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 present application, filed, January 5, 2023, is a national stage application of PCT/US21/41827, filed July 15, 2021, and claims the benefit of U.S. provisional applications 63/053208, filed July 17, 2020, and 63/130117, filed December 23, 2020.
Support for the subject matter of claim 42 is not present in either of 63/053208 or 63/130117. Therefore, claim 42 is examined with the effective filing date of July 15, 2021, the filing date of the PCT/US21/41827 application.
Status of the Application
Applicant’s preliminary amendment, received August 7, 2023, wherein claims 3, 4, 7-9, 28, 30, 33-39, and 41-43 are amended, claims 5-6, 10-27, 29 and 40 are canceled, and new claim 44 is added, is acknowledged.
Claims 1-4, 7-9, 28, 30-39, and 41-44 are pending and examined on the merits herein.
Claim Objections
Claim 38 is objected to because of the following informalities:
Claim 38 recites “claim4430-37”. The examiner believes this to be a typographical error wherein Applicant intended to remove “30-37,” consistent with the amendment to claim 39. For the purposes of expedited prosecution, claim 38 is interpreted as reciting “The method of claim 44…”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-4, 7-9, 28, 30-39, and 41-44 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "the second therapeutic agent" in claim 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1 earlier recites “at least one additional therapeutic agent,” but does not recite a “second therapeutic agent.” For the purposes of expedited prosecution, “the second therapeutic agent” is interpreted as “the at least one additional therapeutic agent,” which is consistent with language used in claims depending from claim 1.
Because claims 2-4, 7-9, 28, 30-39, and 41-44 depend from claim 1 and fail to cure this deficiency, claims 2-4, 7-9, 28, 30-39, and 41-44 are also indefinite.
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 8, 38, 39, and 41 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.
Claim 8 depends from claim 3 and wherein the at least one additional therapeutic agent is selected from Velpatasvir and Elbasvir, further comprising administering Sofosbuvir. However, claim 3 does not permit Velpatasvir alone as an additional therapeutic agent. Additional therapeutic agents i), ii), iii), and iv) of claim 3 recite Velpatasvir, but those also require additional agents. Accordingly, claim 8 fails to include all the limitations of the claim upon which it depends. For the purposes of expedited prosecution, claim 3, from which claim 8 depends, is interpreted as reciting velpatasvir as an at least one additional therapeutic agent.
A proper dependent claim must refer to a previous claim and include a further limitation. Because claims 38, 39, and 41 depend from claim 44, they do not depend from a previous claim, and thus are not proper dependent claims.
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 § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4, 28, are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Choy (Choy, K.-T.; et al. Antiviral Research 2020, vol. 178, no. 104786; cited in PTO-892).
Claim 1 claims a method of treating a viral infection caused by an RNA virus, the method comprising administering a first therapeutic agent and at least one additional therapeutic agent in combined effective amounts, wherein: a) the first therapeutic agent is an inhibitor of an RNA-dependent RNA polymerase (RdRp); and b) the second therapeutic agent is an agent other than an RdRp inhibitor.
Claim 4 requires the first therapeutic agent and the at least one additional therapeutic agent are administered in synergistically effective amounts, and claim 28 requires the RdRp inhibitor is sofosbuvir, remdesivir, ribavirin, favipiravir, pimodivir, or baloxavir.
Choy teaches the antiviral effect of compounds previously reported to inhibit coronavirus replication and compounds that were being evaluated in clinical trials for
SARS-CoV-2 patients (p. 1, Abstract, lines 1-4). Choy teaches the report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells (p. 1, Abstract, lines 8-10). Choy further teaches that remdesivir and emetine showed synergy, with remdesivir at 6.25 μM in combination with emetine at 0.195 μM achieving 64.9% inhibition in viral yield. Choy teaches that combinational therapy may help to reduce the effective concentration of compounds below the therapeutic plasma concentrations and provide better clinical benefits (p. 1, Abstract, lines 8-10).
Choy teaches emetine is a protein synthesis inhibitor (p. 2, right column, second full paragraph, lines 1-2). In this instance, remdesivir is the RdRp inhibitor required by claim 1, and emetine is the additional therapeutic agent.
Thus Choy anticipates claims 1, 4, and 28.
Claims 1, 4, 28, 30, 33-34, 41, and 44 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Jensen (U.S. pre-grant publication no. US 20230277524 A1; cited in PTO-892).
