DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application is a national stage filing of PCT/JP2021/041053, filed 10/29/21, and claims the benefit of foreign priority to JP 2020-183229, filed 10/30/20. Applicant has provided a certified translation of the JP document in the response to the outstanding office action on 2/16/26.
It is noted that not all strains of SARS-CoV-2 recited in claims 4 and 5 were known at the time of the JP filing (see, for example, ALEEM, IDS 4/28/23, shows alpha, beta, and delta first reported 12/2020, gamma in 1/2021, and omicron in 11/21), nor do they find explicit support in the document, and thus claims 4 and 5 do not get benefit of priority to the JP foreign priority date.
Response to Amendments/Arguments
Claims 1, 4, and 5 are amended and new claims 6-9 have been presented in the response filed 2/16/26. Claims 1-9 are pending and have been examined on the merits.
Any rejection and/or objection not specifically addressed below in original or modified form is herein withdrawn.
With regards to the obviousness rejection, applicant has provided the certified translation, and thus the rejection has been reconsidered. Applicant provided no additional arguments that the claims were not obvious over the art as combined. As noted, the priority document does not provide explicit, inherent, or implicit support for the variants, and as such the translation would not be sufficient to overcome the rejection of claims 4 and 5. However, the rejection is withdrawn in favor of the rejections set forth below, which provides a more clear argument as to why the claims are rendered obvious over the art.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2-5 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. COVID-19 is the disease caused by any strain of SARS-CoV-2, and you cannot have COVID-19 without infection of SARS-CoV-2. They are intertwined such that you could not ever have COVID-19 without infection by SARS-CoV-2. With regards to the patient being symptomatic/asymptomatic, these are the only two possibilities for a patient with an infection, and you could not have any other option, and thus it is fully embraced by the claim from which it depends. In contrast, the claim would be further limiting if it were, for example, limited to “where the patient is asymptomatic.” This would exclude the “symptomatic” patient and be limiting. With regards to claims 4 and 5, the recited strains were all the known strains
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-3 and 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over MA (Ma, C., et al. Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease. Cell Res 30, 678–692 (2020)), in view of SHIRASAKI (Shirasaki, H.M. et al, Exploration of orally available calpain inhibitors: Peptidyl α-ketoamides containing an amphiphile at P3 site, Bioorg. Med. Chem. 13(14) 4473-4484 (2005)), KENI (Keni R, et al COVID-19: Emergence, Spread, Possible Treatments, and Global Burden. Front. Public Health 8(216) 1-13 (2020) ). and PRINCE (WO 2009/145956 A2).
Ma teaches methods of inhibiting SARS-CoV-2 viral replication through targeting of the Mpro, specifically identifying calpain inhibitors as effective and that, “the promising results of the calpain inhibitor MG-132” led to the “testing of other calpain and calthepsin inhibitors that are commercially available” (page 681). “This result suggests that calpain/cathepsin inhibitors are rich sources of drug candidates for SARS-CoV-2. Indeed, previous studies have shown that calpain II and cathepsin L are required for the proteolytic processing of the coronavirus S protein, a step that is essential for the viral fusion and genome release during the early stage of viral replication. Calpain and cathepsin inhibitors such as MDL28170 (calpain inhibitor III), MG-132, calpain inhibitor VI have been shown to inhibit SARS-CoV replication in cell culture. Other than the increased potency of targeting both Mpro and calpain/cathepsin, an additional benefit of such dual inhibitors might be their high genetic barrier to drug resistance. A significant number of calpain/cathepsin inhibitors have been developed over the years for various diseases including cancer, neurodegeneration disease, kidney diseases, and ischemia/reperfusion injury. Given our promising results of calpain inhibitors II (61) and XII (62) in inhibiting the SARS-CoV-2 Mpro and their potent antiviral activity in cell culture, it might be worthwhile to repurpose them as antivirals for SARS-CoV-2.” (page 687).
Ma does not teach the compounds
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Shirasaki teaches the compounds I and II as 18Bd (also known in the art as SNJ-1945) and SJA6017 (also known in the art as Calpain Inhibitor VI), respectively. Shirasaki teaches that SJA6017 was a known calpain inhibitor and that the developed compound 18Bd had good PK properties (page 4476) with enhanced 2h and 4h plasma levels (page 4476 and Figure 4).
