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 .
Election/Restrictions
To summarize the current election, the applicant elected the species where the viral infection is a SARS CoV-2 infection. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The restriction is deemed proper and therefore made FINAL.
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situations as detailed below.
Claims 48, 54, 58, 63, and 68 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The invention relates to the antiviral treatment of an infection with SARS-CoV-2 in a subject or a method of treating hypercytokinemia due to SARS-CoV-2 in a subject where, in each instance, the replication of SARS-CoV-2 is reduced by administering sodium meta-arsenite or potassium meta-arsenite to the subject. The relative skill of those in the art is high, that of an MD or PHD. Sodium meta-arsenite is taught to act as an anti-inflammatory agent, generally, and to treat inflammation associated with viral infection (see Hwang et al. – US PGPub No. 2008/0193560 - previously cited - paragraphs 1 and 27). Hwang et al. also show it to reduce the production of several pro-inflammatory cytokines in mice in an induced inflammatory state (see example 2). Lee et al. (previously cited) teach sodium meta-arsenite as a treatment for hepatitis C. Here they detail a cell line based assay where the application of sodium meta-arsenite reduced replication of hepatis C in the cells (see example 2 and figure 4). No tests in primary cells or animals were performed to verify efficacy. Simonis et al. (previously cited) teach that known anti-viral compounds are not necessarily effective in reducing replication of all coronavirus in all susceptible animals. They detail that cyclosporine was a known antiviral against a hepatis virus and a human coronavirus, but was ineffective against SARS-CoV (see page 8 first column last full paragraph). In addition, Kumar et al. (previously cited) teach that the ability of two known anti-viral agents to reduce SARS-CoV-2 replication in the Vero cell line was not able to be achieved in primary human airway epithelial cells. (see abstract). They stress that the cells of the airway are the primary target in human infection with SARS-CoV-2 and that the Vero cell line did not adequately mimic the relevant in vivo environment (see page 7-page 8 first partial paragraph). Thus they teach that the cell line could be useful for primary screening, but more rigorous model systems should be employed prior to entering clinical trial (see page 8 first partial paragraph).
The instant specification tests for the impact of sodium meta-arsenite on SARS-CoV-2 replication in Vero cells and show a reduction occurs (see example 5 and figure 17). No other cells models were assessed nor were any subjects tested for the effect of sodium meta-arsenite on SARS-CoV-2 replication.
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed method could be practiced. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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 43, 46-49, 52-54, 59, 61-66, 68, and 71-74 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.
The claims recite or depend from a claim that recites the preamble, “method for the antiviral treatment of an infection with SARS-CoV-2. The claims go on to recite, except in the case of claim 59 and its dependent claims, an outcome that occurs as a consequence of the recited step of “administering an effective amount of sodium meta-arsenite or potassium meta-arsenite to the subject”. The discussion of the term “antiviral” in the specification is linked to reducing replication of virus in Vero cells (see specification section 5.2). The meaning of the term could include reducing virus or virus infected cell replication and growth as well as also embracing reducing symptoms associated with the viral infection (see Hancock et al. US PGPub no. 2003/0176337 paragraph 24 and Leyland-James US PGPub No. 2003/0195350 paragraph 51). It is unclear if the preamble implies additional unrecited outcomes from the administration step (e.g., reduction in viral replication) and it is also unclear which function the “therapeutically effective amount” must achieve. No particular dosing concentration is linked to viral replication inhibition in a subject since only in vitro work in a single cell type was conducted in the instant disclosure. Further, it is unclear if the same concentration effective to recued an inflammatory response or condition due to the infection will also act to inhibit SARS-CoV-2 replication. Thus the metes and bounds of the claims are unclear.
For the sake of application of prior art, the preamble of the claim will be viewed as being achieved when the active steps are conducted on a subject with an infection with SARS-CoV-2. Clarification is still required.
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 43, 46-47, 49, 52-53, 59, 61-62, and 64-66 are rejected under 35 U.S.C. 103 as being unpatentable over Hwang et al. in view of Kawai et al. previously cited) and Zhu et al. (previously cited).
