DETAILED ACTION
Applicant's remarks filed May 27, 2025 are acknowledged and entered. Claims 1-3, 7-13, 15, 18, and 20-33 are under examination with regard to the tdsRNA species rIn·r(C11-14U)n. Claims 6, 15, 17-19 and 34-37 are withdrawn from consideration being directed to non-elected subject matter (i.e., product claims or non-elected species). The embodiment of rugged dsRNA remains withdrawn from consideration.
In the remarks filed May 27, 2025, Applicant reiterates that a definition of rugged dsRNA is provided on pages 11-12 of the specification, and that rugged dsRNA is a subset of tdsRNA. The specification indicates on pages 11-12 that rugged dsRNA is resistant to denaturation under conditions that are able to separate hybridized poly(riboinosinic acid) and poly(ribocytosinic acid) strands (rIn·rCn). (In light of this definition, it is understood that not all tdsRNA is resistant to denaturation under conditions that are able to separate hybridized poly(riboinosinic acid) and poly(ribocytosinic acid) strands (rIn·rCn).) Therefore, claim 15, directed to rugged dsRNA (according to the claim limitation and the definition in the specification), is withdrawn from consideration.
The provisional rejection of claims 1, 3, 7-11, 15, 16, 18, 20 and 21 on the ground of nonstatutory double patenting as being unpatentable over claims 15-20, 22 and 28 of copending Application No. 17/773,545 (reference application), in view of Mitchell and Carter (Emerging Microbes and Infections, 2014, 3, e77) is withdrawn in view of the cancellation of those claims in the copending application.
Claims Summary
Claim 1 is directed to a method of preventing, treating, inhibiting or attenuating (claim 3) an Ebola virus infection of a subject (e.g., a human (claim 13)), comprising administering an effective amount of a composition comprising a therapeutic double stranded RNA (tdsRNA), and a pharmaceutically acceptable carrier to the subject. The tdsRNA is rIn·r(C11-14U)n (claim 1 and 18), wherein n is selected from 40 to 50,000, for example (claim 16). This refers to a double-stranded RNA comprising two ssRNA. One strand, rIn, is poly ribo-inosine of n bases in length. The other strand is ssRNA in n bases in length, and a ratio of C bases to U bases in the random sequence ssRNA is 11-14 C to 1 U. One strand is hybridized to the other. The tdsRNA has one or more physical properties selected from about 4 to about 5000 helical turns of duplexed RNA, 30-38 helical turns of duplexed RNA, etc. (claim 20). At least 30 weight percent of total tdsRNA in the composition is a linear structure (claim 21). The tdsRNA is complexed with a stabilizing polymer (claim 22), such as polylysine (claim 23).
Administering is performed within a period of time from 96 hours before to 96 hours after exposure to Ebola virus, among other periods of time listed in claim 2. The composition does not further comprise an Ebola virus antigen, among others, listed in claim 7. The composition further comprises one or more selected from an absorption-promoting agent, a delivery-enhancing agent, etc. (claim 8). The subject is converted from seronegative to seropositive for Ebola without symptoms of infection (claim 9). The method produces immune resistance to Ebola virus infection after exposure to Ebola virus (claim 10), lasting for at least 6 months, at least 1 year, or at least 2 years (claim 11). The composition further comprises a purified natural-source human alpha interferons (claim 12) which is a purified mixture of at least three human IFN alpha proteins with native amino acid sequences and glycosylation patterns (claim 26), and is administered in a dosage from 5 IU per pound body weight/day to 100,000 IU per pound body weight/day (claim 27). The composition is administered at a dosage of about 25-600 mg of tdsRNA (claim 24). The composition is administered at a rate which is one dose per day, one dose every 2 days, etc. (claim 25). Administering is systemic, IV, etc. (claim 28), via a delivery system selected from nebulizer, sprayer, etc. (claim 29). The composition is a prophylactic or therapeutic vaccine and further comprises one or more Ebola virus antigens, a nucleic acid encoding one or more Ebola virus antigen, an inactivated Ebola virus, or an attenuated Ebola virus (claims 30 and 32). The composition is a nasal vaccine (claim 31). The combination of the tdsRNA and the Ebola antigen provides a vaccine effect that is superior than that of the Ebola antigen administered alone (claim 33).
