a method of treating, ameliorating, and/or preventing an RNA virus infection”. The claims further encompass broad Markush genera of Formula (I) and (II) defined by numerous alternative substituents. Although the specification provides experimental data for merafloxacin and a limited number of closely related analogs, it does not provide representative species or structural guidance commensurate with the breadth of Formula (I) and (II). No predictive structure activity relationship for several different RNA virus infections is provided that would enable one of ordinary skill in the art to identify, without extensive screening, which embodiments within the claimed genera retain PRF modulating or antiviral activity.
The amount of direction or guidance provided and the presence or absence of working examples
The specification does not provide direction or guidance for the treatment, amelioration, and/or prevention of an RNA virus infection. No reasonably specific guidance is provided concerning useful therapeutic protocols for treating an RNA virus infection with said compounds. The specification absences working examples for reasonably specific guidance of the treatment including in vivo model data, pharmacodynamic data, dosing regiments, formulation and/or therapeutic window analyses for each RNA virus infections of each compound from Formula (I) and (II).
The claim 10 recites that “the compound of Formula (I) enhances PRF of the RNA virus”, and the specification recites that “out of the eight candidates, two compounds, ivermectin and merafloxacin, were validated as an enhancer and an inhibitor of PRF (page 58, lines 4-5). Ivermectin does not share the structure with Formula (I), and the specification does not provide Formula (I) enhances PRF of the RNA virus, and PRF enhancement confer therapeutic benefit for any RNA virus infection.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed the treatment, amelioration, and/or prevention of an RNA virus infection using compounds of Formula (I) and (II) via PRF mechanism could be predictably used for the treatment of every single RNA virus infection as inferred by the claims and contemplated by the specification.
Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim Rejections - 35 USC § 112, Written Description
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, 2, 6, 10, 11, 13, and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by applicants. (see MPEP 2163.02)
An objective standard for determining compliance with the written description requirement is, "does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed." In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989). Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed.
Further, the MPEP states that for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. (see MPEP 2161.01)
For instance, generic claim language in the original disclosure does not satisfy the written description requirement if it fails to support the scope of the genus claimed. Ariad, 598 F.3d at 1349-50, 94 USPQ2d at 1171 ("[A]n adequate written description of a claimed genus requires more than a generic statement of an invention’s boundaries.") (citing Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1405-06); Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002) (holding that generic claim language appearing in ipsis verbis in the original specification did not satisfy the written description requirement because it failed to support the scope of the genus claimed); Fiers v. Revel, 984 F.2d 1164, 1170, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) (rejecting the argument that "only similar language in the specification or original claims is necessary to satisfy the written description requirement").
As set forth in the en banc decision in Ariad Pharmaceuticals Inc. v. Eli Lilly and Company, 94 USPQ2d 1161 (Fed. Cir. 2010) at 1171, the court stated as follows:
We held that a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus. Id. At 1568-69. We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. At 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 [25 USPQ2d 1601] (Fed. Cir. 1993)). We have also held that functional claim language can meet the written description requirement when the art has established a correlation between structure and function. See Enzo, 323 F.3d at 964 (quoting 66 Fed. Reg. 1099 (Jan. 5, 2001)). But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.
With respect to claims 1, and 13, the claims recite “a compound of Formula (I), or a salt, solvate, isotopically labelled derivative, stereoisomer, tautomer, or geometric isomer thereof, and any mixtures thereof” and “the compound of Formula (I) is a compound of Formula (II) or a salt, solvate, isotopically labelled derivative, stereoisomer, tautomer, or geometric isomer thereof, and any mixtures thereof”. Claims 1 and 13 define a genus that includes (1) compounds of formula (I) or (II); (2) with extensive variable substituents (R10~R27); (3) optionally substituted substituents; (4) multiple types of structural variation, including salts, solvates, isotopically labelled derivatives, stereoisomers, tautomer, or geometric isomers.
In view of the extensive number of variable substituents and optical substituents permitted within the claimed genus, the claims encompass a huge number of structurally distinct compounds. Although claim 12 recites selected compounds of Formula (I), the specification fails to provide a representative number of species across the full scope of the claimed genus, structural derivative guidance, and/or a structure function correlation. Therefore, the specification fails to reasonably convey possession of the full scope of the claimed genus.
