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 .
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.
DETAILED ACTION
Applicants’ amendment and arguments filed on 12/15/2025 is acknowledged. Claims 1, 6, 10, 12, and 15 are amended, claims 4 and 13 have been cancelled, and claim 21 is newly added.
Claims 1-3, 5-12, and 14-21 are pending in the instant application, and are examined on its merits herein.
Priority
This application is a National Stage entry of PCT/US2021/053538 filed on 10/5/2021 and claims priority to U.S. provisional applications 63/176,445 filed on 4/19/2021, 63/175,977 filed on 4/16/2021, 63/124,578 filed on 12/11/2020, 63/087,766 filed on 10/5/2020, and 63/087,524 filed on 10/5/2020. A certified copy of the priority documents in English has been received.
Drawings
The replacement drawings of Fig. 2A-2D and Fig. 3C, filed on 12/15/2025, is acknowledged. The drawings are now in compliance with 37 CFR 1.121(d).
Rejections Withdrawn
Applicant’s amendment and arguments, with respect to the rejection of claims 4, 6, 13 and 15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, have been carefully considered and are persuasive. Claims 4 and 13 have been cancelled. Claims 6 and 15 have been amended to remove the parenthetical language. The rejection has been withdrawn.
Applicant’s amendment and arguments, with respect to the rejection of claims 1-4 and 7 under 35 U.S.C. 102(a)(1) as being anticipated by Nguyenla, as evidenced by Lahser, have been carefully considered and are persuasive. Claim 1 has been amended to limit the claims to a subset of PLpro that does not include the previously rejected species. The rejection has been withdrawn.
Applicant’s amendment and arguments, with respect to the rejection of claims 1, 8-13, and 16-18 under 35 U.S.C. 103 as being unpatentable over Nguyenla, as evidenced by Lahser, have been carefully considered and are persuasive. Claims 1 and 10 have been amended to limit the claims to a subset of PLpro that does not include the previously rejected species. The rejection has been withdrawn.
Applicant’s amendment and arguments, with respect to the rejection of claims 5 and 14 under 35 U.S.C. 103 as being unpatentable over Nguyenla, as evidenced by Lahser, as applied to claims 1 and 10, further in view of Klemm, have been carefully considered and are persuasive. Claims 1 and 10 have been amended to limit the claims to a subset of PLpro that does not include the previously rejected species. The rejection has been withdrawn.
Applicant’s amendment and arguments, with respect to the rejection of claims 6 and 15 under 35 U.S.C. 103 as being unpatentable over Nguyenla, as evidenced by Lahser, as applied to claims 1 and 10, further in view of Beeraka and Peng, have been carefully considered and are persuasive. Claims 1 and 10 have been amended to limit the claims to a subset of PLpro that does not include the previously rejected species. The rejection has been withdrawn.
The following are modified and/or new grounds of rejections necessitated by applicant’s amendment to the claims.
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.
Claims 1-3, 7-12, 16-18, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over PG Pub No. US 2023/0346812 to Cihlar (PTO-892), in view of Nguyenla (IDS dated 4/5/2023).
Cihlar ‘812 is drawn to methods and compounds for treating SARS-CoV-2 comprising administering a therapeutically effective amount of a compound of Formula I (paragraph 0005). Remdesivir is particularly disclosed as being administered in the disclosed method to a mammal, including a human (paragraph 0070). The compound of Formula I can be administered in combination with at least one additional therapeutic agent (paragraphs 0072 and 0360). The additional therapeutic agent is a nucleoside reverse transcriptase inhibitor, including sangivamycin, β-d-N4-hydroxycytidine, EIDD-2801 (also known as molnupiravir as evidenced by the instant specification at paragraph [0008]), EIDD-1931, or a combination thereof (paragraph 0365). The additional therapeutic agent can be a protease inhibitor (paragraph 0367). The protease inhibitor can be an HCV NS3/4A protease inhibitor. The additional therapeutic agent can be selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, faldaprevir, vedroprevir, sovaprevir, deldeprevir, narlaprevir and combinations thereof. The additional therapeutic agent can be an HCV NS5A or NS5B inhibitor (paragraph 0372). Exemplary NS5B polymerase inhibitors can be selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, and combinations thereof. The additional therapeutic could be polymerase inhibitor, including ribavirin, favipiravir, and combinations thereof (paragraph 0373). For the treatment of 2019-nCoV virus infections, preferably, the other active therapeutic agent is active against coronavirus infections (paragraph 0367). Cihlar ‘812 teaches that other small molecule or biologic antiviral agents targeting 2019-nCoV, including lopinavir/ritonavir, EIDD-1931, favipiravir, amongst others. The compounds are formulated with conventional carriers and excipients (paragraph 0309).