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.
Claims 1-3, 7-11, 13, 16, 20-23, 25 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Kende et al. (Antiviral Research, available online January 3, 2019, 163:179-184, “Kende”) in view of Mitchell and Carter (Emerging Microbes and Infections, 2014, 3, e77, 2 pages, of record in the IDS filed 12/21/2021, “Mitchell”). The claims are summarized above and correlated with the teachings of the prior art in bold font below.
Kende discloses the administration of PolyICLC to mice and non-human primates (NHPs) in both a prophylactic and therapeutic protocol (see abstract). PolyICLC, comprising polylysine and carboxymethyl cellulose in a sterile NaCl solution, or liposomal PolyICLC was administered subcutaneously (see page 180, section 2.2) (claims 1, 7, 8, 13, 25 and 28). In some embodiments, mice and NHPs were challenged on day 0 (see page 180, sections 2.4 and 2.5), or treated on day 0, +2, +4, etc. (see page 181, section 3.4) (claim 2). Regarding claim 3, directed to a limitation wherein the method attenuates replication of Ebola virus in the subject, the fact that Kende observed protection against challenge means that replication of virus was attenuated. Although Kende does not describe the pathogen free mice as seroconverting after viral challenge and showing no symptoms of Ebola virus infection, it is clear that seroconversion took place because the mice were completely protected from an otherwise lethal dose of virus (see page 180, section 3.1, for example) (claims 9 and 10).
The teachings of Kende are outlined above, however, the elected species, rIn·r(C11-14U)n, is not taught. It would have been obvious to have substituted Kende’s tdsRNA, PolyICLC, with an alternative tdsRNA with predictable results. Mitchell discloses the use of either PolyICLC or rintatolimod rIn·r(C12U)n for Ebola treatment (see page 1, right column, last paragraph through end of page 2) (claim 1).
In Kende’s treatment protocol, mice were protected against a back-challenge at 8 weeks (see page 181, right column, first full paragraph). Administering rintatolimod is expected to have the claimed effect of immune resistance for at least 6 months, since it is a compound that falls within the scope of the claimed formula (claim 11).
Claim 16 is directed to an embodiment wherein the n, of rIn·r(C11-14U)n, is selected from 40-50,000; 50-10,000; 60-9,000; 70-8,000; 8-7,000; 40-500; 380-450; or a combination thereof. Mitchell does not suggest a value for n, however it would have been obvious to have determined the optimal value of n, as it is a result-effective variable concerning the efficacy of the tdsRNA for the intended purpose of treating Ebola virus infection.
Since there is no indication that rintatolimod is branched or contains any loops, it is linear (claim 21). It is also expected to have about 4 to about 5000 helical turns of duplexed RNA (clam 20). The use of the stabilizing polymer, polylysine, (present in PolyICLC) in combination with rintatolimod would have been obvious for the purposes of stabilization, with a reasonable expectation of success (claims 22 and 23). Therefore, the claimed embodiments would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Applicant’s arguments filed May 27, 2025 are similar in content to those previously presented in the remarks filed November 8, 2024. The remarks are acknowledged but fail to persuade. Applicant argues that Kende and Mitchell do not teach or suggest that polyICLC and rIn·r(C11-14U)n are interchangeable for treatment of Ebola virus. Applicant notes that Mitchell merely stated that polyICLC (Hiltonol®) and/or rintatolimod (rIn·r(C12U)n) “are attractive evidence-based candidates for the treatment of EVD” (Ebola virus disease) (see Mitchell, second page, right column). Applicant argues that no one was reported to have treated Ebola with these compounds, or any other poly IC compound. Applicant asserts that given the complexity of Ebola pathogenesis and the lack of empirical evidence, one would not conclude that poly-ICLC and rintatolimod (rIn·r(C12U)n) would be interchangeable.