The U.S. patent application associated with Jensen, application 17/925,783, claims the benefit of U.S. provisional applications 63/071,848, filed August 28, 2020, 63/057,829, filed July 28, 2020, and 63/028,844, filed May 22, 2020, and thus Jensen qualifies as eligible prior art under 35 U.S.C. 102(a)(2) because it has an earlier effective filing date. The citations in the rejection below are fully supported by provisional application 63/028,844, filed May 22, 2020.
Claim 1 claims a method of treating a viral infection caused by an RNA virus, the method comprising administering a first therapeutic agent and at least one additional therapeutic agent in combined effective amounts, wherein: a) the first therapeutic agent is an inhibitor of an RNA-dependent RNA polymerase (RdRp); and b) the second therapeutic agent is an agent other than an RdRp inhibitor.
Claim 4 requires the first therapeutic agent and the at least one additional therapeutic agent are administered in synergistically effective amounts, and claim 28 requires the RdRp inhibitor is sofosbuvir, remdesivir, ribavirin, favipiravir, pimodivir, or baloxavir.
Claim 30 requires said treating is to an individual infected with the virus is SARS-CoV2 virus, claims 33-34 require the individual has been diagnosed as having Covid-19 and exhibits one or more symptoms of a SARS-Co V2 infection, claim 44 requires the individual is administered remdesivir, and claim 41 requires remdesivir is administered intravenously.
Jensen teaches combination therapies for treating viral infections, particularly infections by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19) (cover page, Abstract, lines 1-4).
Jensen teaches that synergy was detected between (a) elacridar and curcumin, (b) curcumin and remdesivir, and (c) remdesivir and elacridar (p. 20, [0127], lines 8-12; support in 63/028,844 on p. 6, Example 2).
Jensen also claims a method of treating a subject infected with a virus, or a subject at risk of infection with a virus, comprising administering to the subject an effective amount of a combination of compound A and compound B, or pharmacological analogues thereof, wherein:
compound A is a dual-specificity ABCB1/ABCG2 inhibitor and compound B is remdesivir, or a functional analog thereof, and optionally, wherein the combination comprises compound
C, wherein compound C is a NRF2 agonist, and wherein the subject is treated (p. 25, claim 1).
Jensen further claims compound A is elacridar, tariquidar, or zosuquidar, and/or wherein compound C is curcumin, or functional analogs thereof (p. 25, claim 2), and wherein the virus is selected from a group that includes SARS-CoV-2 (COVID-19) (p. 25, claim 6). The subject matter of these claims with compound A as elacridar is supported by claims 1 and 4 of 63/028,844. In this instance, remdesivir is the RdRp inhibitor, and elacridar is the additional therapeutic agent.
Moreover, Jensen claims compound B (remdesivir as recited in claim 1) is administered
once daily in an amount of 200 mg or at a dose of 5 mg/kg (p. 25, claim 13), and wherein compound B is administered intravenously (p. 25, claim 15). The subject matter of these claims with compound A as elacridar is supported by claims 11 and 13 of 63/028,844.
Finally, Jensen claims the subject is identified as Sars-CoV-2 positive for virus RNA (p. 25, claim 21), wherein the subject is diagnosed with bilateral pulmonary pneumonia (p. 26, claim 23), and wherein the subject is diagnosed with SARS-CoV-2 related organ failures (p. 26, claim 24). These are interpreted as symptoms of a SARS-CoV-2 infection. The subject matter of these claims with compound A as elacridar is supported by claims 15, 17, and 18 of 63/028,844.
Thus Jensen anticipates claims 1, 4, 28, 30, 33-34, 41, and 44.
Claims 1, 2, and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Field (Field, J. J.; et al. New England Journal of Medicine 2015, vol. 373, pp. 2599-2607; cited in PTO-892).
Field teaches a phase 3 study involving untreated and previously treated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection. Field teaches that patients with HCV genotype 1, 2, 4, or 6 were randomly assigned in a 5:1 ratio to receive the nucleotide polymerase
inhibitor sofosbuvir and the NS5A inhibitor velpatasvir in a once-daily, fixed-dose
combination tablet or matching placebo for 12 weeks (p. 2599, Abstract, Methods section, lines 1-6). Field teaches that because of the low prevalence of genotype 5 in the study regions, patients with genotype 5 did not undergo randomization but were assigned to the sofosbuvir-velpatasvir group (p. 2599, Abstract, Methods section, lines 1-6).
Field teaches their study showed once-daily sofosbuvir-velpatasvir for 12 weeks provided high rates of sustained virologic response among both previously treated and untreated patients infected with HCV genotype 1, 2, 4, 5, or 6, including those with compensated cirrhosis (p. 2599, Abstract, Conclusions section, lines 1-3).