Although Cihlar ‘812 does not exemplify any compositions recited in the instant claims, it would have been prima facie obvious for one of ordinary skill in the art to combine remdesivir with a second additional therapeutic active, such as vaniprevir, paritaprevir, favipiravir, EIDD-1931, and/or EIDD-2801 for treatment of SARS-CoV-2. The combination would have been prima facie obvious to one of ordinary skill in the art with a reasonable expectation of success since Cihlar ‘812 teaches remdesivir as a disclosed compound within the scope of Formula I, further teaching that the composition containing a compound of Formula I can be administered together with a second therapeutic agent, including actives such as vaniprevir, paritaprevir, favipiravir, EIDD-1931, and/or EIDD-2801, for treatment of SARS-CoV2. Thus, it would have been prima facie obvious for one of ordinary skill in the art to arrive at a combination of remdesivir with any of the disclosed secondary additional therapeutic actives as taught by Cihlar ‘812, including vaniprevir, paritaprevir, grazoprevir, favipiravir, EIDD-1931, and/or EIDD-2801.
Cihlar ‘812 does not expressly teach that the combination of the compound of formula I, together with a second active agent, results in a synergistic effect. Furthermore, Cihlar ‘812 does not expressly teach that their combination of a first and second active agent includes about 5 to about 10-fold less SARS-CoV-2 RdRp inhibitor than the recommended dose of the SARS-CoV-2 RdRp inhibitor, nor a 5 to 10-fold less of SARS-CoV-2 PLpro inhibitor than the recommended dosage of the SARS-CoV-2 PLpro inhibitor.
Nguyenla discloses antiviral synergy in combinations of remdesivir with approved drugs in human lung cells. Remdesivir is a 1’-cyano-substituted adenine C-nucleoside ribose analogue which interferes with the activity of viral RNA-dependent RNA-polymerases (RdRp) (p. 2, paragraph 2). Nguyenla showed that the combination of velpatasivir/sofosbuvir increased the synergy of remdesivir (p. 5, first paragraph). Additionally, the triple combination of elbasvir, grazoprevir, and remdesivir showed stronger synergy with remdesivir than elbasivir alone. Specifically, the triple combination shifted the EC50 value of remdesivir about 20-fold, to about 50 nM at 10 mM elbasvir/grazoprevir (p. 5, first paragraph).
It would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Cihlar ‘812 with Nguyenla, and adjust the dosing of remdesivir with a second additional active, such as paritaprevir, for treatment of SARS-CoV2 infection, with a reasonable expectation of obtaining a synergistic effect. The combined teachings of the prior art do not expressly teach a synergistic effect as recited in claim 1, or the reduced-fold dosing of the RdRp inhibitor, as recited in instant claims 8 and 17, nor the reduced-fold dosing of the PLpro inhibitors, as recited in instant claims 9 and 18. However, in Fig. 4e and 4g, Nguyenla provides a dose response interaction matrix showing the EC50 value of the grazoprevir/remdesivir combination and triple combination (elbasivir/grazoprevir/remdesivir), respectively, in SARS-CoV-2-infected Calu-3 cells (p. 16). Nguyenla additionally teaches that the triple combination shifted the EC50 value of remdesivir about 20-fold, to about 50 nM at 10 mM elbasvir/grazoprevir. Additionally, Cihlar ‘812 particularly teach grazoprevir and paritaprevir as alternative additional therapeutic agents with HCV NS5B inhibitory activity. Since Nguyenla teaches antiviral synergistic combinations with remdesivir, and Cihlar ‘812 teaches alternative second therapeutic agents that are NS5B inhibitors, of which at least elbasivir, sofosbuvir, and grazoprevir are taught by Nguyenla to have a synergistic effect with remdesivir, one of ordinary skill in the art would have a reasonable expectation of success adjusting the dose of remdesivir when combined with paritaprevir, taught in Cihlar ‘812 as a NS5B inhibitor, for a synergistic effect.