With respect to claims 1, 2, and 10, the claims recite that “the Formula (I) disrupts the programmed ribosomal frameshifting (PRF) of the RNA virus” in claim 2, and “the compound of Formula (I) enhances PRF of the RNA virus”. The specification states that “In certain embodiments, the compound of Formula (I) or Formula (II) inhibits the PRF of the RNA virus. In certain embodiments, the compound of Formula (I) or Formula (II) enhances the PRF of the RNA virus” (page 30 lines 4-8).
However, the specification fails to provide the compound of Formula (I) or Formula (II) enhances the PRF of the RNA virus. The experimental examples only provide detailed data demonstrating inhibition of PRF by merafloxacin in SARS-CoV-2 and related beta coronaviruses. For example, Figure 4 provides anti-frameshifting (i.e., inhibitory) ability results for synthesized merafloxacin analogs, but no data demonstrate PRF enhancement by compound within the claimed genus.
As recognized in the review article from Atkins et al., that mentions above, ribosomal frameshifting is not a uniform or conserved mechanism across RNA viruses, and modulation of ribosomal frameshifting is not an established or predictable therapeutic modality (introduction section, and framing fidelity section). Thus, the disclosure does not provide a structural relationship to perceive which compounds within the claimed genus would enhance PRF – no structure function correlation.
With respect to claims 10, and 11, the claims recite that “the compound of Formula (I) enhances PRF of the RNA virus” and “the RNA virus is at least one of human immunodeficiency virus, sindbis virus, west nile virus, and combinations thereof.”
However, the HIV experiment of the specification states that “no antiviral activity against an HIV-I reporter virus was observed (FIG. 7)” (page 61 line 4). No data are provided demonstrate PRF enhancement in HIV, sindbis virus, west nile virus and combinations thereof. Accordingly, the specification does not provide representative examples or structural guidance supporting PRF enhancement in these recited viruses.
As recognized in the review article from Atkins et al., PRF is not an established or predictable antiviral strategy across mechanistically diverse RNA viruses, and highly dependent on virus specific sequence and structural correlation (introduction, framing fidelity, and occurrence and function in mobile elements, derivatives and secondary genomes section). Consistent with this state of the art, the specification fails to identify any structural features of the claimed compounds that correlate with PRF enhancement, as opposed to PRF inhibition, in the recited viruses. Moreover, Clercq et al. (Clinical Microbiology Reviews, 2016, 29, 695-747, pub’d 06/08/2016) explains developed and approved antiviral agents with distinct mechanisms for diverse viral targets (Figure 4).
Accordingly, in the absence of any working or representative examples demonstrating PRF enhancement in human immunodeficiency virus, sindbis virus, west nile virus, and combinations without any disclosed structural relationship/mechanism supporting such activity does not support the full scope of claims 10 and 11.
With respect to claims 6, and 17, the claims recite co-administration with additional pharmaceutical active compounds including remdesivir. The specification states that “In certain embodiments, the compound believed to aid in the treatment and/or prevention of a coronavirus infection is remdesivir” (page 36 lines 28-30).
However, the specification fails to provide experimental data demonstrate co-administration, structural relationship, synergy effects, and dosing compatibility, or therapeutic interaction between compounds of Formula (I) or (II) interact additively, synergistically or antagonistically with remdesivir. Moreover, the drugs recited in claims 6, and 17 act through distinct mechanisms of action, with remdesivir functioning as a viral RNA dependent RNA polymerase inhibitor, whereas the claimed compounds are directed to modulation of PRF.
As recognized in the review article from Clercq et al., mentions above, the article explains broad antiviral drug development strategies, developed and approved antiviral agents with distinct mechanisms for diverse viral targets, and the clinical outcomes of combination therapies. Consistent with these states of the art, the specification provides no guidance or rational explaining why the claimed combinations of PRF modulating compounds and co-administration would be expected to be effective. Therefore, the specification fails to reasonably convey possession of the full scope of the claimed combination therapies.
As set forth in the en banc decision in Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010), to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention at the time of filing. Specifically, the specification must describe the claimed invention in a manner understandable to a person of ordinary skill in the art in a way that shows that the inventor actually invented the claimed invention at the time of filing. Id.; Ariad, 598 F.3d at 1351, 94 USPQ2d at 1172. (see MPEP 2161.01).