Keni teaches that COVID-19 presents with severe pneumonia, fever, and cough, frequently progressing to acute respiratory distress syndrome (ARDS) with high mortality, particularly in older individuals or those with comorbidities. The main cause of death is acute respiratory distress resulting from inflammation in the lungs due to a cytokine storm, leading to respiratory failure and multi-organ complications, stating, “The main cause of death in COVID-19 patients was acute respiratory distress due to the inflammation in the linings of the lungs caused by the cytokine storm, which is seen in all non-survival cases and in respiratory failure. The resultant inflammation in the lungs, served as an entry point of further infection, associated with coagulopathy end-organ failure, septic shock, and secondary infections leading to death.” (page 5).
Further, Prince teaches the use of SJA6017 to reduce inflammation (e.g. claim 10), where the inflammation is in the pulmonary system (e.g. para 0047), such as a respiratory infection, bronchial condition, or pulmonary inflammation (e.g. claim 5). It is contemplated that the method can be practiced to treat inflammation associated with viral infections (e.g. para 0098) and SARS viral infections (e.g. para 109 and 110). Prince further teaches the calpain inhibitor can be administered with one or more additional therapeutic agents (e.g. claim 18), and contemplates that one or more calpain inhibitors can be administered together (e.g. para 0065).
In light of the teachings of Ma, it would have been obvious to look to the art for other calpain inhibitors, with improved functionality and/or commercially available, to use in the method of treating, or inhibiting COVID-19/SARS-CoV-2 infections, and used the commercially available SJA6017 and SNJ-1945 and SNJ-1495 is taught to have an desirable PK profile that would make it a target for therapeutic use with a reasonable expectation for success, as they are both taught to be calpain inhibitors and Ma teaches that, “… calpain/cathepsin inhibitors are rich sources of drug candidates for SARS-CoV-2”. Further, Prince teaches that the compounds also have the desirable property of use in reducing/treating respiratory inflammation, and contemplated the use of such compounds in treating SARS-CoV infections and such a strategy would be beneficial to the patients identified in Keni, which describes inflammation as a critical nexus to COVID infection and therapeutic intervention.
With regards to the use of the compounds in combination, Prince provides that the calpain inhibitor can be administered with one or more therapeutic agents (e.g. claim 18), and contemplates that one or more calpain inhibitors can be administered together (e.g. para 0065). Ma suggests a dual inhibitor approach to SARS-CoV-2 therapeutic regimens, and it would have been obvious to have looked to the art for compounds, such as the commercially available SNJ-1945 and SJA6017 where the compounds have improved pharmacokinetic properties, such as SNJ-1945, to use in combination, in order to obtain the benefit of the treatment of COVID-19/SARS-CoV-2 with the calpain inhibitors, and the advantage of the reduction in inflammation in SARS virus pulmonary infections suggested by Prince.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a). From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over MA, in view of SHIRASAKI, KENI, and PRINCE, as applied to claims 1-3 and 6-9, above, and in further view of CHAND (M. Chand et al. Public Health England. Investigation of novel SARS-COV-2 variant Variant of Concern 202012/01, 11 pages published 12/21/2020) and DEL RIO (del Rio C, Malani PN, Omer SB. Confronting the Delta Variant of SARS-CoV-2, Summer 2021. JAMA. 2021;326(11):1001–1002. published online 8/18/21)
The instant claims and teachings of Ma, Shirasaki, Keni, and Prince are above. The claims are further drawn to the method where the subject has a mutant variant of SARS-CoV-2.
Chand teaches the alpha variant (B.1.1.7) increased in proportion (see FIgure 2) and that “a novel variant has been identified which has spread rapidly within the UK.” Similarly, del Rio teaches that, “The US Department of Health and Human Services established a SARS-CoV-2 Interagency Group that created a classification system that includes variants of interest, variants of concern, and variants of high consequence. The B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) variants are all “variants of concern,” and that the delta variant first was identified in India in December 2020 (page 1001). Del Rio further teaches that “SARS-CoV-2 constantly mutates with new variants emerging as long as ongoing transmission persists.” (page 1001).
It would have been obvious to employ the strategy of treating emerging variants with the calpain inhibitors described above, because the patient population would continue to shift based on the art-recognized fact that the virus was constantly mutating and generating new strains. Because the condition remained a respiratory virus that negatively impacted the lungs through inflammation, one would have continued to use the commercially available calpain inhibitors with advantageous properties, especially since development of new therapeutics would take time and Keni teaches that the infection in the lungs and the deleterious outcomes were driven by inflammation.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a). From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Andrew D Kosar whose telephone number is (571)272-0913. The examiner can normally be reached Monday-Friday, 7am-3:30pm.
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/Andrew D Kosar/ Supervisory Patent Examiner, Art Unit 1625
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