Although the combined teachings of the prior art do not expressly teach identifying a SARS-CoV-2 infection in a patient prior to administration of the combination to the patient infected with SARS-CoV-2, both Cihlar ‘812 and Nguyenla expressly teach administration of their disclosed compositions for treatment of SARS-CoV-2. Thus, it would have been prima facie obvious for one of ordinary skill in the art to first identify the patient as being infected with SARS-CoV-2 virus before administering the combination.
Claims 5 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over PG Pub No. US 2023/0346812 to Cihlar (PTO-892), in view of Nguyenla (IDS dated 4/5/2023), as applied to claims 1 and 10, further in view of Klemm (PTO-892 of 9/15/2025).
The combined teachings of Cihlar ‘812 and Nguyenla are as discussed above.
The combined teachings of Cihlar ‘812 and Nguyenla differ from that of the instantly claimed invention in that the combined teachings of the prior art do not teach a composition that includes one or more inhibitors of viral proteins that are generated by SARS-CoV-2 PLpro cleavage. The instant specification teaches at paragraph [0005] that PLpro cleavage generates NSP3.
Klemm teaches the mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2. SARS-CoV-2 encodes two proteases, the papain-like protease (PLpro, encoded within NSP3) and 3-chymotrypsin-like “main” protease (3CLpro or Mpro, encoded by NSP5) (p. 1, right column, paragraph 2). PLpro cleaves NSP1, NSP2, AND NSP3. Klemm tested the ability of rac5c to inhibit the NSP3 (p, 8, right column, subheading “SARS2 PLpro inhibitors targe nsp3 protease and DUB activity”). It was determined that non-covalent small molecule SARS PLpro inhibitors target SARS2 PLpro, preventing self-processing of NSP3 in cells, and display high potency and excellent antiviral activity in a SARS-CoV-2 infection model (abstract). Klemm teaches that their studies suggest that a PLpro inhibitor can target viral replication directly and efficiently, and that these direct antiviral effects of PLpro inhibitors are likely further supplemented by suppressing PLpro’s role in subverting the innate immune system. Thus, Klemm suggests that PLpro inhibitors may prove useful in restarting (and/or rebalancing) host innate immune processes that are pathologically deregulated in Covid-19.
It would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Cihlar ‘812 and Nguyenla with Klemm, by including rac5c, taught by Klemm to be an inhibitor of NSP3, into the composition of Cihlar ‘812 for treatment of SARS-CoV2. One of ordinary skill in the art would have been motivated to make the combination because Klemm suggests that that PLpro inhibitors, such as rac5c, may be useful in restarting (and/or rebalancing) host innate immune processes that are pathologically deregulated in Covid-19. One of ordinary skill in the art would have a reasonable expectation of success as each of the teachings of Cihlar ‘812, Nguyenla, and Klemm are drawn to treatment of SARS-CoV-2 infection.
Claims 6 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over PG Pub No. US 2023/0346812 to Cihlar (PTO-892), in view of Nguyenla (IDS dated 4/5/2023), as applied to claims 1 and 10, further in view of Klemm (PTO-892 of 9/15/2025), as applied to claims 5 and 14, further in view of Beeraka (PTO-892 of 9/15/2025) and Peng (PTO-892 of 9/15/2025).
The combined teachings of Cihlar ‘812, Nguyenla, and Klemm are as discussed above.
The combined teachings of Cihlar ‘812, Nguyenla, and Klemm differ from that of the instantly claimed invention in that the combined teachings of the prior art do not teach a composition that further includes one or more inhibitors of the Markush of non-structural proteins recited in instant claims 6 and 15.
Beeraka teaches strategies for targeting SARS CoV-2. The genome of coronaviruses is reported to be significantly involved in coding both structural proteins, and non-structural proteins (NSPs) for effective viral replication (paragraph bridging columns on p. 8). NSP8C AND NSP7 are required for novice CoV viral particle formation through viral ORF lab polyprotein processing. Several novel small molecule inhibitors (NSMIs) were reported to target these NSPs in coronavirus infections to treat SARS. A “combination of zinc derivatives with pyrithione” targets NSP12, and ranitidine bismuth citrate targets NSP13, and have been tested in in vivo models of SARS. Beeraka teaches that these NSMIs should be tested against SARS-CoV-2 viral associated proteins and against the activity of NSP’s to derive an effective therapeutic intervention. Beeraka suggests that the development of NSMIs to target the synthesis of NSP’s in SARS-CoV-2 may deliver cellular antiviral responses by blocking their replication in host cells.