Hwang et al. teach orally administering sodium meta-arsenite to act as an anti-inflammatory agent, generally, and to treat inflammation associated with viral infection as well as pneumonia (see paragraphs 1, 27, 41, 64, and 75, claims 7, 13). Hwang et al. show that treatment of broad scale inflammation in a subject due to pre-treatment with sodium meta-arsenite reduced mortality that would have otherwise occurred (see example 2). They additionally teach a dosing range of 0.5 to 70 mg/kg per day that is selected based upon condition severity (see paragraph 28). A dosing of 10 mg/kg is shown to be effective in a mouse inflammation model and superior to a 1 mg/kg dosing (see paragraph 81-83 and intervening table). This dose also reduces interleukin 6 expression (see paragraph 83). Hwang et al. teach a conversion factor for moving to larger animals and if shifted to a monkey, the 10 mg/kg dose would correspond to 8.75 mg in a 3.5 kg monkey (see table 1; calculated by the examiner (Monkey dose [mg] = (1/4) x (Mouse dose [mg/kg] x Monkey mass [kg])). Treatment of SARS-CoV-2 is not discussed.
Kawai et al. teach that the infection of mammal/human with a virus results in an inflammatory response due to the triggering of the innate immune system (see page 131 first column).
Zhu et al. teach of a coronavirus that infects humans called 2019-nCoV (also known as SARS-CoV-2) (see abstract). They further discuss multiple particular cases of the infection as well as its characterization as viral pneumonia (see pages 729-731).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to orally administer sodium meta-arsenite as taught by Hwang et al. to a subject infected with SARS-CoV-2 to treat the pneumonia and inflammatory condition it was known to cause in light of Zhu et al. and Kawai et al. This choice of pathology would have been obvious because it is identified as causing inflammation and pneumonia which are two conditions Hwang et al. teach their compound to treat. It would follow to administer a dose within the taught range and adjust its amount as needed. The taught range embraces or meets the claimed range, depending on the animal to whom an anti-inflammatory dose is administered, thereby rendering the claimed range obvious. “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed.Cir. 1990)” (see MPEP 2144.05). Therefore claims 43, 46-47, 49, 52-53, 59, 61-62, and 64-66 are obvious over Hwang et al. in view of Kawai et al. and Zhu et al.
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 43, 46-47, 49, 52-53, 59, 61-62, and 64-66 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18-27 of U.S. Patent No. 12,257, 347 in view of Hwang et al., Kawai et al. and Zhu et al.
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims recite treating inflammation in a subject by orally administering sodium meta-arsenite. SARS CoV-2 is not explicitly recited as the underlying cause of the inflammation.
Hwang et al. teach orally administering sodium meta-arsenite to act as an anti-inflammatory agent, generally, and to treat inflammation associated with viral infection (see paragraphs 1, 27, 41, 64, and 75, claims 7, 13). Hwang et al. show that treatment of broad scale inflammation in a subject due to pre-treatment with sodium meta-arsenite reduced mortality that would have otherwise occurred (see example 2). They additionally teach a dosing range of 0.5 to 70 mg/kg per day that is selected based upon condition severity (see paragraph 28). A dosing of 10 mg/kg is shown to be effective in a mouse inflammation model and superior to a 1 mg/kg dosing (see paragraph 81-83 and intervening table). This dose also reduces interleukin 6 expression (see paragraph 83). Hwang et al. teach a conversion factor for moving to larger animals and if shifted to a monkey, the 10 mg/kg would correspond to 8.75 mg in a 3.5 kg monkey (see table 1; calculated by the examiner (Monkey dose [mg] = (1/4) x (Mouse dose [mg/kg] x Monkey mass [kg])).
Kawai et al. teach that the infection of mammal/human with a virus results in an inflammatory response due to the triggering of the innate immune system (see page 131 first column).
Zhu et al. teach of a coronavirus that infects humans called 2019-nCoV (also known as SARS-CoV-2) (see abstract). They further discuss multiple particular cases of the infection as well as its characterization as viral pneumonia (see pages 729-731).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to choose SARS-CoV-2 induced inflammation as the variety of inflammation treated by the method of the patented claims. This choice of pathology would have been obvious because Hwang et al. teach the sodium meta-arsenite for treating viral infection induced inflammation, SARS-CoV-2 was a known virus in light of Zhu et al., and Kawai et al. suggest its infection would induce inflammation. It would follow to administer a dose within the range taught by Hwang et al. and adjust its amount as needed. The taught range embraces or meets the claimed range, depending on the animal to whom an anti-inflammatory dose is administered, thereby rendering the claimed range obvious (see MPEP 2144.05). Therefore claims 43, 46-47, 49, 52-53, 59, 61-62, and 64-66 are obvious over claims 18-27 of U.S. Patent No. 12,257, 347 in view of Hwang et al., Kawai et al. and Zhu et al.