As evidenced by the instant specification, sofosbuvir is an inhibitor of an RNA-dependent RNA polymerase (see p. 7, [0027]). In addition, velpatasvir is an inhibitor of NS5A, and thus is considered as at least one additional therapeutic agent in claim 1. In addition, because velpatasvir is used to treat patients with HCV, it is reasonably considered as an HCV inhibitor, as recited in claim 2.
Thus Field anticipates claims 1, 2, and 28.
Claims 1, 2, 3, 7, 9, and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lawitz (Lawitz, E.; et al. Lancet 2015, vol. 385, pp. 1075-1086; cited in PTO-892).
Lawitz teaches a study to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response (p. 1075, Summary, Background section, lines 3-6).
Lawitz teaches that 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, 60 patients were assigned to the 12-week regimen (31 with ribavirin and 29 with no ribavirin) and 63 to the 18-week regimen (32 with ribavirin and 31 with no ribavirin), and in cohort 2, 65 patients were assigned to the 12-week regimen (32 with ribavirin and 33 with no ribavirin) and 65 to the 18-week regimen (33 with ribavirin and 32 with no ribavirin) (p. 1075, Summary, Findings section, lines 1-4). Lawitz teaches that high sustained virological response rates 12 weeks after end of therapy (SVR12) were achieved irrespective of the use of ribavirin or extension of the treatment duration from 12 to 18 weeks (p. 1075, Summary, Findings section, lines 5-6).
Lawitz concludes by stating that treatment with grazoprevir plus elbasvir, both with and without ribavirin and for both 12 and 18 weeks’ treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis (p. 1075, Summary, Interpretation section, lines 1-3).
As evidenced by the instant specification, ribavarin is an inhibitor of an RNA-dependent RNA polymerase (see p. 7, [0027]). In addition, elbasvir and grazoprevir are considered as additional therapeutic agents. In addition, because elbasvir and grazoprevir are used to treat patients with HCV, they are reasonably considered as HCV inhibitors, as recited in claim 2.
Thus Lawitz anticipates claims 1, 2, 3, 7, 9, and 28.
Claims 1, 2, 3, 8, 9, and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Curry (Curry, M. P.; et al. New England Journal of Medicine 2015, vol. 373, pp. 2618-2628; cited in PTO-892).
Curry teaches a phase 3, open-label study involving previously treated and
previously untreated patients infected with HCV genotypes 1 through 6 who had
decompensated cirrhosis. Curry teaches that patients were randomly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks, and that the primary end point was a sustained virologic response at 12 weeks after the end of therapy (p. 2618, Abstract, Methods section, lines 1-8).
Curry teaches that overall rates of sustained virologic response were 83% among patients who received 12 weeks of sofosbuvir-velpatasvir, 94% among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 86% among those who received 24 weeks of sofosbuvir-velpatasvir (p. 2618, Abstract, Results section, lines 3-7).
Curry concludes by stating that treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis (p. 2618, Abstract, Conclusions section, lines 1-3).
As evidenced by the instant specification, ribavarin is an inhibitor of an RNA-dependent RNA polymerase (see p. 7, [0027]). In addition, velpatasvir is considered as additional therapeutic agent that is not an RdRp inhibitor. Finally, because velpatasvir is used to treat patients with HCV, it is reasonably considered as an HCV inhibitor, as recited in claim 2.
Thus Curry anticipates claims 1, 2, 3, 8, 9, and 28.
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, 4, 28, 30, 33-34, 38-39, 41, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Jensen (U.S. pre-grant publication no. US 20230277524 A1; cited in PTO-892).
As described in the above rejection under 35 U.S.C. 102, the examiner believes that claims 1, 4, 28, 30, 33-34, 41, and 44 are anticipated by Jensen. However, for the sake of argument, if Jensen does not anticipate these claims because, for example, Jensen does not teach a specific embodiment showing the treatment of an individual with SARS-CoV-2 using the method of Jensen, then claims 1, 4, 28, 30, 33-34, 41, and 44 would have been obvious over Jensen.
Jensen teaches as described in the above rejection under 35 U.S.C. 102.
In addition, Jensen teaches and claims administration of remdesivir (compound B) in a dosage amount of about 100 to about 200 mg (p. 25, claim 3), and further wherein remdesivir is administered daily in an amount of 200 mg or 5 mg/kg (p. 25, claim 13), and wherein remdesivir is administered intravenously (p. 25, claim 15).
Jensen does not teach a specific embodiment showing the treatment of an individual with SARS-CoV-2, then claims 1, 4, 28, 30, 33-34, 41, and 44. In addition, Jensen does not teach the specific dose and dosing schedule required by claims 38 and 39.
