FINAL REJECTION
Receipt is acknowledged of Applicants' Amendments and Remarks, filed Dec. 17, 2025.
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The rejections and/or objections set forth below are either maintained or newly applied, and constitute the complete set presently applied to the instant claims.
STATUS OF THE CLAIMS
Claims 8, 9, 14, 15, 27, 28, 33, 34, 36, and 37 have been canceled.
Claims 1 and 4 have been amended and incorporate no new matter.
Claims 7, 30, and 31 have been amended to correct improper dependencies.
No new claims have been added.
Thus, claims 1-4, 6, 7, 10-13, 16-26, 29-32, and 35 now represent all claims currently pending and under consideration.
INFORMATION DISCLOSURE STATEMENT
The information disclosure statements (IDS) submitted on Jul. 15, 2025 and Jan. 8, 2026 were filed after the mailing date of the non-final action on Jun. 17, 2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
MAINTAINED REJECTIONS
The following rejection is maintained from the previous Office Action dated Jun. 17, 2025, on the ground that the references cited therein continue to read on the limitations of the amended claims.
Rejections under 35 U.S.C. § 103
Claims 1-4, 6, 7, 10-13, 16-26, 29-32, and 35 stand rejected under 35 U.S.C. 103 as being
unpatentable over Irie et al. (US Pub. 2023/0165826, filed 3/18/2020), further in view of
Hanazawa et al. (JP 2006/169156A) and Oishi (WO 2003/070235).
Irie et al. claim methods of treating a COVID-19 viral infection in a subject comprising
orally administering to the subject an effective amount of a pharmaceutical composition
comprising nafamostat mesylate (claims 21 and 26). COVID-19 (Coronavirus disease 2019) is
caused by the SARS-CoV-2 coronavirus (para. [0004]).
Thus, Irie et al. disclose methods of treating a SARS-CoV-2 coronavirus infection in a
subject comprising orally administering nafamostat or a salt thereof, which reads on a method of
treating or inhibiting a viral infection in a subject comprising orally administering nafamostat or a salt thereof, as recited by claims 1 and 16;
wherein the viral infection comprises infection by the coronavirus SARS-CoV-2, as recited by claims 2, 3, 19, and 20.
Irie et al. disclose that "the methods and compositions provided herein can be used
preventatively in subjects that do not yet exhibit any clear or detectable clinical indicators or
symptoms of COVID-19 but that are believed to be at risk of developing such symptoms, for
example due to infection with SARS-Cov-2 or contact with an individual infected with SARS-
Cov-2" (para. [0062]; see also para. [0070]), which reads on the step of administering nafamostat
before a symptom of a viral infection is observed in the subject, as recited by claim 17; and
wherein the subject has been exposed to a virus, as recited by claim 18.
The methods and compositions of Irie et al. are disclosed for administration to elderly
subjects (para. [0073]), i.e., patients aged 65 or older, as recited by claim 21. The patient
population of Irie et al. also includes subjects with heart disease, hypertension, lung disease,
diabetes, cancer, liver dysfunction, coagulation dysfunction, organ failure, or is immuno-suppressed or immuno-compromised (para. [0073]), as recited by claims 22 and 23.
Irie et al. disclose that an effective amount of nafamostat mesylate is in the range of about
100-1000 mcg/kg (para. [0086]), i.e., 0.1 mg to 1 mg/kg. This dosage range lies inside the open-
ended range of "at least about 0.1 mg/kg," as recited by claims 11 and 30.
In addition, the dosage range of Irie et al.:
overlaps the nafamostat mesylate dosage range of about 0.75 mg/kg/day to about 20
mg/kg/day, as recited by claims 12 and 31; and
overlaps the endpoint of the nafamostat mesylate dosage range of about 1 mg/kg to about
10 mg/kg, as recited by claims 13 and 32.