Peng teaches the structural and biochemical characterization of the NSP12-NSP7-NSP8 core polymerase complex from SARS-CoV-2. This complex of SARS-CoV-2 was compared with the SARS-CoV counterpart to improve our understanding of coronavirus replication and evolution which might indicate clues for the fitness of SARS-CoV-2 to human hosts (p. 2, left column, paragraph 2). Peng teaches that the structure of the SARS-CoV-2 polymerase complex highly resembles that of SARS-CoV (p. 2, right column, first full paragraph). There are 1, 4, and 25 residue substitutions between the two viruses in the structurally visualized regions of the NSP7, NSP8, AND NSP12 subunits, respectively, but these variations did not result in obvious structural changes in the polymerase complex.
It would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Cihlar ‘812, Nguyenla, and Klemm, with Beeraka and Peng, by including inhibitors of NSP12, such as a “combination of zinc derivatives with pyrithione”, as taught by Beeraka, into the composition of Cihlar ‘812 and Nguyenla for treatment of SARS-CoV-2. One of ordinary skill in the art would have been motivated to make the modification because Beeraka suggests that the development of NSMIs to target the synthesis of NSP’s in SARS-CoV-2 may deliver cellular antiviral responses by blocking their replication in host cells. Furthermore, it is prima facie obvious for one or ordinary skill in the art combine two compositions, each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose. See MPEP 2144.06(I). Alternatively, it would have been obvious for one to try the combination for treatment of SARS-CoV-2. One of ordinary skill in the art would have a reasonable expectation of success because Peng teaches that the structure of the SARS-CoV-2 polymerase complex highly resembles that of SARS-CoV.
Claims 1-3, 7-12, 16-19, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Nguyenla (IDS dated 4/5/2023), in view of Shah (IDS dated 4/5/2023).
The teachings of Nguyenla are as discussed above. Although Nguyenla does not expressly teach identifying a SARS-CoV-2 infection in a patient and administering their disclosed synergistic combination for the treatment of Covid-19, as discussed above, it would have been prima facie obvious for one of ordinary skill in the art to apply the disclosed combinations for treatment in Covid-19 patients infected with SARS-CoV-2. Furthermore, since the efficacy of the combination is disclosed to be useful for treating Covid-19, it would have been obvious for one of ordinary skill in the art to first identify the patient as being infected with SARS-CoV-2 virus before administering of the combination.
The teachings of Nguyenla differ from that of the instantly claimed invention in that it does not teach a SARS-CoV-2 PLpro inhibitor that is paritaprevir.
Shah teaches in silico studies on therapeutics agents for Covid-19 by repurposing drugs. Docking studies were performed over binding pocket of Covid-19 to find the potential small molecule to combat life threatening coronavirus disease. Molecular docking studies were performed on over 61 antiviral agents on the binding pocket of Covid-19, which are known to be active against different viral diseases, and have different mechanisms of action, including on DNA polymerase inhibition, protease inhibition, and inhibition of reverse-transcriptase (p. 8-9, section 3.1). Of those tested, 37 molecules showed binding interactions with different Covid-19 structures. Of the 37 molecules, lopinavir, asunaprevir, remdesivir, CGP421112A, indinavir, ritonavir, ABT450, marboran, and galidesivir were found to interact with more than 2 protein structures of Covid-19. ABT450 is also known as paritaprevir, and is an inhibitor of non-structural protein 3-4A (NSP 3/4A) protease for the treatment of hepatitis C (p. 11, left column, first paragraph). ABT450 shows many H-bonding interactions with the enzyme, similar to that of remdesivir (p. 12, left column, first paragraph). Shah teach that the specific H-bonding interactions may give rise to clinical potency of ABT450 against SARS-CoV-2.
It would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Nguyenla and Shah, by further including ABT450 (paritaprevir), taught by Shah to be an inhibitor of NS3/4A protease, into the triple combination of Nguyenla. One of ordinary skill in the art would have been motivated to make the combination because Shah suggests ABT450 as having potential clinical potency against SARS-CoV-2. One of ordinary skill in the art would have a reasonable expectation of success as both the teachings of Nguyenla and Shah are drawn to treatment of Covid-19.
