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 .
Status
Claims 1, 2, 6-10, 13, 17-18, 20-23, 27, 29, 34, and 35 are pending. Claim 29 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Therefore, Claims 1, 2, 6-10, 13, 17-18, 20-23, 27, 34, and 35 are presented for examination.
Election/Restrictions
Applicant elected Group I in the reply filed on 11/15/2024 without traverse.
NOTE: The restriction requirement between the process claims of Groups I-IV in the 09/16/2024 restriction was withdrawn (see 3/13/2025 Office action, p. 2) and the groups were combined into a single group called “Group I”. The restriction requirement between the process Group I and the product of Group V was maintained.
Priority
This application is a U.S. national stage application claiming the benefit of International Application No. PCT/US2020/030697, filed April 30, 2020, which claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62/842,803, filed May 3, 2019.
Information Disclosure Statement
No Information Disclosure Statement filed was filed with applicant’s most recent reply.
Withdrawn Claim Rejections
Claims 15, 17, 18, and 20 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite. Applicant’s amendment and corresponding reply pertaining to the newly added limitation have overcome the rejection made of record in the previous Office Action, specifically, the change to make Claim 17 dependent from Claim 1 instead of Claim 10.
Claim Rejections - 35 USC § 112 – not further limiting
Maintained, slightly modified due to change of claim dependency
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.
Claim 23 is 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 23 does not further limit Claim 1 because it recites the agents are administered before infection but it does not include all limitations of the claim from which it depends as Claim 1 requires the agents to be administered to a subject infected with the virus, i.e., after infection. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 6-10, 13, 17-18, 20-23, 27, 34, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Genentech, Inc. (TAMIFLU® (oseltamivir phosphate): Highlights of prescribing information. (Jun 2016) https://web.archive.org/web/20170209084148/https://www.gene.com/download/pdf/tamiflu_prescribing.pdf) in view of Hsieh et al. ("Strategies of Development of Antiviral Agents Directed Against Influenza Virus Replication." Current Pharmaceutical Design (2007); 13: 3531-3542) and Haruki et al. ("Inhibition of nuclear factor-κB enhances the antitumor effect of tumor necrosis factor-α gene therapy for hepatocellular carcinoma in mice." Surgery, Volume 154, Issue 3, (2013); Pages 468-478. ISSN 0039-6060. https://doi.org/10.1016/j.surg.2013.05.037.)
Claimed invention
Independent Claim 1 is drawn to a method for reducing influenza virus titer in a subject, comprising administering to a subject infected with influenza virus a combination of nafamostat mesylate and oseltamivir in an effective amount to reduce influenza virus titer in the subject by at least 20% relative to a control.
Independent Claim 9 is drawn to a method for preventing influenza virus infection in a subject, comprising administering to a subject a combination of nafamostat mesylate and oseltamivir in an effective amount to prevent influenza virus infection in the subject.
Independent Claim 10 is drawn to a method comprising contacting an airway cell with nafamostat mesylate and oseltamivir.
Independent Claim 13 is drawn to a method for inhibiting influenza virus replication in a subject, the method comprising administering to a subject having an influenza virus infection nafamostat mesylate and oseltamivir in effective amounts for inhibiting replication of the influenza virus.
Prior art
Genentech teaches prescribing information for oseltamivir (i.e., TAMIFLU®) which is used for prophylaxis and treatment of acute influenza A and B in patients 2 weeks of age and older who have been symptomatic for no more than 48 hours as well as for prophylaxis of influenza A and B in patients 1 year and older. See p. 1 under 'INDICATIONS AND USAGE'. Genentech further teaches that oseltamivir potentially inhibits viral replication. See p. 24, second to last paragraph. Genentech further teaches that influenza viruses change over time and emergence of resistance substitutions could decrease drug effectiveness. See p. 3. Dosage amounts for treatment include administration of 75 mg twice daily for adults and adolescents. The dosage is administered twice daily for pediatric patients 1 to 12 years of age and based on weight. Pediatric patients 2 weeks to less than 1 year of age is administered 3mg/kg twice daily. See p. 1, under 'DOSAGE AND ADMINISTRATION'. Dosage amounts for prophylaxis include administration of 75 mg once daily. See Id. Dosage amounts can be reduced depending on factors such as the presence of another illness (e.g., renally impaired). See Id.
While Genentech teaches the use of oseltamivir for the treatment of influenza A and B infection, Genentech does not teach nafamostat mesylate or that the effective amount reduces influenza virus titer in the subject by at least 20% relative to a control.
However, nafamostat mesylate was already known to inhibit influenza virus. For example, Hsieh teaches that "nafamostat mesilate" (same compound as "nafamostat mesylate") inhibit virus replication in vitro or in vivo. The EC50 (the concentration required to inhibit virus replication by 50% or 50% effective concentration) of nafamostat mesilate is 0.44 μg/mL (i.e., 0.815 µM) as evaluated in an in vitro cell culture system for influenza A virus. See p. 3532, left column; see also Fig. 2. It showed similar activity against influenza virus B. See p. 3532, left column.