It would have been prima facie obvious before the effective filing date of the present application to administer a combination of remdesivir and an additional therapeutic agent, such as elacridar or tariquidar, for the purposes of treating a subject infected with SARS-CoV-2. One of ordinary skill in the art would have been motivated to administer a combination of remdesivir and an additional therapeutic agent, such as elacridar or tariquidar, for the purposes of treating a subject infected with SARS-CoV-2 because Jensen teaches and claims a composition for treating a subject infected with SARS-CoV-2 comprising a combination elacridar or tariquidar (compound A), remdesivir (compound B), and curcumin (compound C). In addition, Jensen teaches and claims this composition for treating a subject infected with a virus, including with SARS-CoV-2 Accordingly, one of ordinary skill in the art would have contemplated administering said composition for the purposes of treating a subject infected with SARS-CoV-2.
Regarding the dosage of remdesivir recited in claims 38 and 39, because Jensen suggests a daily dose of remdesivir of 200 mg or 5 mg/kg, one of ordinary skill in the art would have contemplated the day 1 dose as recited in claims 38 and 39. Regarding the reduced daily dose beginning on day 2, absent a showing of the criticality of the dose and dosing schedule, a modification of dose amount would have obvious to one of ordinary skill in the art depending on patient symptoms and side effects. Because Jensen teaches a daily dose of remdesivir of 200 mg or 5 mg/kg, and additionally teaches a recommended dose between 100 and 200 mg, one of ordinary skill in the art would have recognized the specific dosing amount may be adjusted to suit an individual’s needs.
In addition, one of ordinary skill in the art would have identified the optimal dosing regimen via routine experimentation MPEP 2144.05 (II) at A states: “Generally, differences in
concentration or temperature will not support the patentability of subject matter encompassed by
the prior art unless there is evidence indicating such concentration or temperature is critical.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to
discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454,
456, 105 USPQ 233, 235 (CCPA 1955).”
In this instance, in view of Jensen disclosing dosages of 200 mg or 5 mg/kg, and additionally disclosing suggested dosages between 100 mg and 200 mg, one of ordinary skill in the art would have recognized these conditions as result-effective variables would have adjusted the dose and dosing frequency of each through routine experimentation to identify the optimal dose and dosing schedule, considering patient symptoms and side effects when determining said optimal dose and doing schedule.
Therefore the invention taken as a whole is prima facie obvious.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Jensen as applied to claims 1, 4, 28, 30, 33-34, 38-39, 41, and 44 above, and further in view of Brouwer (Brouwer, P. J. M.; et al. Science 2020, vol. 369, pp. 643-650; cited in PTO-892).
Brouwer was published online June 15, 2020, and thus qualifies as prior art under 35 U.S.C. 102(a)(1).
Claim 31 depends from claim 30 and requires further administering an antibody specific for the SARS-CoV2 spike glycoprotein.
Jensen teaches as described in the above rejections under 35 U.S.C. 102 and 35 U.S.C. 103.
Jensen does not teach the method of claim 30, further comprising administering an antibody specific for the SARS-CoV2 spike glycoprotein, as required by claim 31.
Brouwer teaches the isolation of monoclonal antibodies from three convalescent coronavirus disease 2019 (COVID-19) patients using a SARS-CoV-2 stabilized prefusion spike protein. Brouwer teaches these antibodies had low levels of somatic hypermutation and showed a strong enrichment in VH1-69, VH3-30-3,and VH1-24 gene usage (p. 1, Abstract, lines 3-6).
