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 .
DETAILED ACTION
Claims 1 – 10 are pending in this application. Applicant’s preliminary amendment, submitted May 8, 2024, is entered, wherein claims 5 – 6 are amended.
Claims 1 – 10 are examined on the merits herein.
Priority
This application is a national stage application of PCT/JP2022/041473, filed November 8, 2022, which claims benefit of foreign priority documents JP2021-184546 and JP2022-050466, filed November 12, 2021 and March 25, 2022, respectively.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/08/2024 and 01/13/2025 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Objections
Claims 2 – 9 are objected to because of the following informalities:
Claims 2 – 9, lines 1 and 2, respectively, “Claim” should read “claim”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 – 9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “[wherein in the formulas…an aryl group]” as well as “(and when the alkyl group has 2 or more…between the carbon atoms)” in lines 6 – 15. The phrases are written within a bracket and a parenthesis. It is unclear whether the bracket phrase and the parenthetical phrase are limiting and they intended to define the structure or are merely providing non-limiting descriptive information. Thus, the metes and bounds of the claim are not clear and the phrases render the claim indefinite. Claims 2 – 9 depends from claim 1 and are, therefore, indefinite.
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 7 – 9 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 a pharmaceutical composition for treating an infection caused by an enveloped virus having a positive-sense single-stranded RNA gene, a coronavirus, or COVID-19, does not reasonably provide enablement for the full scope of the claimed pharmaceutical composition for preventing an infection caused by an enveloped virus having a positive-sense single-stranded RNA gene, a coronavirus, or COVID-19. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The Applicant’s attention is drawn to re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider where 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 nature of the invention;
(2) the state of the prior art;
(3) the relative skill of those in the art;
(4) the predictability or unpredictability of the art;
(5) the breadth of the claims;
(6) the amount of direction or guidance presented;
(7) the presence or absence of working examples; and
(8) the quantity of experimentation necessary.
The nature of the invention & The breadth of claims:
The claimed invention is directed to a pharmaceutical composition used in treating or preventing an infection caused by an enveloped virus having a positive-sense single-stranded RNA gene, a coronavirus, or COVID-19. In order to be enabled for the full scope of the invention, one skilled in the art must reasonably be able to ascertain which compositions are effective to prevent an infection caused by an enveloped virus having a positive-sense single-stranded RNA gene, a coronavirus, or COVID-19. Moreover, “preventing” an infection caused by an enveloped virus having a positive-sense single-stranded RNA gene, a coronavirus, or COVID-19 including administering the claimed formulation to a subject not suffering from an infection caused by an enveloped virus having a positive-sense single-stranded RNA gene, a coronavirus, or COVID-19 in such a manner that the subject does not experience the infection in the future.
The relative skill of those in the art:
The relative skill of those in the art is high.
The amount of direction or guidance presented & The presence or absence of working examples:
The specification provides several examples demonstrating antiviral activity of 2-thiouridine. Examples 1 and 2 describe in vitro assays in which cultured cells are infected with various coronaviruses, flaviviruses, and a togavirus and were thereafter evaluated for inhibition of virus-induced cell death or viral RNA replication. The results shown in Figures 1A – 1J demonstrate dose-dependent reductions in viral RNA levels in infected cells. These examples provide evidence that 2-thiouridine possesses antiviral activity after viral infection has occurred, but they do not demonstrate that administration of the claimed pharmaceutical composition prevents establishment of infection in an uninfected subject (para. [0063-0082]).
Example 3 evaluates therapeutic activity in mice infected with DENV2. The mice are infected on day 0, and administration of 2-thiouridine begins immediately following infection and continues thereafter. The reported increased survival and reduced serum viral RNA infection demonstrate treatment of an existing viral infection rather than prevention of infection (para. [0083 – 0089]).
Example 4 describes preparation of several structural analogs and reports in vitro antiviral activity against SARS-CoV-2. However, the example does not provide prophylactic animal data for those analogs or demonstrate that administration before viral exposure prevents infection (para. [0090 – 0102]).
Example 5 is the only example in which 2-thiouridine is administered before viral challenge. In the prevention study, mice receive a single intravenous dose of 2-thiouridine two hours before intranasal inoculation with a mouse-adapted SARS-CoV-2 strain. One day after inoculation, infectious viral titer and viral RNA are measured in the lungs. As shown in Figures 3A and 3B, the treated animals continue to exhibit measurable infectious viral and measurable viral RNA. The reported effect is a dose-dependent reduction in post-challenge viral burden relative to the vehicle control. Thus, the study demonstrates that pre-exposure administration can reduce viral replication following challenge, but it does not demonstrate that the treated animals remain free from infection or that the infection is prevented (para. [0103 – 0109]).