The combined teachings of Nguyenla and Shah do not teach the reduced-fold dosing of the RdRp inhibitor, and reduced-fold dosing of the PLpro inhibitors. However, in Fig. 4e and 4g, Nguyenla provides a dose response interaction matrix showing the EC50 value of the grazoprevir/remdesivir combination and triple combination (elbasivir/grazoprevir/remdesivir), respectively, in SARS-CoV-2-infected Calu-3 cells (p. 16). Nguyenla additionally teaches that the triple combination shifted the EC50 value of remdesivir about 20-fold, to about 50 nM at 10 mM elbasvir/grazoprevir. Thus, it would have been prima facie obvious for one of ordinary skill in the art to adjust the dosing of remdesivir and/or grazoprevir and/or paritaprevir when included in the triple combination based on the desired inhibitory effects.
Claims 5 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Nguyenla (IDS dated 4/5/2023), in view of Shah (IDS dated 4/5/2023), as applied to claims 1 and 10, further in view of Klemm (PTO-892 of 9/15/2025).
The combined teachings of Nguyenla and Shah are as discussed above.
The combined teachings of Nguyenla and Shah differ from that of the instantly claimed invention in that the combined teachings of the prior art do not teach a composition that includes one or more inhibitors of viral proteins that are generated by SARS-CoV-2 PLpro cleavage. The instant specification teaches at paragraph [0005] that PLpro cleavage generates NSP3.
Klemm teaches the mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2. SARS-CoV-2 encodes two proteases, the papain-like protease (PLpro, encoded within NSP3) and 3-chymotrypsin-like “main” protease (3CLpro or Mpro, encoded by NSP5) (p. 1, right column, paragraph 2). PLpro cleaves NSP1, NSP2, AND NSP3. Klemm tested the ability of rac5c to inhibit the NSP3 (p, 8, right column, subheading “SARS2 PLpro inhibitors targe nsp3 protease and DUB activity”). It was determined that non-covalent small molecule SARS PLpro inhibitors target SARS2 PLpro, preventing self-processing of NSP3 in cells, and display high potency and excellent antiviral activity in a SARS-CoV-2 infection model (abstract). Klemm teaches that their studies suggest that a PLpro inhibitor can target viral replication directly and efficiently, and that these direct antiviral effects of PLpro inhibitors are likely further supplemented by suppressing PLpro’s role in subverting the innate immune system. Thus, Klemm suggests that PLpro inhibitors may prove useful in restarting (and/or rebalancing) host innate immune processes that are pathologically deregulated in Covid-19.
It would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Nguyenla and Shah with Klemm, by including rac5c, taught by Klemm to be an inhibitor of NSP3, into the composition of Nguyenla and Shah for treatment of SARS-CoV2. One of ordinary skill in the art would have been motivated to make the combination because Klemm suggests that that PLpro inhibitors, such as rac5c, may be useful in restarting (and/or rebalancing) host innate immune processes that are pathologically deregulated in Covid-19. One of ordinary skill in the art would have a reasonable expectation of success as each of the teachings of Nguyenla, Shah, and Klemm are each drawn to treatment of SARS-CoV-2 infection.
Claims 6 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Nguyenla (IDS dated 4/5/2023), in view of Shah (IDS dated 4/5/2023), as applied to claims 1 and 10, further in view of Klemm (PTO-892 of 9/15/2025), as applied to claims 5 and 14, further in view of Beeraka (PTO-892 of 9/15/2025) and Peng (PTO-892 of 9/15/2025)..
The combined teachings of Nguyenla, Shah, and Klemm are as discussed above.
The combined teachings of Nguyenla, Shah, and Klemm differ from that of the instantly claimed invention in that the combined teachings of the prior art do not teach a composition that includes one or more inhibitors of viral proteins that are generated by SARS-CoV-2 PLpro cleavage. The instant specification teaches at paragraph [0005] that PLpro cleavage generates NSP3.
The teachings of Beeraka are as discussed above.
The teachings of Peng are as discussed above.