Allowable Subject Matter
Tanaka et al. teach inhibition of IL-6 as an avenue to treat hypercytokinemia which is also known as cytokine storm (see Immunotherapy 2016 8(8):959-970; abstract and page 962 first column last partial paragraph-second column). Both Hwang et al. and the instant applicant show that sodium meta arsenite has the ability to reduce IL-6 upregulation due to excessive inflammatory responses induced in a mouse model (see Hwang et al. paragraph 81-83 and intervening table and paragraph 85-87; instant specification section 4.3 and figure 14). The instant specification also details a reduction in mortality for a mouse model with acute respiratory distress syndrome (ARDS) similar to that seen for a dexamethasone dosing (see instant figure 16 and example 4). Song et al. discuss the occurrence of cytokine storm in more severe cases of SAR-CoV-2 infection which culminates in ARDS (see Clinica Chimica Acta 2020 509:280-287, page 280 second column, page 281 second column second full paragraph). Since the instant meta arsenite compound was able to reduce the IL-6 already known to be targeted for cytokine storm treatment and to treat the downstream condition induced by a cytokine storm, the disclosure is deemed sufficient to support the practice of the method of claims 55, 69, and 70. It is not evident that the connection between the occurrence of SARS-CoV-2 infection and cytokine storm was recognized in the prior art prior to the time of filing of the instant invention, thus selecting this patient population for treatment would have been non-obvious.
Response to Arguments
Applicant's arguments filed December 30, 2025 have been fully considered. In light of the amendment to the claims, the objection and rejection under 35 USC 112(b) are hereby withdrawn. In addition, the amendment also overcomes the rejection under 35 USC 112(a) due to the recitation of preventing an inflammatory condition, due to SARS-CoV-2 infection in a subject, and due to preventing hypercytokinemia due to SARS-CoV-2 infection in a subject. The arguments against the remaining rejections are unpersuasive.
Regarding rejections under 35 USC 112(a):
The applicant argues that the Vero cell testing is sufficient to enable the instantly claimed compounds as SARS-CoV-2 replication reducing compounds in a subject because remdesivir was effective in both Vero cells and clinically. This observation does not negate the failure of Vero cells to predict how other anti-viral compounds impact viral replication in a subject. Since it is known that a compound’s SARS-CoV-2 replication reduction in Vero cells is not fully predictive of the compound’s ability to reduce replication in other cell types and living subjects, the disclosure is insufficient to show that the claimed compounds would predictability reduce SARS-CoV-2 replication in a subject, as claimed, based solely on this cell type.
Regarding rejections under 35 USC 103:
The applicant argues that Hwang et al. do not teach suppressing viral replication of SARS-CoV-2. While true, the oral administration of the instantly claimed sodium meta arsenite to a subject to treat inflammation, and pneumonia in particular, due to viral infection is taught by Hwang et al. The secondary references place SARS-CoV-2 within this category of conditions which makes these patients obvious to treat and yields the same active step employing the same compound as instantly claimed. Hwang et al. also suggest dose amounts and dosing levels (e.g., mg/kg) that meet or overlap with the instantly claimed and disclosed ranges. Both Hwang et al. and the applicant conduct lipopolysaccharide (LPS) testing with nearly the same concentration of sodium meta-arsenite in mice and see a significant reduction in inflammatory cytokine production. Thus the artisan of ordinary skill would have expected the administration of the arsenite compound to treat SARS-CoV-2 via treating the inflammation it induces. The characterization by the applicant of other coexistent outcomes, such as viral replication reduction, that may also occur at the same dosing does not make the treatment unobvious. The single subject with a SARS-CoV-2 infection that was tested does not disclose the dose of sodium meta arsenite that was administered. Additionally, the applicant has not detailed any particular dosing that is critical for viral replication reduction in a subject or provided any evidence that distinguishes the dosing effective for viral replication reduction as different than that for inhibiting inflammation.
The applicant discounts the contribution of Kawai et al. and Zhu et al. to the rejection. As members of the combination of references relied upon in the rejection, no singular reference is required to teach all the claim limitations in order to support the obviousness of the claims. However these references point to the obviousness of administering the claimed compound to the claimed patient population in order to treat a claimed condition.
Conclusion
No claim is 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARALYNNE E HELM whose telephone number is (571)270-3506. The examiner can normally be reached Mon-Fri 9-5.
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/CARALYNNE E HELM/Examiner, Art Unit 1615
/MELISSA S MERCIER/Primary Examiner, Art Unit 1615