Although the specification provides guidance for identifying antiviral activity and includes one pre-exposure SARS-CoV-2 study, the disclosure does not provide a working example demonstrating that the claimed pharmaceutical composition prevents establishment of infection. Further, the specification does not provide criteria for distinguishing prevention of infection from reduction of viral burden after infection nor does it provide guidance showing how to obtain prevention across the full scope of the claimed viruses. In particular, no prophylactic working examples are provided for flaviviruses, togaviruses, or the broader class of enveloped positive-sense single-stranded RNA viruses encompassed by claims 7 – 8.
The state of prior art:
Yao et al. (Journal of Medical Virology, February 2020, Vol. 92, Issue 6, See PTO-892) teach that there are different coronaviruses, such as COVID-19, SARS-CoV, and MERS-CoV (page 536, Right Col., para. 2). Some in-vitro studies of SARS-CoV demonstrate that the combination of lopinavir and ritonavir may inhibit the SARS-CoV 3CLpro enzyme. Another study shows that neither lopinavir nor ritonavir has an effect on the replication of SARS-CoV. However, studies have revealed that lopinavir has antiviral activity against SARS-CoV (page 557, Left Col., para. 2 – 3). Some in-vitro studies of MERS-CoV shows LPV inhibition. Other study shows that LPV is not effective (page 557, Left Col., para. 5). For COVID-19, there are no reported in-vitro studies. A treatment of LPV/r was given to four patients and three patients showed significant improvement in pneumonia-associated symptoms (page 562, Left Col., para. 4). Yao et al. demonstrate variability in the antiviral efficacy of LPV/r across different coronavirus species, indicating that a single treatment cannot be presumed effective against all coronaviruses. Yao et al. also assert that there is no specific antiviral therapies for COVID-19 (Abstract), thus, there was no established therapies for treating COVID-19 at the time of filing, let alone for prevention of infection or transmission. Moreover, Virology Research Service (Virology Research Service, 2019, See PTO-892) teaches that individuals differ in their susceptibility to viral infections (page 3, para. 1). Multiple innate factors, such as age, nutritional status, genetics, immune competency, and pre-existing chronic diseases, and external variables, such as concurrent drug therapy, influence the overall susceptibility of a person exposed to a virus (page 3, para. 2).
The quantity of experimentation necessary:
In order to carry out the claimed preventative treatment, one of ordinary skill in the art would need to develop specifically preventative treatment from scratch with no assistance from Applicant’s declaration beyond the general idea that the claimed composition is capable of treating an infection caused by an enveloped virus having a positive-sense single-stranded RNA gene, a coronavirus, or COVID-19. Because an infection caused by an enveloped virus having a positive-sense single-stranded RNA gene, a coronavirus, or COVID-19 is caused by multiple factors as mentioned above, determining which healthy patients would benefit from this treatment would be difficult and unpredictable based on the state of the art, and any treatment is likely to be imperfectively effective given the influence of other factors.
The predictability or unpredictability of the art:
As disclosed by Yao et al., the antiviral efficacy of LPV, alone or in combination with ritonavir, varies across different coronaviruses species. This variability in antiviral activity across closely related coronavirus species indicates that therapeutic efficacy could not be reliably extrapolated from one coronavirus to another. Given the unpredictability of the therapeutic agents, the use of antiviral agents for prevention of infection would also have been uncertain. Moreover, the wide range of factors make it impossible to predict which subjects will develop a viral infection in the future and medication for treating coronaviruses are generally given to subjects already displaying symptoms rather than to healthy subjects who might develop the infection in the future.
Genentech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion.” And “patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.”
Therefore, in view of the Wands factors, as discussed above, particularly the state of art and the lack of guidance or working examples, Applicant fails to provide information sufficient to practice the claimed invention.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 – 2 and 4 – 10 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Hassan (WO2022/008025A1 with an international filing date July 5, 2021).