In response to Applicant’s arguments, Mitchell’s teaching that polyICLC and/or rintatolimod “are attractive evidence-based candidates for the treatment of EVD” (Ebola virus disease) (see Mitchell, second page, right column) is motivation to use rintatolimod in Kende’s method as an alternative to PolyICLC, with a reasonable expectation of success. A constructive reduction to practice is not required. Mitchell does not have to perform any experiments in order for one of ordinary skill in the art to be motivated to use rintatolimod to treat Ebola with a reasonable expectation of success based on the reasoning provided (see page 2, right and left columns, bridging paragraph). Applicant has not submitted any evidence to cast doubt on Mitchell’s teachings. Applicant’s arguments cannot take the place of evidence. Therefore, the rejection is maintained.
Claims 12, 26 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Kende et al. (Antiviral Research, available online January 3, 2019, 163:179-184, “Kende”) in view of Mitchell and Carter (Emerging Microbes and Infections, 2014, 3, e77, 2 pages, of record in the IDS filed 12/21/2021, “Mitchell”), as applied to claim 1 above, and further in view of Carter and Strayer (US Patent 7,678,774 B2, “Carter”). Claims 12, 26 and 27 are directed to embodiments wherein the composition further comprise a purified natural source of human alpha interferons. The claims are correlated with the teachings of the prior art in bold font below.
The teachings of Kende and Mitchell are outlined above, neither of which discloses co-administration of a natural mixture of human alpha interferons. However, it would have been obvious to have included such a mixture of interferons with the composition of Kende/Mitchell. Carter discloses a composition for treating SARS comprising rintatolimod and Alferon N Injection®, which is comprised of at least seven natural species of alpha interferon (claim 12) and is produced in human white blood cells (thus having human glycosylation patterns (claim 26)) (see Carter, col. 2, lines 1-19). Carter notes that administration of the interferon mixture increased survival of subjects receiving 1.0, 10.0 or 20 IU (see Carter, col. 2, lines 29-30) (claim 27). One would have been motivated to include the interferon mixture with the rintatolimod composition of Kende/Mitchell in order to improve the antiviral response, as was shown for SARS using rintatolimod and the interferon mixture, with a reasonable expectation of success. Therefore, the claimed embodiments would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Applicant argues that Carter’s teachings deal with treating SARS, not Ebola. Applicant asserts that because the two diseases are divergent in terms of their mode of transmission, i.e., airborne versus direct contact with infected bodily fluids or tissues, it would not have been obvious to have applied the teachings of Carter to Kende/Mitchell. In response to Applicant’s argument, the combination of rintatolimod and the interferon mixture was shown to improve the antiviral response of rintatolimod. Given that the same compound is taught by Mitchell, there is a reasonable expectation of success that the interferon mixture of Carter will improve the antiviral response of rintatolimod against another viral infection, regardless of the mode of transmission. (Note that some of the modes of transmission are shared between the two viruses, such as direct contact with infected bodily fluids.) Therefore, the rejection is maintained.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Kende et al. (Antiviral Research, available online January 3, 2019, 163:179-184, “Kende”) in view of Mitchell and Carter (Emerging Microbes and Infections, 2014, 3, e77, 2 pages, of record in the IDS filed 12/21/2021, “Mitchell”) as applied to claim 1 above. Claim 24 is directed to an embodiment wherein the composition is administered at a dosage of about 25-700 mg of tdsRNA.
The teachings of Kende are outlined above, however, the dosing amount of 25-700 mg of tdsRNA is not disclosed. However, it would have been obvious to have determined the dosing amount of tdsRNA, as it is a result-effective variable concerning the efficacy of the tdsRNA for the intended purpose of treating Ebola virus infection. Therefore, the claimed embodiment would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. Applicant’s arguments have been addressed above.
Claims 28 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Kende et al. (Antiviral Research, available online January 3, 2019, 163:179-184, “Kende”) in view of Mitchell and Carter (Emerging Microbes and Infections, 2014, 3, e77, 2 pages, of record in the IDS filed 12/21/2021, “Mitchell”) as applied to claim 1 above, and further in view of Jonsson-Schmunk and Croyle (Expert Rev. Anti Infect. Ther., 2015, 13(5):527-530, “Jonsson-Schmunk”).