In addition, Brouwer teaches that a subset of the isolated antibodies was able to potently inhibit authentic SARS-CoV-2 infection at a concentration as low as 0.007 micrograms per milliliter, and that competition and electron microscopy studies illustrate that the SARS-CoV-2 spike protein contains multiple distinct antigenic sites, including several receptor-binding domain (RBD) epitopes as well as non-RBD epitopes. Finally, Brouwer teaches these antibodies described here are promising candidates for COVID-19 treatment and prevention (p. 1, Abstract, lines 6-11), and suggests that simultaneous targeting of multiple non-RBD and RBD epitopes with antibody cocktails paves the way for safe and effective COVID-19 prevention and treatment (p. 7, right column, Conclusions section, last five lines). This is taken as an express teaching that the antibodies taught by Brouwer may be administered for the purposes of treating COVID-19.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to administer the therapy taught by Jensen to an individual infected with the SARS-CoV-2 virus together with an antibody specific for the SARS-CoV-2 spike glycoprotein. One of ordinary skill in the art would have been motivated to administer the therapy taught by Jensen to an individual infected with the SARS-CoV-2 virus together with an antibody specific for the SARS-CoV-2 spike glycoprotein because Jensen teaches combination therapies for treating viral infections that satisfy the limitations of claims 1 and 30, and because Brouwer teaches anti-SARS-CoV-2 neutralizing monoclonal antibodies that target the spike protein and suggests their use in therapies against SARS-CoV-2. In this instance, the rationale “combining prior art elements according to known methods to yield predictable results” would apply. Because the therapy taught by Jensen and the neutralizing antibodies that target SARS-CoV-2 spike protein are each recognized by the prior art as therapies for treating a SARS-CoV-2 infection, one of ordinary skill in the art would have contemplated administering a combination of the therapy of Jensen and a neutralizing antibody taught by Brouwer for the purposes of treating a SARS-CoV-2 infection, because the combination of the therapy of Jensen and antibody of Brouwer may be a more effective treatment for a SARS-CoV-2 infection than either therapy alone.
One of ordinary skill in the art would have had a reasonable expectation of success administering the therapy of Jensen with an antibody specific for the SARS-CoV-2 spike glycoprotein because each are recognized by the prior art as potential treatments for a SARS-CoV-2 infection, and thus one of ordinary skill in the art would have had a reasonable expectation that their combination would also be effective in treating a SARS-CoV-2 infection.
Therefore the invention taken as a whole is prima facie obvious.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Jensen as applied to claims 1, 4, 28, 30, 33-34, 38-39, 41, and 44 above, and further in view of Brouwer as applied to claim 31 above, further in view of Freedberg (Freedberg, D. E.; et al. Gastroenterology 2020, vol. 159, pp. 1129-1131; cited in PTO-892).
Claim 32 depends from claim 31 and requires further administering famotidine.
Freedberg was published online May 22, 2020 and thus qualifies as prior art under 35 U.S.C. 102(a)(1), as evidenced by the PubMed entry of Freedberg (cited in PTO-892).
Jensen and Brouwer teach as described in the above rejections under 35 U.S.C. 102 and 35 U.S.C. 103.
Jensen and Brouwer do not teach the method of claim 31, further comprising famotidine, as required by claim 32.
Freedberg teaches a retrospective cohort study that found that, in patients hospitalized with COVID-19, famotidine use was associated with a reduced risk of clinical deterioration leading to intubation or death (p. 1131, left column, Conclusions section, lines 1-4). Freedberg concludes by stating that in patients hospitalized with COVID-19 and not initially intubated, famotidine use was associated with a 2-fold reduction in clinical deterioration leading to intubation or death (p. 1131, left column, Conclusions section, fourth paragraph, lines 1-4) (emphasis added).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to administer the therapy taught by Jensen to an individual infected with the SARS-COV2 virus together with an antibody specific for the SARS-CoV2 spike glycoprotein and with famotidine. One of ordinary skill in the art would have been motivated to administer the therapy taught by Jensen to an individual infected with the SARS-COV2 virus together with an antibody specific for the SARS-CoV2 spike glycoprotein because Jensen teaches combination therapies for treating viral infections that satisfy the limitations of claims 1 and 30, because Brouwer teaches the therapeutic benefit of anti-SARS-CoV-2 neutralizing antibodies, and because Freedberg teaches the benefits of famotidine in treating patients with SARS-CoV-2. In this instance, the rationale “combining prior art elements according to known methods to yield predictable results” would apply. Because the therapy taught by Jensen, neutralizing antibodies that target SARS-CoV-2 spike protein, and famotidine are all recognized by the prior art as therapies for treating a SARS-CoV-2 infection, one of ordinary skill in the art would have contemplated administering a combination of the therapy of Jensen, a neutralizing antibody that targets the SARS-CoV-2 spike protein, and famotidine, because such a combination may be a more effective treatment for a SARS-CoV-2 infection than any of these therapies administered alone.
One of ordinary skill in the art would have had a reasonable expectation of success administering the therapy of Jensen with an antibody specific for the SARS-CoV-2 spike glycoprotein and famotidine because all are recognized by the prior art as potential treatments for a SARS-CoV-2 infection, and thus one of ordinary skill in the art would have had a reasonable expectation that their combination would also be effective in treating a SARS-CoV-2 infection.
Therefore the invention taken as a whole is prima facie obvious.
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Jensen as applied to claims 1, 4, 28, 30, 33-34, 38-39, 41, and 44 above, and further in view of Li (Li, K.; et al. Investigational Radiology 2020, doi: 10.1097/RLI.0000000000000672; cited in PTO-892).