Hassan teaches 2-hydroxyiminopyrimidine nucleosides and derivatives and antiviral uses thereto (Title). Hassan teaches a compound of Formula I (page 2, para. 3):
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In one embodiment, sugar for formula I is ribose or a modified ribose of general formula (I-A) (page 3, para. 7):
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Hassan teaches an exemplary compound (page 44, para. 1):
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which corresponds to the general formula (A-1) of claim 1 and general formula (3) of claim 2, wherein R1 is an oxygen atom; R2 is =N-OR11, wherein R11 is a hydrogen atom; and R4, R5, and R6 are hydrogen. Thus, the disclosure of Hassan addresses independent claims 1 and 10 and dependent claims 2 and 4. The disclosed nucleosides and nucleotides analogs are used for treating and/or ameliorating infection caused by a Coronaviridae virus, a Caliciviridae virus, and Orthomyxoviridae virus, a Herpesviridae virus, a Flaviviridae virus, Filoviridae virus, and a Pneumoviridae virus (Abstract). The Coronaviridae virus include 2019-novel coronavirus (2019 nCoV) (page 36, para. 2). In some embodiments, the compound is in a pharmaceutical composition (page 42, para. 2). In certain embodiments, compounds disclosed by Hassan can be administered alone (page 42, para. 3), which indicates that the compound disclosed by Hassan is an active ingredient to treat the viral infection.
Regarding claims 5 and 7, Hassan teaches that the disclosed compounds are useful as antiviral agents for treating and/or ameliorating infections caused by numerous enveloped positive-sense single-stranded RNA viruses. Specifically, Hassan teaches treatment of infections caused by Coronaviridae virus and further identifies 2019 novel coronavirus as a Coronaviridae virus. Coronaviruses are enveloped viruses having positive-sense single-stranded RNA genomes, which addresses the limitation of claim 7. Accordingly, Hassan teaches that the disclosed compound possesses antiviral activity against enveloped viruses having a positive-sense single-stranded RNA genome, as recited in claim 5.
With respect to claim 9, Hassan teaches that the disclosed nucleoside compounds may be included in pharmaceutical compositions and used for treating or ameliorating infections caused by Coronaviridae viruses. Hassan explicitly identifies the 2019 novel coronavirus, also known as SARS-CoV-2, as a Coronaviridae virus encompassed by the disclosed treatment. SARS-CoV-2 causes the viral respiratory illness COVID-19. Therefore, Hassan’s disclosure of treating infection caused by SARS-CoV-2 discloses use of the pharmaceutical composition for treating COVID-19, thereby meeting the “used in treatment of COVID-19” limitation.
For these reasons, Hassan anticipates the claimed invention.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1 and 3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kumar (Nucleic Acids Research, 1997, Vol. 25, Issue 6, page 1272 – 1280, PTO-892).
Kumar teaches a synthesis (page 1274, Scheme 1):
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wherein the synthesis produces compound 3 identified as 2-thiouridine (page 1274, Left Col., para. 5):
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which corresponds to the general formula (A-1) of claim 1 and formula (A1) of claim 3, wherein R1 is an oxygen atom; R2 is a sulfur atom; and R4, R5, and R6 are hydrogen. The synthesis of 2-thiouridine is achieved in high yields by the coupling of the bis silyl derivative of 2-thiouracil with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose following the procedure of Vorbruggen and the hydroxyl protecting groups are removed with 2M NH3 in MeOH (page 1274, Right Col., para. 1). 2-thiouridine denotes the naturally occurring β-D-ribofuranosyl nucleoside of 2-thiouracil and therefore inherently possesses the stereochemical configuration of the ribose moiety shown in formula (A1). The differences between Kumar’s depiction of compound 3 and Applicant’s drawing are merely differences in the illustration of the molecule and do not represent different stereochemical configurations. Thus, the disclosure of Kumar addresses independent claim 1 and dependent claim 3.
The preamble recitation of “An antiviral agent” is considered a statement of intended use or intended property that does not impart a structural difference to the claimed compound. 2-thiouridine of Kumar and the compound recited in claims 1 and 3 are chemically and stereochemically identical. The characterization of the identical compound as an “antiviral agent” does not alter the chemical structure. Products of identical chemical composition cannot possess mutually exclusive properties; therefore, the antiviral property disclosed by Applicant is necessarily a property of the identical 2-thiouridine of Kumar.
For the reasons above, Kumar anticipates the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 – 2 and 4 – 10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 22, 24, and 26 – 27 of copending Application No. 18/262,326 (claim set of March 4, 2024) in view of Hassan (WO2022/008025A1 with an international filing date July 5, 2021) and Kataev (Chemistry of Heterocyclic Compounds, May 2021, Vol. 57, Issue 4, page 326 - 341, PTO-892).