It was known that nafamostat mesylate can be used in in vivo at a concentration of 40 μg/mL, i.e., 74 μM. See Haruki, p. 469, 2nd column. The amount can be administered via intraperitoneal injections at 30 mg/kg. See p. 470, 2nd column.
A POSA would have found it obvious to prevent (instant Claim 9) or treat an influenza virus A or B infection in a subject with influenza virus A or B by administering a combination of oseltamivir and nafamostat mesylate at known amounts to the subject because Genentech teaches 75 mg bid (150 mg/d) oseltamivir for prophylaxis and treatment of influenza virus A and B infection in patients while Hsieh teaches nafamostat mesylate inhibits virus replication in vitro (0.44 μg/mL, 0.815 µM) or in vivo of influenza virus A and B. The POSA would have combined 150 mg/d oseltamivir and nafamostat mesylate to add together their individual inhibitory activity against influenza virus A and B. The POSA would have reasonably expected that each agent would provide their inhibitory activity against the virus. Given that nafamostat mesylate can be used in vivo at a concentration of 40 μg/mL, i.e., 74 μM, to provide a dose of 30 mg/kg (see Haruki), the POSA would have found it obvious to use a concentration of 40 μg/mL, i.e., 74 μM, to provide 30 mg/kg with a reasonably expectation that it would provide its effects in an in vivo setting. Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Regarding the effective amount to reduce influenza virus titer (instant Claim 1) in the subject by at least 20% relative to a control, because the prior art suggests the amounts encompassed by the range of effective amounts disclosed in the present invention - 0.1-100 μM nafamostat mesylate and 25-100mg at least once daily (see instant Claims 15 and 16) - the claimed effect of reducing influenza virus titer in the subject by at least 20% relative to a control would have been obvious. “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established.” See MPEP § 2112.01. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). In this case, the prior art suggest the same method of administration of a substantially identical combination comprising 75 mg oseltamivir twice a day and 74 μM nafamostat mesylate to treat or prevent influenza virus infection. Therefore, the benefits that the method reduces influenza virus titer in the subject by at least 20% relative to a control would have been obvious.
Regarding contacting an airway cell with nafamostat mesylate and oseltamivir (instant Claim 10), while the references do not teach contacting the cells with both agents, it would have been obvious to contact airway cells with the drugs because Hsieh teaches that the virus infects the airway cells and suggest targeting the membrane fusion between influenza and cell membranes. See paragraph bridging pages 3532 and 3533. Hsieh further teaches the virus enters and exits the cell through activity of neuraminidase on airway cells. See paragraph bridging pages 3536 and 3537; see also p. 3541, reference [92] which states “[n]euraminidase is important for the initiation of influenza virus infection in human airway epithelium.” Hsieh further teaches that oseltamivir works by inhibiting neuraminidase. See p. 3538, second column. Hsieh further teaches that oseltamivir is bioavailable orally, i.e., administered systemically. See p. 3538, second column. Haruki teaches nafamostat mesylate can be administered systemically via ip injections. See Haruki, p. 470, second column. Thus, the POSA would have found it obvious to contact airway cells with the combination of drugs because both are systemically administered and the POSA would have understood that the systemic administration would lead to the drugs being delivered to the airway cells. The POSA would have further found it obvious to deliver the drugs to the airway cells because it was known that the virus infects by entering airway cells and is then released from them. The POSA would have sought to inhibit the virus at the site of infection, i.e., airway cell.
Independent Claim 13 is drawn to a method for inhibiting influenza virus replication in a subject, the method comprising administering to a subject having an influenza virus infection nafamostat mesylate. Genentech teaches that oseltamivir has the potential inhibiting viral replication (see p. 24, second to last paragraph) and Hsieh teaches nafamostat mesylate inhibits viral replication (see p. 3532, fist column). Thus, the administration of the drug combination to treat or prevent influenza infection would inhibit viral replication.
Claim 2 limits Claim 1, wherein the combination is administered to the subject within 24 hours of infection in an effective amount to reduce influenza virus titer in the subject by at least 20% relative to a control, wherein the control is a subject administered only nafamostat mesylate or only oseltamivir within 24 hours of influenza virus infection. Genentech teaches that the treatment of infection should occur within 48 hours of influenza symptoms onset. See p. 1. It is also used prophylactically and should be administered within 48 hours following close contact with an infected individual. See pp. 1, 4 and 22. Thus, while the references do not explicitly mention administration to the subject within 24 hours of infection, the POSA would have found it obvious to administer treatment as immediately as possible including within 24 hours in order to reduce or prevent infection.
Claim 6 limits Claim 1, wherein the nafamostat mesylate and the oseltamivir are administered simultaneously. Claim 7 limits Claim 1, wherein the nafamostat mesylate and oseltamivir are administered sequentially. While the prior art does not expressly mention whether the agents should be administered simultaneously or sequentially, the POSA would have found both sequences to be obvious. For simultaneous administration, the POSA would have found it obvious to administer the two drugs together in combination in order to decrease the number of drug administration which would reasonably be considered a convenience of having to engage in a single event of administration. For sequential administration, the POSA would have found it obvious to administer the drugs separately because the prior art teaches two separate compositions comprising one of the drugs in each. The POSA would have reasonably understood that each compositions can be provided one behind the other to reasonably provide their effects to the subject.