Accordingly, the specification does not reasonably convey to those skilled in the art that the inventors are in possession of 1) the fill genus of compounds encompassed by Formula (I) and Formula (II); 2) compounds that enhance PRF; 3) methods of modulating PRF in diverse RNA viruses beyond beta coronaviruses; 4) the full scope of claimed combination therapies.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-6, 8, 13-17, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Morrison et al. (WO 2015/051281 A1, pub’d 04/09/2015), in view of Wang et al. (“Treatment with Arbidol and Moxifloxacin in Ordinary and Severe Adult Patients Infected with COVID-19” ChemRxiv, pub’d 06/05/2020).
As discussed above with respect to the rejection under 35 USC § 112(a), the specification provides experimental support at most for the treatment of SARS-CoV-2 infection using specific exemplified compounds, such as merafloxacin, and its analogs. The present rejection under 35 USC § 103 is therefore directed to this enabled subject matter, namely, methods of treating RNA virus infections including SARS-CoV-2 by administering a therapeutically effective amount of a quinolone compound exemplified by Formular (I) and (II) including merafloxacin.
With respect to independent claim 1, the claim recite that a method of treating, ameliorating, and/or preventing an RNA virus infection by administering to the patient a therapeutically effective amount of a compound of Formula (I), or variant thereof. To the extent that the claim is enabled for treatment of SARS-CoV-2 using quinolone compounds of Formula (I).
Morrison teaches methods of preventing, treating or ameliorating a viral infection in a mammal by administering a quinolone compound (abstract, claims 3-5, and 10-12). Morrison further teaches that the viral infection is caused by RNA virus including alphavirus, flavivirus, and chikungunya virus (claims 6-9).
Morrison fails to explicitly disclose the elected specie, merafloxacin, and SARS-CoV-2.
However, Morrison teaches quinolone compounds such as clinafloxacin and moxifloxacin (claim 5), which are structurally related the embodiments within the same genus. The instant specification cites that “the quinolone compound is a compound of Formula (I) or Formula (II). In certain embodiments, the quinolone compound is selected from the group consisting of merafloxacin, trovafloxacin, moxifloxacin, clinafloxacin, and combinations thereof.” (instant specification page 31, lines 5-11). Thus, Morrison and the instant specification both recognize that these quinolone compounds belong to a common structural genus relevant to the claimed compounds of Formula (I). For example, in clinafloxacin, A is quinolone core with cyclic alkyl, R11a/b, R12a/b, and R14a/b are hydrogen, and R13 is NH2, R10 is C(=O)OR15, and R15 is hydrogen in Formula (I). The cyclic alkyl attached to N-site of quinolone core is inferred as claims 12 and 13.
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It would have been obvious to a PHOSITA at the time of the invention to administer the quinolone compounds of Formula (I) for preventing, treating or ameliorating for RNA virus infections as required in claim 1 (page 1, lines 8-10, and claims 1, and 5-9). Morrison teaches antiviral activity of quinolone compounds against multiple class of RNA viruses, including alphavirus and flavivirus (claims 6-9). Therefore, the application of such known quinolone compounds to the treatment of RNA virus infections broadly would have been expected to extend their antiviral utility.
The references is directed to the same field of endeavor and address related to the application. The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham.
Examples of 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.
Applying KSR example rationale (A) in the claim 1, it would have been prima facie obvious to administer the compounds of Formula (I) disclosed by Morrison for using the treatment, amelioration, or prevention of a RNA viral infection using quinolone compounds including clinafloxacin, and moxifloxacin, as corresponding genus structure with Formula (I). The claimed method therefore merely involves the use of known compounds according to their established antiviral function, yielding predictable results. (see MPEP 2141)
With respect to claims 3-5, 8, 13-16, and 19, Morrison further teaches the specific limitations recited in the dependent claims. As discussed above with respect to independent claim 1, Morrison teaches (1) methods of preventing, treating or ameliorating a viral infection in a mammal by administering a quinolone to the mammal (abstract, claims 3-5, and 10-12); (2) specific chemical structures corresponding to the genus structures of Formula (I) and (II) including clinafloxacin (claim 5 and instant specification page 31, lines 5-11), as required instant claim 3, 4, and 13-15; (3) quinolones and fluoroquinolones concluding ciprofloxacin are identified though screening for inhibitors of SARS-CoV, a beta coronavirus (page 6, lines 8-14), as required instant claims 5, 8, 16 and 19.