Li was published online February 29, 2020, and thus qualifies as eligible prior art under 35 U.S.C. 102(a)(1).
Claim 35 depends from claim 34 and requires the individual has an oxygen saturation of less than 94%.
Jensen teaches as described in the above rejections under 35 U.S.C. 102 and 35 U.S.C. 103.
Jensen does not teach the method of claim 34, wherein the individual has an oxygen saturation of less than 94%, as required by claim 35.
Li teaches the clinical and CT features associated with severe and critical COVID-19 pneumoniae (p. 1, Abstract, Objective section, lines 1-2). Specifically, Li teaches that the severe/critical COVID-19 patients met any of the conditions taught by Li, including (1) respiratory rate of 30 breaths per minute or greater; (2) finger of oxygen saturation of 93% or less in a resting state; (3) arterial oxygen tension (PaO2)/inspiratory oxygen fraction (FiO2) of 300 mm Hg or less (1 mm Hg = 0.133 kPa); (4) respiratory failure occurred and mechanical ventilation required; (5) shock occurred; and (6) patients with other organ failure needed intensive care unit monitoring and treatment (p. 3, Study Population section, lines 9-13).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to administer the therapy taught by Jensen to an individual infected with the SARS-COV2 virus and having the symptom of oxygen saturation of less than 94%. One of ordinary skill in the art would have been motivated to administer the therapy taught by Jensen to an individual infected with the SARS-COV2 virus and having the symptom of oxygen saturation of less than 94% because Jensen teaches combination therapies for treating viral infections that satisfy the limitations of claims 1, 30, and 34, and because Li teaches one symptom of severe or critical patients is an oxygen saturation of 93% or less in a resting state. Thus one of ordinary skill in the art would have administered the treatment taught by Jensen for treating SARS-CoV-2 in a patient with an oxygen saturation of 93% or less in a resting state, because one of ordinary skill in the art would have recognized said patient as an individual suffering from severe COVID-19 and would have administered said treatment for the purposes of treating the viral infection, which would have been expected to also treat the symptoms of COVID-19.
Therefore the invention taken as a whole is prima facie obvious.
Claims 36 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Jensen as applied to claims 1, 4, 28, 30, 33-34, 38-39, 41, and 44 above, and further in view of Whittle (Whittle, J. S.; et al. JACEP Open 2020, vol. 1, pp. 95-101; cited in PTO-892).
As evidenced by its PubMed entry (cited in PTO-892), Whittle was published online April 13, 2020, and thus qualifies as eligible prior art under 35 U.S.C. 102(a)(1).
Claim 36 depends from claim 34 and requires the individual is receiving supplemental oxygen. Claim 37 depends from claim 36 and requires the individual requires mechanical ventilation or extracorporeal membrane oxygenation.
Jensen teaches as described in the above rejections under 35 U.S.C. 102 and 35 U.S.C. 103.
Jensen does not teach the method of claim 34, wherein the individual is receiving supplemental oxygen, as required by claim 36, or wherein the individual requires mechanical ventilation or extracorporeal membrane oxygenation, as required by claim 37.
Whittle teaches that treatment of patients with COVID-19 who are hypoxic should follow
the principles of treatment of hypoxic patients resulting from other etiologies. Specifically, for patients with O2 saturation less than 90% and mild to moderately increased work of breathing, supplemental oxygen should be considered with a goal of O2 saturation greater than 90% (p. 99, left column, first paragraph, lines 1-5). Whittle teaches that for those with increasing work of breathing, worsening hypoxia or failure to maintain oxygen saturation >90%, high flow oxygen should be considered (p. 99, left column, first paragraph, lines 5-7).
Whittle further teaches that patients who do not respond to high flow oxygen (HFNO/HVNI) in the first 2 hours should be placed on to mechanical ventilation (p. 99, left column, second paragraph, lines 1-2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to administer the therapy taught by Jensen to an individual infected with the SARS-CoV-2 virus and receiving supplemental oxygen or requiring mechanical ventilation. One of ordinary skill in the art would have been motivated to administer the therapy taught by Jensen to an individual infected with the SARS-COV-2 virus and receiving supplemental oxygen or requiring mechanical ventilation because Jensen teaches combination therapies for treating viral infections that satisfy the limitations of claims 1, 30, and 34, and because Whittle suggests that for patients with O2 saturation less than 90% and mild to moderate increased work of breathing, one should consider administering supplemental oxygen with goal of O2 saturation greater than 90%, and because Whittle further teaches one should administer mechanical ventilation for patients who do not respond to high flow oxygen therapy in the first two hours. Thus one of ordinary skill in the art would have administered the treatment taught by Jensen for treating SARS-CoV-2 in patients received supplemental oxygen and requiring mechanical ventilation because one of ordinary skill in the art would have recognized said patients as individuals suffering from severe COVID-19, and would have contemplated administering said treatment for the purposes of treating the viral infection, which would have been expected to also treat the symptoms of COVID-19 that cause a patient to need supplemental oxygen and mechanical ventilation.