Claim 8 limits Claim 7, wherein the nafamostat mesylate is administered before the oseltamivir is administered. While the sequence of administration of the claimed drugs is not discussed by the prior art, the administration of oseltamivir first would have been obvious because the individual steps of administering oseltamivir and nafamostat mesylate are known and arranging them in any order would have been prima facie obvious. See MPEP 2144.04 IV - stating "selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results." Because the specification does not demonstrate new or unexpected results stemming from the arrangement of the claimed process steps, the administration of oseltamivir first is rendered obvious.
Claim 17 limits Claim 10, wherein the effective amount reduces influenza virus titers by at least 2-fold. Claim 18 limits Claim 17, wherein the effective amount reduces influenza virus titers by at least 10-fold. Claim 20 limits Claim 17, wherein the effective amount reduces influenza titers by 2-fold to 100-fold. While the references do not expressly teach the claimed amount of titer reduction, the prior art suggests the amounts encompassed by the ranges of effective amounts disclosed in the present invention - 0.1-100 μM nafamostat mesylate and 10-1000mg at least once daily (see specification paragraph bridging pages 7 and 8; see p. 8, last full paragraph) - the claimed effect of reducing influenza virus titer in the subject would have been obvious. “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established.” See MPEP § 2112.01. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). In this case, the prior art suggest the same method of administration of a substantially identical combination comprising 75 mg oseltamivir twice a day and 74 µM nafamostat mesylate to treat or prevent influenza virus infection. Therefore, the benefits that the method reduces influenza virus titer in the subject by the claimed amounts would have been obvious. Furthermore, a POSA would have found it obvious to reduce the titer of virus by at least half in order to reduce the number of virus titers infecting a subject since antiviral activity is an obvious goal of administering the antiviral agents and oseltamivir carboxylate is an inhibitor of influenza virus neuraminidase affecting release of viral particles. See Genentech, section 12.4 ‘Microbiology’ beginning at p. 16.
Claim 21 limits Claim 1, wherein the nafamostat mesylate and oseltamivir are administered within 24 hours - 96 hours after influenza infection. Claim 22 limits Claim 21, wherein the nafamostat mesylate and oseltamivir are administered within 72 hours after influenza infection. As outlined above, for Claim 2, while the references do not explicitly mention administration to the subject within 24 hours of infection, the POSA would have found it obvious to administer treatment as immediately as possible including within 24 hours in order to reduce or prevent infection.
Claim 23 limits Claim 1, wherein the nafamostat mesylate and oseltamivir are administered prior to influenza virus infection. Genentech teaches influenza can be prophylactic treated by administering treatment is there is a community outbreak (see p. 1, first column) and treating those at risk of developing complications associated with influenza infection (see p. 7, last paragraph; see also Table 5).
Claim 27 limits claim 1, wherein the nafamostat mesylate is administered in an effective amount to prevent emergence of influenza virus strains that are resistant to nafamostat mesylate.
Claim 34 limits Claim 1 composition of claim 29, wherein the ratio of nafamostat mesylate to oseltamivir is 1:1 - 20:1. Claim 35 limits Claim 1 composition of claim 29, wherein the ratio of nafamostat mesylate to oseltamivir is 1:1 - 1:20. While the prior art does not teach the claimed ratio, Genentech teaches that the amount of oseltamivir can be adjusted based on the patient age, size and the presence of other complications. For example, dosage amounts for treatment include administration of amounts that may be reduced to 30 mg a day depending on factors such as the presence of another illness (e.g., renally impaired). See p. 1. The amount of nafamostat mesylate disclosed by Hsieh is 30 mg, i.e., a 1:1 ratio of oseltamivir to nafamostat mesylate.
Response to arguments
Applicant contends that Genentech merely provides prescribing information for oseltamivir and that Hsieh discloses numerous influenza inhibitors without providing a reason to specifically select nafamostat or to combine it with oseltamivir. Applicant further asserts that there was no reason to combine nor a reasonable expectation of success at the time of the invention. Applicant's arguments have been fully considered but have not been found to be persuasive. As stated in the Office action, Genentech discloses oseltamivir as a neuraminidase inhibitor useful for the treatment of influenza infection. Hsieh teaches that protease inhibitors such as nafamostat are effective against influenza viruses A and B by inhibiting virus replication through blockade of host proteases such as TMPRSS2 and HAT involved in viral entry (see Hsieh, Fig. 1-2 and text, pp. 3531-3534). Hsieh expressly identifies nafamostat as an “effective anti-influenza virus strategy.” Thus, Hsieh provides not merely a list of potential inhibitors, but an enabling disclosure identifying nafamostat as one of several known agents that inhibit influenza virus replication. A POSA would have recognized that improvement of antiviral therapy for influenza may be obtained by combining agents known for inhibiting influenza virus.
Conclusion
No claims are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622