Applying KSR example rationale (A) and (B), it would have been prima facie obvious to combine and/or substitute Morrison’s disclosure of quinolone antiviral treatment methods with the specifically recited quinolone species and subclasses, as purpose, yielding predictable results.
With respect to claims 6 and 17, Wang discloses evaluating the therapeutic effects of Arbidol (i.e., umifenovir) and moxifloxacin in patients with COVID-19. Wang reiterates that the compound, moxifloxacin, shares genus structure with Formula (I) and (II) (instant specification page 31, lines 5-11), and teaches its use in treating an RNA virus infection, namely SARS-CoV-2 as a beta coronavirus (abstract), as required instant claims 5, 8, 16, and 19.
Wang further teaches the patient is further administered an additional pharmaceutically active compound including umifenovir (abstract), as required instant claim 6 and 17.
Applying KSR example rationale (A) and/or (F), it would have been prima facie obvious to administer moxifloxacin in combination with another known antiviral agent, such as umifenovir, for treating SARS-CoV-2 infection, as combining known antiviral agents for enhanced therapeutic effect represents a predictable use of prior art elements according to established treatment strategies.
Claims 1, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Morrison et al. (WO 2015/051281 A1, pub’d 04/09/2015), in view of Liu et al. (“The application of rough sets in SAR analysis of N1-site substituted fluoroquinolones” Chemometrics and Intelligent Laboratory Systems, 2007, 87, 155–160, pub’d 01/17/2007).
With respect to claim 12, as discussed above with respect to independent claim 1, Morrison teaches methods of preventing, treating or ameliorating a viral infection in a mammal by administering a quinolone to the mammal with the genus structures of Formula (I) (abstract, claims 3-5, and 10-12), and quinolones and fluoroquinolones concluding ciprofloxacin are identified though screening for inhibitors of SARS-CoV, a beta coronavirus (page 6, lines 8-14).
Morrison fails to teach the specific merafloxacin analogs recited in claim 12.
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Liu discloses the 3-dimension structure–activity relationships (3D-SAR) for N1-site substituted fluoroquinolones for developing pharmacodynamics function and resistance mechanism of new fluoroquinolones. Liu teaches structural modification at the N1 position of the fluoroquinolone core, including structures corresponding to N1-site substituted merafloxacin (figure 2). Two of N1-site substituted fluoroquinolone structures disclosed in Liu correspond to the specific structures recited in instant claim 12.
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Although, Liu does not teach that the compounds are related to antiviral activity, Liu provides structural guidance regarding N1-site substitution of fluoroquinolones, identifying substituents that maintain biological activity and desirable pharmacological properties. Therefore, Liu teaches structurally predictable modifications within the same fluoroquinolone genus disclosed by Morrison.
It would have been obvious to a PHOSITA at the time of the invention to modify the quinolone compounds disclosed by Morrison, including fluoroquinolones, by incorporating N1-site substitutions as taught by Liu, in order to obtain structurally related analogs with predictable biological properties. Morrison provides the motivation to use quinolone compounds for antiviral treatment, while Liu provides guidance on structurally viable N1 site substitutions within the same medicinal chemical scaffold. A person of ordinary skill in the art would have had a reasonable expectation of success in applying Liu’s N1 substitution strategies to Morrison’s antiviral quinolone compounds, as such modifications represent routine optimization within a known class of compounds.
Applying KSR example rationale (A), (B), and (E), it would have been prima facie obvious to (1) combine prior art elements according to known methods to yield predictable results; (2) substitute one known elements (e.g., N1 substituent) for another within a known fluoroquinolone scaffold to obtain predicable results; (3) choose from a finite number of identified, predictable N1 substitution options with a reasonable expectation of success.
Conclusion
Claims 1-6, 8, 10-17, 19, and 20 are rejected.
Claims 1, and 13 are objected to.
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/SEONG JONG KIM/ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621