Therefore, it would have been predictable to one of ordinary skill in the art to adjust or optimize the dosages for oral administration recited by claims 11-13 and 30-32, because Irie et
al. teach that this can be accomplished by routine experimentation (para. [0079]):
an appropriate 'effective amount' in any individual case may be determined using
standard techniques known in the art, such as dose escalation studies and studies performed to determine the EC₅₀ and/or maximum tolerated dose of an active agent. For example, in some embodiments an 'effective amount' of an active agent may be calculated based on studies performed in vitro or, preferably, in vivo (e.g., preclinical animal studies or human clinical trials) to assess the efficacy of the active agent. Furthermore, the 'effective amount' may be determined taking into account such factors as the desired route of administration, the desired delivery device, the desired frequency of dosing, the desired duration of dosing, and patient characteristics including age, body weight and the presence of any medical conditions affecting drug metabolism.
Further, as recognized by MPEP § 2144.05 (I), 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, 191USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
Irie et al. do not explicitly disclose that
the amount of nafamostat or salt thereof measurable in the plasma of the subject 1 to 8
hours after administering is below about 5 ng/mL, as recited by claim 1; or
orally administering nafamostat mesylate to a subject having a viral infection reduces the
risk of experiencing an adverse event associated with intravenous administration of nafamostat mesylate, as recited by claim 35.
However, these limitations merely recite the inherent biological effects which result from
carrying out the methods of Irie et al., which discloses orally administering the identical active agent to the identical patient population to treat identical viral infections.
As recognized by MPEP § 2112, "the discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. V. Ireco, Inc. 190 F.3d 1342, 1347, 51 USPQ 2d 1943, 1947 (Fed. Cir.) 1999). Thus, while known compositions may be claimed in new methods of treating conditions for which they were previously unknown to have therapeutic value, the claiming of a new property which was inherently present in the prior art composition at all times does not distinguish it over the prior art. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430,433 (CCPA 1977).
There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. V. Geneva Pharm. Inc. 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).
Thus, Irie et al. disclose, teach, and suggest all the limitations of claims 1-3, 11-13, 16-23, 30-32, and 35, as detailed above.
While Irie et al. teach oral administration of nafamostat mesylate and a nafamostat mesylate dosage range of 0.1 mg to 1 mg/kg. Irie et al. do not explicitly disclose the solid dosage forms or dosage amounts recited by claims 4-7, 10, 24-26, and 29.
However, one of ordinary skill in the art would have had a reasonable expectation of
success in arriving at the dosage ranges recited by claims 4, 7, 10-13, 26, and 29-32, because
orally administering nafamostat mesylate was known in the art, and thus it would have been predictable to modify the oral dose of nafamostat mesylate by routine experimentation.
For example, Hanazawa et al. and Oishi et al. disclose oral administration of nafamostat mesylate for treating respiratory conditions similar to COVID-19.
Hanazawa et al. disclose compositions comprising nafamostat mesylate as an immuno-modulator which suppresses the infiltration of inflammatory cells and the production of inflammatory cytokines at the site of inflammation, to alleviate the symptoms of various diseases
thought to be caused by abnormalities in the immune system (para. [0001]).
In particular, the nafamostat mesylate compositions of Hanazawa et al. are disclosed as
solid compositions for oral administration, including tablets, pills, capsules, powders, granules,
and the like (para. [0023]), which may be coated with a film of a gastric or enteric substance, or
may be coated with two or more layers (para. [0024]).
Thus, Hanazawa et al. disclose nafamostat mesylate formulated as a solid dosage form
for oral administration, e.g., a tablet, as recited by claims 1, 6, 7, and 24-26.
Hanazawa et al. teach that the dosage of nafamostat mesylate varies depending on the
subject, administration route, target discase, symptoms, etc., but for example, when administered
orally to a patient, it is desirable to administer 2.8 mg/kg to 9.6 mg/kg per day (para. [0022]).
Assuming an average adult patient weight of 70 kg, this corresponds to a range of 196-672 mg nafamostat mesylate per day. Thus, the oral dosage range disclosed by Hanazawa et al.:
falls within the range of a total daily dose of about 100 mg to about 1500 mg of
nafamostat mesylate, as recited by claim 4;
overlaps the range of about 50 mg to about 200 mg of nafamostat mesylate or an
equivalent amount of nafamostat or salt thereof, as recited by claim 7;
overlaps the range of about 50 mg to about 500 mg nafamostat mesylate, as recited by
claim 10;
falls within the range of at least about 0.1 mg/kg/day nafamostat mesylate, as recited by
claims 11 and 30;
falls within the range of about 0.75 mg/kg/day to 20 mg/kg/day nafamostat mesylate, as
recited by claims 12 and 31;
falls within the range of about 1 mg to about 10 mg/kg/day nafamostat mesylate, as
recited by claims 13 and 32;
overlaps the range of about 50 mg to about 600 mg of nafamostat mesylate, as recited by
claim 26; and
closely encompasses the range of 200 mg to about 500 mg nafamostat mesylate, as
recited by claim 29.