Therefore the invention taken as a whole is prima facie obvious.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Jensen as applied to claims 1, 4, 28, 30, 33-34, 38-39, 41, and 44 above, and further in view of Graham (Graham, M. S.; et al. The Lancet 2021, vol. 6, pp. e335-e345; cited in PTO-892).
Graham was published on April 12, 2021. Because claim 42 is examined with an effective filing date of July 15, 2021, Graham is eligible as prior art under 35 U.S.C. 102(a)(1).
Claim 42 depends from claim 30 and requires the SARS-CoV-2 is a variant SARS-CoV-2 selected from the B.1.1.7 variant, the B.1.351 variant, the B.1.617.2 variant, and the P.1 variant.
Jensen teaches as described in the above rejections under 35 U.S.C. 102 and 35 U.S.C. 103.
Jensen does not teach SARS-CoV-2 is a variant SARS-CoV-2 selected from the B.1.1.7 variant, the B.1.351 variant, the B.1.617.2 variant, and the P.1 variant, as recited in claim 42.
Graham teaches the SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020 (p. e335, Summary, Background section, line 1). Graham teaches an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility (p. e335, Summary, Background section, line 1), and concludes from the results of this study that the lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant (p. e335, Summary, Background section, line 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to administer the method of Jensen for treating a SARS-CoV-2 infection in an individual, wherein the SARS-CoV-2 is the variant SARS-CoV-2 B.1.1.7. One of ordinary skill in the art would have been motivated to administer the method of Jensen for treating a SARS-CoV-2 infection in an individual, wherein the SARS-CoV-2 is the variant SARS-CoV-2 B.1.1.7 because Jensen teaches combination therapies for treating viral infections that satisfy the limitations of claims 1 and 30, and because Graham teaches the SARS-CoV-2 B1.1.1.7 variant, in which individuals infected with this variant display the same symptoms as those infected with pre-existing SARS-CoV-2. In this instance, the rationale “obvious to try” would apply. Because Jensen teaches a combination therapy for treating SARS-CoV-2, and because Graham teaches a new SARS-CoV-2 variant in which individuals infected with this variant exhibit the same symptoms as pre-existing variants, one of ordinary skill in the art would have reasonably contemplated administering the combination therapy taught by Jensen for treating individuals infected with the SARS-CoV-2 B1.1.1.7 variant, because said treatment may also be effective in treating the SARS-CoV-2 B1.1.1.7 variant.
Therefore the invention taken as a whole is prima facie obvious.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Jensen as applied to claims 1, 4, 28, 30, 33-34, 41, and 44 above, and further in view of Cook (Cook, S. E.; et al. bioRxiv 2020, doi: 10.1101/2020.07.09.195016; cited in PTO-892).
Cook was published online July 9, 2020, and thus qualifies as prior art under 35 U.S.C. 102(a)(1).
Jensen teaches as described in the above rejections under 35 U.S.C. 102 and 35 U.S.C. 103.
Jensen does not teach a method of treating an individual infected with the virus is SARS-CoV-2 virus by administering a combination of remdesivir, velpatasvir, and grazoprevir, as required by claim 43.
Cook teaches that feline infectious peritonitis (FIP), caused by a genetic mutant of feline enteric coronavirus known as FIPV, is a highly fatal disease of cats with no currently available vaccine or FDA-approved cure (p. 1, Abstract, lines 28-30). Cook teaches that there is a
critical need for effective and approved antiviral therapies against coronaviruses including FIPV
and zoonotic coronaviruses such as SARS-CoV-2, the cause of COVID-19. With regards to SARS-CoV-2, Cook teaches that preliminary evidence suggests that there may be potential clinical and pathological overlap with feline coronaviral disease including enteric and neurological involvement in some cases (p. 1, line 32 to p. 2, line 37). This is interpreted herein as an express suggestion that compounds with activity against FIPV may be effective against other coronaviruses, including SARS-CoV-2.