It would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Nguyenla, Shah, and Klemm, with Beeraka and Peng, by including inhibitors of NSP12, such as a “combination of zinc derivatives with pyrithione”, as taught by Beeraka, into the composition of Nguyenla, Shah, and Klemm for treatment of SARS-CoV-2. One of ordinary skill in the art would have been motivated to make the modification because Beeraka suggests that the development of NSMIs to target the synthesis of NSP’s in SARS-CoV-2 may deliver cellular antiviral responses by blocking their replication in host cells. Furthermore, it is prima facie obvious for one or ordinary skill in the art combine two compositions, each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose. See MPEP 2144.06(I). Alternatively, it would have been obvious for one to try the combination for treatment of SARS-CoV-2. One of ordinary skill in the art would have a reasonable expectation of success because Peng teaches that the structure of the SARS-CoV-2 polymerase complex highly resembles that of SARS-CoV.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Nguyenla (IDS dated 4/5/2023), in view of Shah (IDS dated 4/5/2023), as applied to claim 19, further in view of WO/2020/210376 to Yadavalli (PTO-892 of 9/15/2025).
The combined teachings of Nguyenla and Shah are as discussed above.
The combined teachings of Nguyenla and Shah differ from that of the instantly claimed invention in that the combined teachings of Nguyenla and Shah do not teach that the SARS-CoV-2 polymerase inhibitor is orally ingestible by the patient.
Yadavalli ‘376 teaches compositions and drug delivery systems comprising highly porous activated carbon (HPAC) and a therapeutic, as well as methods of treating a disorder using the compositions. Synergy studies with acylclovir revealed that acyclovir may be adsorbed and/or is encapsulated within HPAC, resulting in a sustained release of acyclovir that generated a stronger therapeutic effect (paragraph 0006). Thus, the composition can comprise drug encapsulated carbon for delivery of many types of drugs for treatment of human and non-human diseases (paragraph 0007). In an exemplary embodiment, the therapeutic can be an anti-viral agent, such as, grazoprevir, paritaprevir, and remdesivir, recited in a Markush of other anti-viral agents (paragraphs 0010, 0018 and 0026). The compositions can be used for treating a viral infection, and used in preparation of a medicament for treatment of a viral infection (paragraph 0031). The disclosed Markush of viral infections include hepatitis C (p. 7), Coronaviridae, and SARS (p. 10). For sustained release, the HPAC compositions may be compressed into tablets, filled into capsules, or loaded into stick packs to sprinkle over food or into water or other liquid drinks (paragraph 0079). The HPAC is part of a pharmaceutical composition comprising HPAC and a pharmaceutically acceptable carrier, diluent, or excipient (paragraph 0092). The pharmaceutical composition may be administered to a subject via parenteral, nasal, oral, pulmonary, topical, vaginal, or rectal administration (paragraph 0097).
Thus, it would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Nguyenla and Shah, with that of Yadavalli ‘376, to prepare the combination of elbasivir/grazoprevir/remdesivir and ABT450 (paritaprevir) in an oral dosage form that can be orally ingestible by the patient since Yadavalli ‘376 teaches oral administration as one suitable route of administration. One of ordinary skill in the art would have a reasonable expectation of success since Yadavalli ‘376 teaches their composition is suitable for treatment of Coronaviridae and SARS, and further teaches grazoprevir, paritaprevir, and remdesivir as suitable therapeutics in their disclosed compositions.
Claims 1-3, 7-12, 16-19, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Nguyenla (IDS dated 4/5/2023), in view of Shah (IDS dated 4/5/2023), and Lahser (PTO-892 of 9/15/2025).
The teachings of Nguyenla are as discussed above. Although Nguyenla does not expressly teach identifying a SARS-CoV-2 infection in a patient and administering their disclosed synergistic combination in the treatment of Covid-19, as discussed above, it would have been prima facie obvious for one of ordinary skill in the art to apply the disclosed combinations for treatment in Covid-19 patients infected with SARS-CoV-2. Furthermore, since the efficacy of the combination is disclosed to be useful for treating Covid-19, it would have been obvious for one of ordinary skill in the art to first identify the patient as being infected with SARS-CoV-2 virus before administering of the combination.
The teachings of Nguyenla differ from that of the instantly claimed invention in that it does not teach a SARS-CoV-2 PLpro inhibitor that is paritaprevir.
The teachings of Shah are as discussed above.
Lahser teaches that grazoprevir is a hepatitis C virus NS3/4A protease inhibitor (title).
It would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Nguyenla and Shah, by substituting grazoprevir in the triple combination of Nguyenla, with paritaprevir, with a reasonable expectation of success, because, similar to grazoprevir, ABT450 is taught to function by inhibiting NSP 3/4A.