The teachings of Kende/Mitchell are outlined above. Kende does not disclose nasal administration, rather, subcutaneous administration. However, it would have been obvious to have made a nasal formulation for human subjects. Jonsson-Schmunk discloses a nasal vaccine for Ebola, noting advantages such as needle-free, can be administered by non-professional (see page 528, left column, last full paragraph), acceptable for all ages, genders, regions and cultures (see page 529, right column). One would have been motivated to formulate Martins’ composition for nasal administration for humans, with a reasonable expectation of success. Therefore, the claimed embodiment would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Applicant’s arguments have been addressed above. Additionally, Applicant argues that Jonsson-Schmunk’s disclosure is limited to nasal vaccine delivery, and does not address administration of dsRNA, Ebola, interferon signaling nor rIn·r(C11-14U)n. In response, the rejection is based on a combination of references, not a piecemeal analysis of each one. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Kende et al. (Antiviral Research, available online January 3, 2019, 163:179-184, “Kende”) in view of Mitchell and Carter (Emerging Microbes and Infections, 2014, 3, e77, 2 pages, of record in the IDS filed 12/21/2021, “Mitchell”) as applied to claim 1 above, and further in view of Schmunk and Croyle (Expert Rev. Anti Infect. Ther., 2015, 13(5):527-530, “Jonsson-Schmunk”) and Djupesland (Drug Deliv. Transl. Res., 2013, 3(1):46-62, “Djupesland”). Claim 29 is directed to embodiments specifying a nasal delivery system
The teachings of Kende/Mitchell are outlined above. Kende does not disclose nasal administration, rather, subcutaneous administration. However, it would have been obvious to have made a nasal formulation for human subjects. Jonsson-Schmunk discloses a nasal vaccine for Ebola, noting advantages such as needle-free, can be administered by non-professional (see page 528, left column, last full paragraph), acceptable for all ages, genders, regions and cultures (see page 529, right column). One would have been motivated to formulate Kende’s composition for nasal administration for humans, with a reasonable expectation of success. Particular delivery devices are not disclosed for nasal vaccines. However, it would have been obvious to have selected any device from Djupesland’s Table 1, such as a spray pump/device, with predictable results. Therefore, the claimed embodiment would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. Applicant’s arguments have been addressed above.
Claims 30, 32 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Kende et al. (Antiviral Research, available online January 3, 2019, 163:179-184, “Kende”) in view of Mitchell and Carter (Emerging Microbes and Infections, 2014, 3, e77, 2 pages, of record in the IDS filed 12/21/2021, “Mitchell”) as applied to claim 1 above, and further in view of Martins et al. (PLoS One, February 2014, 9(2):e89735, 12 pages, cited in the IDS filed 12/21/2021, “Martins”). Claims 30, 32 and 33 are directed to embodiments wherein the composition further comprises a prophylactic or therapeutic vaccine comprising one or more Ebola antibodies, an inactivated Ebola virus, or an attenuated Ebola virus.
The teachings of Kende/Mitchell are outlined above, neither of which suggest administering a vaccine along with rintatolimod. However, it would have been obvious to have administered a prophylactic or therapeutic vaccine to induce an immune response against Ebola virus infection, with a reasonable expectation of success. Martins discloses a composition comprising Ebola VLPs diluted in sterile saline (a pharmaceutically acceptable carrier) and combined with polyICLC, administered to mice and guinea pigs intramuscularly, resulting in augmented protection against challenge (see abstract and page 2, bridging paragraph between left and right columns, and Figs. 1B and 1C). Therefore, the claimed embodiments would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. Applicant’s arguments have been addressed above.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
(Provisional Rejection) Claims 1-3, 7-13, 16, 20, 21, 24, 25, 28, 29 and 31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-17 and 19-33 of copending Application No. 18/692,244 (reference application; amended claims filed 3/24/2024). Although the claims at issue are not identical, they are not patentably distinct from each other. The instant claims are directed to a method of preventing, treating, inhibiting or attenuating an Ebola virus infection comprising administering a composition comprising a tdsRNA and a pharmaceutically acceptable carrier to a subject. The copending claims are directed to a method of treating a nasal virus infection by administering a composition comprising a tdsRNA comprising rIn·r(CxU)n, wherein x is, for example, 11-14, among other values. Copending claim 17 is directed to Ebola treatment. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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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/STACY B CHEN/Primary Examiner, Art Unit 1671
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