In addition, Oishi et al. claim compositions comprising nafamostat mesylate for treating
asthma, interstitial lung disease, pulmonary fibrosis, etc. (claims 1-5), which are disclosed for
oral administration as tablets, granules, capsules, etc. While the dose depends, e.g., on the
method of administration, the purpose of treatment or prevention, the age and weight of the
patient, the dose is preferably about 0.005 to about 100 mg/kg body weight (p. 4).
Further, Oishi et al. exemplify solid oral dosage forms comprising 100 mg nafamostat
mesylate in the form of a capsule (Formulation Example 5); and 50 mg nafamostat mesylate in
the form of a granule (Formulation Example 6), any number of which could be packaged in a
capsule to reach the desired dosage amount.
Thus, Oishi et al. explicitly disclose and exemplify solid oral dosage forms comprising
nafamostat mesylate in amounts falling squarely within the ranges recited by claims 4, 7, 10-13,
26, and 29-32.
Therefore, it would have been predictable to one of ordinary skill in the art as of the effective filing date to treat a SARS-CoV-2 viral infection (COVID-19) by orally administering nafamostat mesylate as taught by Irie et al., formulated as solid oral dosage forms in the amounts taught by Hanazawa et al. and Oishi et al., with a reasonable expectation of success, because solid dosage forms of nafamostat mesylate for oral administration were known, and Irie et al. teach that optimizing the dosage of nafamostat mesylate for oral administration to treat COVID-19 is routine and may be determined using standard techniques known in the art.
As recognized by MPEP § 2143, combining prior art elements according to known methods to yield predictable results would motivate the skilled artisan to modify the references
with a reasonable expectation of success. The rationale to support a conclusion of prima facie
obviousness is that all the claimed elements were known in the prior art, and a skilled artisan
could have combined the elements as claimed by known methods with no change in their
respective functions, and the combination yielded nothing more than predictable results to one of
ordinary skill in the art. See KSR Int'l Co. v. Teleflex Inc. (550 U.S. 398, 409).
RESPONSE TO ARGUMENTS
Applicant's arguments filed Dec. 17, 2025 have been fully considered but they are not persuasive.
Applicant contends that independent claim 1 recites three coordinated limitations which define the claimed methods and distinguish them over the prior art:
(1) oral administration of a solid oral dosage form delivering nafamostat locally to the GI tract and effective to reduce GI viral load;
(2) therapeutic treatment of a viral infection via that GI-localized delivery; and
(3) an explicit pharmacokinetic constraint requiring a plasma concentration of nafamostat at 1-8 hours post-dose below about 5 ng/ml (Remarks, pp. 7-8).
Applicant contends that the cited references fail to teach or suggest these limitations, or provide motivation or a reasonable expectation of success that oral nafamostat could treat a viral infection through local GI action while maintaining plasma below about 5 ng/ml.
Applicant contends that the amended claims tie antiviral efficacy to local GI delivery and to a specific low-exposure PK profile (i.e. non-systemic). This combination yields clinical advantages such as reduced adverse events associated with IV nafamostat, which are not predictable results of combining Irie with generic oral teachings, and are not suggested by the cited references, alone or in combination.
While the Examiner points to overlap of dosage ranges, the claim 1 plasma limitation and GI-localized antiviral action are independent and dispositive differentiators that are not subject to the overlapping-range rationale. Further, several dependent claims now recite dosage-forms aligned to GI localization and would not have been obvious to a skilled artisan starting from Irie's inhalational strategy (Remarks, p. 8).