Cook teaches that recent antiviral clinical trials in both experimentally and naturally FIPV-infected cats have shown promise in treating and curing FIP through the use of GS-441524, a nucleoside analog and metabolite of the prodrug Remdesivir, and that the GS-
441524 prodrug Remdesivir has recently shown promise in treating human patients infected
with SARS CoV-2 (p. 4, lines 96-101).
Cook further teaches a screening of 89 putative antiviral compounds and identified 25 compounds with antiviral activity against FIPV, representing a variety of drug classes and mechanisms of antiviral action (p. 2, lines 37-39). Cook teaches that from these 89 compounds, 25 different compounds were determined to possess antiviral activity against FIPV including NPIs, PIs, NS5A inhibitors and two compounds with undetermined mechanisms of action. Cook teaches that successful antivirals include grazoprevir, GS-4415214, and elbasvir.
Cook teaches that Grazoprevir, an NS3/4 serine protease inhibitor, has been used in combination with elbasvir, an NS5A inhibitor, to treat patients infected with HCV, and that in their study grazoprevir possesses anti-FIPV activity when used as monotherapy (p. 18, lines 330-332). Furthermore, Cook teaches that velpatasvir demonstrates anti-FIPV activity (p. 8, line 165; data on p. 7, Figure 2). In addition, velpatasvir is an NS5A inhibitor (p. 766, see table). Therefore, Cook recognizes both grazoprevir and velpatasvir, as well as GS-441524, the metabolite of remdesivir, as having anti-FIPV activity.
It would have been prima facie obvious to one of ordinary skill in the art to administer a combination of remdesivir, grazoprevir, and velpatasvir to an individual for the purposes of treating an infection by SARS-CoV-2. One of ordinary skill in the art would have been motivated to administer a combination of remdesivir, grazoprevir, and velpatasvir to an individual for the purposes of treating an infection by SARS-CoV-2 because Jensen teaches a therapy for SARS-CoV-2 infection that administers remdesivir, and because Cook teaches grazoprevir, velpatasvir, and GS-441524, the metabolite of remdesivir, as having anti-FPV activity, teaches remdesivir as promising for treating human patients infected with SARS CoV-2, and teaches that compounds with activity against FIPV may be effective against other coronaviruses, including SARS-CoV-2. In this instance, the rationale “combining prior art elements according to known methods to yield predictable results” would apply. Because remdesivir is recognized as a treatment for SARS-CoV-2 by Jensen and Cook, and because Cook teaches additional compounds as active against FIPV, including grazoprevir and velpatasvir, and further suggests treatments for FIPV may be effective in treating SARS-CoV-2, one of ordinary skill in the art would have contemplated treating a SARS-CoV-2 infection using remdesivir in combination with other active compounds taught by Cook, including grazoprevir and velpatasvir.
One of ordinary skill in the art would have had a reasonable expectation of success administering the combination of remdesivir, grazoprevir, and velpatasvir because remdesivir is recognized in the prior art as a treatment for SARS-CoV-2, and because grazoprevir and velpatasvir are recognized as having anti-FIPV activity and may possess anti-SARS-CoV-2 activity, as taught by Cook. Therefore, one of ordinary skill in the art would have had a reasonable expectation that the combination of remdesivir, grazoprevir and velpatasvir would be effective in treating a SARS-CoV-2 infection.
Therefore the invention taken as a whole is prima facie obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 28, 30, 33, 34, and 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 17, 19, and 20 of copending U.S. patent application 17/997981 (reference application; hereafter ‘981).
The present application and ‘981 are assigned to The Regents of the University of California.
The amended claims of ‘981 received October 24, 2025 are cited in this provisional nonstatutory double patenting rejection.
Claim 1 of ‘981 claims a method for reducing viral respiratory infection in
a subject in need thereof, the method comprising: administering a formulation intranasally or by inhalation to the subject having a viral respiratory infection, wherein the viral respiratory infection is coronavirus or SARS-CoV-2, wherein the formulation comprises a therapeutically effective amount of a statin; and a pharmaceutically acceptable carrier.
Claim 4 of ‘981 claims the viral respiratory infection is COVID-19.
Claim 17 of ‘981 depends from claim 1 and requires further administering at least one additional therapeutic agent. Claim 19 further narrows the additional therapeutic agent, and claim 20 requires the additional therapeutic agent is remdesivir.
It would therefore have been prima facie obvious to one of ordinary skill in the art to administer the method for treating COVID-19 claimed by ‘981 with remdesivir and a statin, because the claims of ‘227 suggest such a therapeutic system, including claiming remdesivir as the additional therapeutic agent, for treating SARS-CoV-2. Moreover, because the claims of ‘981 specifically recite treatin