‘326 claims an antiviral agent comprising a compound represented by general formula (1) or a derivative thereof:
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wherein R1 is -CH-(-Z1-R11)2, wherein Z1 is a single bond and R11 is a hydrogen atom (claim 22). ‘326 claims compound HUP1136 as an example (claim 24):
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‘326 further claims a pharmaceutical composition comprising the antiviral agent of claim 22 (claim 26) and the therapeutically effective amount of antiviral agent of claim 22 is administered to the subject for treating an infection due to a coronavirus or flavivirus (claim 27).
However, ‘326 does not claim an antiviral agent comprising a compound with general formula (A-1), wherein the C1’ carbon of the ribofuranose ring is connected to the heterocyclic moiety:
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Hassan teaches 2-hydroxyiminopyrimidine nucleosides and derivatives and antiviral uses thereto (Title). Hassan teaches a compound of Formula I (page 2, para. 3):
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In one embodiment, sugar for formula I is ribose or a modified ribose of general formula (I-A) (page 3, para. 7):
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Hassan teaches an exemplary compound (page 44, para. 1):
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which corresponds to the general formula (A-1) of claim 1 and general formula (3) of claim 2, wherein R1 is an oxygen atom; R2 is =N-OR11, wherein R11 is a hydrogen atom; and R4, R5, and R6 are hydrogen. Thus, the disclosure of Hassan reads on independent claims 1 and 10 and dependent claims 2 and 4. The disclosed nucleosides and nucleotides analogs are used for treating and/or ameliorating infection caused by a Coronaviridae virus, a Caliciviridae virus, and Orthomyxoviridae virus, a Herpesviridae virus, a Flaviviridae virus, Filoviridae virus, and a Pneumoviridae virus (Abstract). The Coronaviridae virus include 2019-novel coronavirus (2019 nCoV) (page 36, para. 2). In some embodiments, the compound is in a pharmaceutical composition (page 42, para. 2). In certain embodiments, compounds disclosed by Hassan can be administered alone (page 42, para. 3), which indicates that the compound disclosed by Hassan is an active ingredient to treat the viral infection.
Kataev teaches that antiviral nucleoside analogs are developed by modifying naturally occurring nucleosides. Specifically, Kataev teaches that synthesis of antiviral nucleoside analogs has been accomplished by (1) modifying the nucleobase (heterocyclic fragment), including replacing the nucleobase with another nitrogen-containing heterocycle and (2) modifying the D-ribofuranosyl fragment (page 326, Left Col., para. 2), demonstrating that the heterocyclic base attached to the ribose scaffold is a recognized variable in antiviral nucleoside design. Kataev further describes numerous antiviral nucleoside analogs in which different heterocyclic fragments are attached to the same ribose scaffold, including uracil-, thymine-, cytosine-, adenine-, guanine-, triazole-, and imidazole-containing nucleosides (page 327 – 331, Figures 2 – 7). In discussing the compounds shown in Figure 3, Kataev further teaches that the different nature of the heterocyclic fragment in compounds 21, 22, 23, 26, and 27 does not affect the usefulness of their antiviral action (page 328, Left Col., para. 1), indicating that one would have recognized different nucleobases attached to the ribose scaffold as suitable alternatives for maintaining antiviral activity. Accordingly, Kataev demonstrates that substitution of one antiviral nucleobase for another on the same ribofuranose scaffold is a conventional design strategy in the antiviral nucleoside art.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the antiviral agent of formula (1) as claimed in ‘326 by replacing the heterocyclic nucleobase attached to the C1’ carbon of the ribofuranose ring with the 2-hydroxyiminopyrimidine nucleobase in view of Hassan because Hassan explicitly teaches that 2-hydroxyiminopyrimidine nucleosides, including the exemplary compound corresponding to Formula (A-1), are antiviral agents useful for treating coronavirus infections. Further, Kataev teaches that antiviral nucleoside analogs are conventionally obtained by modifying the heterocyclic fragment, including replacing one nucleobase with another nitrogen-containing heterocycle, and further teaches that the different nature of the heterocyclic fragment does not affect the usefulness of the antiviral activity. Thus, Hassan identifies the 2-hydroxyiminopyrimidine nucleobase as a known alternative nucleobase for ribonucleoside antiviral compounds having the same intended therapeutic application and Kataev demonstrates that substitution of different antiviral nucleobases on the same ribofuranose scaffold is a conventional design strategy for obtaining antiviral nucleosides having the same intended therapeutic application. One of ordinary skill in the art would have been motivated to substitute the nucleobase of formula (1) of ‘326 with the known antiviral nucleobase of Hassan to obtain another antiviral ribonucleoside expected to exhibit antiviral activity against coronavirus infection. One of ordinary skill in the art would have had a reasonable expectation of success to modify the antiviral agent of formula (1) as claimed in ‘326 by replacing the heterocyclic nucleobase attached to the C1’ carbon of the ribofuranose ring with the 2-hydroxyiminopyrimidine nucleobase in view of Hassan and the conventional teachings of Kataev regarding nucleobase substitution in antiviral nucleosides because Hassan teaches complete ribonucleoside compounds incorporating the 2-hydroxyiminopyrimidine nucleobase, pharmaceutical compositions containing those compounds, and their antiviral activity against coronaviruses.