The combined teachings of Nguyenla, Shah, and Lahser do not teach the reduced-fold dosing of the RdRp inhibitor, and reduced-fold dosing of the PLpro inhibitors. However, in Fig. 4e and 4g, Nguyenla provides a dose response interaction matrix showing the EC50 value of the grazoprevir/remdesivir combination and triple combination (elbasivir/grazoprevir/remdesivir), respectively, in SARS-CoV-2-infected Calu-3 cells (p. 16). Nguyenla additionally teaches that the triple combination shifted the EC50 value of remdesivir about 20-fold, to about 50 nM at 10 mM elbasvir/grazoprevir. Thus, it would have been prima facie obvious for one of ordinary skill in the art to adjust the dosing of remdesivir and/or paritaprevir when used in the triple combination based on the desired inhibitory effects.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Nguyenla (IDS dated 4/5/2023), in view of Shah (IDS dated 4/5/2023), and Lahser (PTO-892), as applied to claim 19, further in view of WO/2020/210376 to Yadavalli (PTO-892 of 9/15/2025).
The combined teachings of Nguyenla, Shah, and Lahser are as discussed above.
The combined teachings of Nguyenla, Shah, and Lahser differ from that of the instantly claimed invention in that the combined teachings of Nguyenla, Shah, and Lahser do not teach that the SARS-CoV-2 polymerase inhibitor is orally ingestible by the patient.
The teachings of Yadavalli ‘376 are as discussed above.
Thus, it would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Nguyenla, Shah, and Lahser, with that of Yadavalli ‘376, to prepare the combination of elbasivir, ABT450 (paritaprevir), and remdesivir in an oral dosage form that can be orally ingestible by the patient since Yadavalli ‘376 teaches oral administration as one suitable route of administration. One of ordinary skill in the art would have a reasonable expectation of success since Yadavalli ‘376 teaches their composition is suitable for treatment of Coronaviridae and SARS, and further teaches grazoprevir, paritaprevir, and remdesivir as suitable therapeutics in their disclosed compositions.
Response to Arguments
Applicant’s argument and amendment with respect to the rejection of claim 19 over Nguyenla and Laser, further in view of Shah, have been carefully considered, but are not persuasive. Applicant argues that although Shah cited paritaprevir as a potential PLpro inhibitor that could act synergistically with an RdRp inhibitor such as remdesivir, the teachings of Shah is only based on in silico calculations that paritaprevir could bind to the Mpro RNA polymerase. Applicant notes that there is no disclosure or suggestion in Shah or any combination of Shah and the other cited references that paritaprevir could act as a PLpro inhibitor to show any synergistic effects with a RdRp inhibitor. This argument is not persuasive.
To the extent that Shah does not teach paritaprevir as a PLpro inhibitor, it should be noted that products of identical composition can not have mutually exclusive properties. See MPEP 2112.01(II) and in re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Furthermore, it is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by Applicant. See MPEP § 2144. See also, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006); Cross Med Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”). In other words, so long as the combined teachings of the prior art suggest a combination that includes paritaprevir, whether it is disclosed as a PLpro inhibitor is inconsequential as it would necessarily have that property. As discussed in the rejection above, it would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Nguyenla and Shah, by either further including ABT450 (paritaprevir), taught by Shah to be an inhibitor of NS3/4A protease, into the triple combination of Nguyenla, or by substituting grazoprevir in the triple combination of Nguyenla, with paritaprevir, with a reasonable expectation of success.
With regards to further including paritaprevir into the composition of Nguyenla and Shah, this would have been obvious to one of ordinary skill in the art as both Nguyenla and Shah teach compounds that are useful in the treatment of SARS-CoV-2 infection. See MPEP 2144.06. With regards to the substitution argument, both grazoprevir and ABT450 are each taught to function by inhibiting NSP 3/4A. Thus, it would have been obvious to substitute one known element for another.
One of ordinary skill in the art would have been motivated to make the combination because Shah suggests ABT450 as having potential clinical potency against SARS-CoV-2. One of ordinary skill in the art would have a reasonable expectation of success as both the teachings of Nguyenla and Shah are drawn to treatment of Covid-19. With regards to the claim synergistic effect, Nguyenla teaches the inclusion of a secondary agent results in a synergistic effect, exemplifying such as effect in the combination of elbasivir/grazoprevir/remdesivir, and also with grazoprevir/remdesivir. Thus, the instantly recited synergistic effect does not appear to be unexpected.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SCARLETT Y. GOON/
Supervisory Patent Examiner
Art Unit 1693
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