Finally, Applicant contends that the characterization of both the low-exposure PK feature and the reduction of IV-associated adverse events as inherent is improper because these properties depend on particular formulation choices, release profiles, and dosing regimens not taught by the art, and where the prior art lacks any disclosure of the claimed plasma ceiling. The cited references do not recognize, teach, or enable oral regimens that treat viral infection via local GI action while avoiding therapeutically effective systemic plasma levels. The present claims require a specific PK outcome in conjunction with a local GI therapeutic mechanism, which does not necessarily result from practicing Irie, Hanazawa, or Oishi (Remarks pp. 8-9).
However, amended claim 1 is drawn to a method of treating a viral infection in a subject, comprising the active step of orally administering nafamostat in a solid oral dosage form.
The three "coordinated limitations" alleged by Applicant to define the claimed methods are inherent in the oral administration of nafamostat to a subject with a viral infection, because they naturally flow from said oral administration. These "coordinated limitations" do not depend on the dosage formulation, and do not distinguish the claims from the prior art.
This is evidenced by the instant specification, which establishes that these effects inherently occur when nafamostat is formulated and administered as a liquid solution, and are not dependent on any particular dosage formulation.
For example, the pharmacokinetic study of Example 1 administered nafamostat to rats by oral gavage (para. [0110] of the instant specification), which implies that nafamostat was formulated as a liquid solution. Further, the studies of Examples 2 and 3 administered nafamostat to human patients in the form of an oral solution, which was prepared by dissolving nafamostat mesylate in about 100 ml of EMETROL water (paras. [0118] and [0124]).
Separately, the specification exemplifies solid oral dosage forms of nafamostat (para. [0126]; Tables 3 and 4), without any actual administration to a subject.
Thus, by exemplifying methods of orally administering aqueous solutions of nafamostat, and separately, examples of solid formulations of nafamostat (Tables 3 and 4), the specification discloses little more than the cited references. The specification presents no evidence that orally administered nafamostat must be formulated in a solid dosage form to deliver nafamostat to the GI tract and reduce viral load in the GI tract without achieving a therapeutically effective plasma concentration, as recited by claim 1.
Instead, the specification explains that "[o]ral administration of nafamostat, in contrast to systemic administration, is effectively a local administration to one or more mucosal membranes within the GI tract" (para. [0045]). "Oral administration of a therapeutically effective amount of nafamostat may decrease gut viral concentration/load and therefore may cause a reduction in systemic viral concentration/load when compared to a control non-treated population" (para. [0046]). I.e., any oral administration of nafamostat (e.g., the aqueous oral solution of Examples 2-3) delivers it to the GI tract and reduces viral load in the GI tract without achieving a therapeutically effective plasma concentration, i.e., below about 5 ng/ml.
Thus, the specification itself establishes that oral administration of nafamostat inherently results in delivery of nafamostat locally to the GI tract, which reduces the GI viral load and treats a viral infection via that GI-localized delivery; and inherently results in a plasma concentration of nafamostat at 1-8 hours post-dose below about 5 ng/ml. This is why nafamostat is usually administered by the intravenous route, when used to treat other indications.
There is no evidence in the specification or in the prior art that the particular dosage form of orally administered nafamostat is critical: it is the oral route of administration itself that delivers nafamostat to the GI tract and reduces viral load in the GI tract without achieving a therapeutically effective plasma concentration, regardless of how it is formulated.
Thus, the three "coordinated limitations" of amended claim 1 merely recite the intrinsic results of orally administering nafamostat to a subject to treat a viral infection. While the cited references do not explicitly recognize those results, their discovery is tantamount only to finding a new property intrinsic in carrying out an old method.
Because Irie et al. disclose methods of administering the same compound by the same route in the same dosages to treat the same conditions in the same patient population, the results recited by the instant claims are inherent in the methods disclosed by the cited references.
For the foregoing reasons, the rejection of claims 1-4, 6, 7, 10-13, 16-26, 29-32, and 35 stand rejected under 35 U.S.C. § 103 over Irie et al., Hanazawa et al., and Oishi is maintained.
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.
CORRESPONDENCE
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA E. TOWNSLEY whose telephone number is 571-270-7672. The examiner can normally be reached on Mon-Fri from 9:00 am to 6:00 pm (EST). If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jeff S. Lundgren, can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARA ELIZABETH TOWNSLEY/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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