Regarding claims 5 and 7, Hassan teaches that the disclosed compounds are useful as antiviral agents for treating and/or ameliorating infections caused by numerous enveloped positive-sense single-stranded RNA viruses. Specifically, Hassan teaches treatment of infections caused by Coronaviridae virus and further identifies 2019 novel coronavirus as a Coronaviridae virus. Coronaviruses are enveloped viruses having positive-sense single-stranded RNA genomes. Accordingly, Hassan teaches that the disclosed compound possesses antiviral activity against enveloped viruses having a positive-sense single-stranded RNA genome, as recited in claim 5.
With respect to claim 9, Hassan teaches that the disclosed nucleoside compounds may be included in pharmaceutical compositions and used for treating or ameliorating infections caused by Coronaviridae viruses. Hassan explicitly identifies the 2019 novel coronavirus, also known as SARS-CoV-2, as a Coronaviridae virus encompassed by the disclosed treatment. SARS-CoV-2 causes the viral respiratory illness COVID-19. Therefore, Hassan’s disclosure of treating infection caused by SARS-CoV-2 discloses use of the pharmaceutical composition for treating COVID-19, thereby meeting the “used in treatment of COVID-19” limitation.
This is a provisional nonstatutory double patenting rejection.
Claims 1 – 2 and 4 – 10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2 of copending Application No. 19/711,228 (claim set of June 17, 2026) in view of Hassan (WO2022/008025A1 with an international filing date July 5, 2021) and Kataev (Chemistry of Heterocyclic Compounds, May 2021, Vol. 57, Issue 4, page 326 - 341, PTO-892).
‘228 claims a method of treating an infection due to a coronavirus or flavivirus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antiviral agent comprising HUP1108 (claim 1):
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‘228 claims that the infection due to a coronavirus is an infection due to SARS-CoV-2 (claim 2).
However, ‘228 does not claim an antiviral agent comprising a compound with general formula (A-1), wherein the C1’ carbon of the ribofuranose ring is connected to the heterocyclic moiety:
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Hassan teaches 2-hydroxyiminopyrimidine nucleosides and derivatives and antiviral uses thereto (Title). Hassan teaches a compound of Formula I (page 2, para. 3):
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In one embodiment, sugar for formula I is ribose or a modified ribose of general formula (I-A) (page 3, para. 7):
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Hassan teaches an exemplary compound (page 44, para. 1):
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which corresponds to the general formula (A-1) of claim 1 and general formula (3) of claim 2, wherein R1 is an oxygen atom; R2 is =N-OR11, wherein R11 is a hydrogen atom; and R4, R5, and R6 are hydrogen. Thus, the disclosure of Hassan reads on independent claims 1 and 10 and dependent claims 2 and 4. The disclosed nucleosides and nucleotides analogs are used for treating and/or ameliorating infection caused by a Coronaviridae virus, a Caliciviridae virus, and Orthomyxoviridae virus, a Herpesviridae virus, a Flaviviridae virus, Filoviridae virus, and a Pneumoviridae virus (Abstract). The Coronaviridae virus include 2019-novel coronavirus (2019 nCoV) (page 36, para. 2). In some embodiments, the compound is in a pharmaceutical composition (page 42, para. 2). In certain embodiments, compounds disclosed by Hassan can be administered alone (page 42, para. 3), which indicates that the compound disclosed by Hassan is an active ingredient to treat the viral infection.
Kataev teaches that antiviral nucleoside analogs are developed by modifying naturally occurring nucleosides. Specifically, Kataev teaches that synthesis of antiviral nucleoside analogs has been accomplished by (1) modifying the nucleobase (heterocyclic fragment), including replacing the nucleobase with another nitrogen-containing heterocycle and (2) modifying the D-ribofuranosyl fragment (page 326, Left Col., para. 2), demonstrating that the heterocyclic base attached to the ribose scaffold is a recognized variable in antiviral nucleoside design. Kataev further describes numerous antiviral nucleoside analogs in which different heterocyclic fragments are attached to the same ribose scaffold, including uracil-, thymine-, cytosine-, adenine-, guanine-, triazole-, and imidazole-containing nucleosides (page 327 – 331, Figures 2 – 7). In discussing the compounds shown in Figure 3, Kataev further teaches that the different nature of the heterocyclic fragment in compounds 21, 22, 23, 26, and 27 does not affect the usefulness of their antiviral action (page 328, Left Col., para. 1), indicating that one would have recognized different nucleobases attached to the ribose scaffold as suitable alternatives for maintaining antiviral activity. Accordingly, Kataev demonstrates that substitution of one antiviral nucleobase for another on the same ribofuranose scaffold is a conventional design strategy in the antiviral nucleoside art.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the antiviral agent HUP1108 as claimed in ‘228 by replacing the heterocyclic nucleobase attached to the C1’ carbon of the ribofuranose ring with the 2-hydroxyiminopyrimidine nucleobase in view of Hassan because Hassan explicitly teaches that 2-hydroxyiminopyrimidine nucleosides, including the exemplary compound corresponding to Formula (A-1), are antiviral agents useful for treating coronavirus infections. Further, Kataev teaches that antiviral nucleoside analogs are conventionally obtained by modifying the heterocyclic fragment, including replacing one nucleobase with another nitrogen-containing heterocycle, and further teaches that the different nature of the heterocyclic fragment does not affect the usefulness of the antiviral activity. Thus, Hassan identifies the 2-hydroxyiminopyrimidine nucleobase as a known alternative nucleobase for ribonucleoside antiviral compounds having the same intended therapeutic application and Kataev demonstrates that substitution of different antiviral nucleobases on the same ribofuranose scaffold is a conventional design strategy for obtaining antiviral nucleosides having the same intended therapeutic application. One of ordinary skill in the art would have been motivated to substitute the nucleobase of HIP1108 of ‘228 with the known antiviral nucleobase of Hassan to obtain another antiviral ribonucleoside expected to exhibit antiviral activity against coronavirus infection. One of ordinary skill in the art would have had a reasonable expectation of success to modify the antiviral agent HUP1108 as claimed in ‘228 by replacing the heterocyclic nucleobase attached to the C1’ carbon of the ribofuranose ring with the 2-hydroxyiminopyrimidine nucleobase in view of Hassan and the conventional teachings of Kataev regarding nucleobase substitution in antiviral nucleosides because Hassan teaches complete ribonucleoside compounds incorporating the 2-hydroxyiminopyrimidine nucleobase, pharmaceutical compositions containing those compounds, and their antiviral activity against coronaviruses.
Regarding claims 5 and 7, Hassan teaches that the disclosed compounds are useful as antiviral agents for treating and/or ameliorating infections caused by numerous enveloped positive-sense single-stranded RNA viruses. Specifically, Hassan teaches treatment of infections caused by Coronaviridae virus and further identifies 2019 novel coronavirus as a Coronaviridae virus. Coronaviruses are enveloped viruses having positive-sense single-stranded RNA genomes. Accordingly, Hassan teaches that the disclosed compound possesses antiviral activity against enveloped viruses having a positive-sense single-stranded RNA genome, as recited in claim 5.
With respect to claim 9, ‘228 recites that the coronavirus infection treated is an infection caused by SARS-CoV-2. Hassan further teaches that the disclosed nucleoside compounds are useful for treating and/or ameliorating infections caused by Coronaviridae viruses and explicitly identifies the 2019 novel coronavirus, also known as SARS-CoV-2, as one such virus. COVID-19 is the disease caused by SARS-CoV-2 infection and treatment of SARS-CoV-2 infection constitutes treatment of COVID-19. Accordingly, the combined teachings render obvious the use of the pharmaceutical composition for the treatment recited in claim 9.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is found to be allowable.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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