DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of a subject suffering from sepsis as the subject population species and oseltamivir as the elected antiviral agent species in the reply filed on 07/18/2025 is acknowledged and maintained.
Priority
This application is a National Stage of International Application No. PCT/KR2021/001910 filed on February 15, 2021, claiming priority based on Korean Patent Application No. 10-2020-0018534 filed on February 14, 2020 and Korean Patent Application No. 10-2020-0044119 filed on April 10, 2020.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on November 26, 2025. Claims 1-30 and 32 are canceled. Claims 31 and 33-50 are pending. Claims 34, 36, 40, 44, and 46 are withdrawn. Claims 31, 33, 35, 37-39, 41-43, 45, and 47-50 are examined in accordance to the elected species.
Action Summary
Claims 31, 38, 39, 49, and 50 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lebensburger et al (Blood. 2011 Nov 30;119(8):1915–1921), are withdrawn in light of the claim amendment.
Claims 31, 33, 38-39, 41-43, 48-50 rejected under 35 U.S.C. 103 as being unpatentable over by Lebensburger et al (Blood. 2011 Nov 30;119(8):1915–1921) in view of Cummings et al (Am J Respir Crit Care Med 1997; 156:431–437) and Lin et al (Front Immunol. 2018 Sep 27; 9:2147), are withdrawn in light of the claim amendment.
Claims 35, 37, 45, 47 rejected under 35 U.S.C. 103 as being unpatentable over by Lebensburger et al (Blood. 2011 Nov 30;119(8):1915–1921) in view of Cummings et al (Am J Respir Crit Care Med 1997; 156:431–437) and Lin et al (Front Immunol. 2018 Sep 27; 9:2147) as applied to claims 31, 33, 38-39, 41-43, 48-50 in further view of Treanor et al (JAMA, 2000;283;(8):1016-1024), are withdrawn in light of the claim amendment.
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.
Claims 31, 33, 38, 39, 49, and 50 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lebensburger et al (Blood. 2011 Nov 30;119(8):1915–1921) and Clarke (Can Fam Physician. 1974 Nov;20(11):65–68) as evidenced by.
This rejection embraces the embodiment of preventing.
Lebensburger teaches a method of preventing sepsis caused by pneumococcal comprising administering an effective amount (50 mg/kg) hydroxyurea by injection to the subject by inhibiting E-selectin and by reducing neutrophil extravasation, leukocytosis and lung inflammation. (See Abstract; last paragraph of page 2 bridging first paragraph of page 3, and Method Section.)
Accordingly, even though pneumococcal is a bacterial infection and the fact that Lebensburger teaches the administration of an effective amount of hydroxyurea to a subject with pneumococcal-induced sepsis, the method of Lebensbruger necessarily prevents systemic inflammatory response syndrome (SIRS) that is accompanied by an inflammatory response that occurs upon exposure to a virus, because the Abstract of Clarke teaches preventive medicine occurs in the absence of disease by preventing the occurrence of a disease. In other words, the administration of the effective amount of hydroxyurea to the pneumococcal-induced sepsis subject as taught by Lebensburger would necessarily prevent systemic inflammatory response syndrome (SIRS) that is accompanied by an inflammatory response that occurs upon exposure to an influenza virus in the subject of Lebensburger. It is noted that in re Best (195 USPQ 430) and in re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
Acknowledgement is made of the receipt and entry of Applicant’s arguments/response filed on November 26, 2025.
Applicant argues that the amendment to base claims 31 and 49 to specify that "systemic inflammatory response syndrome (SIRS) that is accompanied by an inflammatory response that occurs upon exposure to a virus" (claim 31) and "sepsis or neutrophilia that occurs upon exposure to a virus" (claim 49), as supported by previous claims 32 and 33, renders the rejection moot.
In response, Applicant’s argument is not persuasive because the claim requires prevention of “systemic inflammatory response syndrome (SIRS) that is accompanied by an inflammatory response that occurs upon exposure to a virus" (claim 31) and "sepsis or neutrophilia that occurs upon exposure to a virus" (claim 49) is which is interpreted to be the absence of the disease. That means the subject the does not have to have sepsis or systemic inflammatory response syndrome (SIRS) that is accompanied by an inflammatory response that occurs upon exposure to a virus. Any subject including the subject taught by Lebensburger is in need of prevention of sepsis or systemic inflammatory response syndrome (SIRS) that is accompanied by an inflammatory response that occurs upon exposure to a virus.
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 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 31-33, 38-39, 41-43, 48-50 are rejected under 35 U.S.C. 103 as being unpatentable over by Lebensburger et al (Blood. 2011 Nov 30;119(8):1915–1921) in view of Cummings et al (Am J Respir Crit Care Med 1997; 156:431–437), Florescu et al (Virulence. 2013 Nov 19;5(1):137–142), Laird et al (Xenotransplantation. 2018 Jan 23;25(2): e12381), and Yang et al (. 2016 Apr 4;13(4):432–442).
This rejection encompasses the embodiment of treating or alleviating.
Lebensburger teaches a method of preventing or treating pneumococcal-induced sepsis comprising administering an effective amount (50 mg/kg) hydroxyurea by injection to the subject by inhibiting E-selectin and by reducing neutrophil extravasation, leukocytosis and lung inflammation. (See Abstract; last paragraph of page 2 bridging first paragraph of page 3, and Method Section.) Pneumococcal is a bacterial infection. E-selectin and by reducing neutrophil extravasation, leukocytosis and lung inflammation in a subject with pneumococcal sepsis is considered a subject exposed to pneumococcal bacteria.
Lebensburger does not teach treating systemic inflammatory response syndrome (SIRS) that is accompanied by an inflammatory response that occurs upon exposure to a virus in a subject with sepsis where the virus is influenza.
Cummings teaches E-selectin, an early mediator of leukocyte-endothelial adhesion, is expressed on activated endothelium. Soluble E-selectin is present in the supernatant of cytokine-activated endothelial cells and elevated serum levels are found in a variety of inflammatory conditions. soluble E-selectin levels are higher in serum of patients with microbiologically documented sepsis than in other critically ill medical ICU patients. Day 1 E-selectin levels correlate highly with hemodynamic compromise and modestly with subsequent organ dysfunction and survival. (See Abstract.) Moreover, Cummings teaches E-selectin to be detectable in increased quantities in patients with SIRS (systemic inflammatory response syndrome (SIRS) and sepsis, but particularly in patients with bacteremia or other microbiological confirmation of sepsis. (See first paragraph of the right column of page 436.)
Florescu teaches severe sepsis is traditionally associated with bacterial diseases. While fungi and parasites can also cause sepsis, they are significantly less common than bacterial causes. However, viruses are becoming a growing cause of severe sepsis worldwide. Among these viruses, influenza is crossing all geographic boundaries and is causing larger epidemics and pandemics. As a consequence, more critically ill patients with severe sepsis caused directly by influenza viruses, or indirectly by influenza-induced secondary bacterial infections are being admitted to hospitals worldwide. (See Abstract.) Moreover, Florescu teaches in the initial response to an infection, severe sepsis is characterized by a pro-inflammatory state, while a progression to an anti-inflammatory state develops and favors secondary infections, such as bacterial infections and cytomegalovirus reactivation. (See Introduction Section of the left column.) Florescu further demonstrated that severity of influenza virus infections is determined by nitric oxide induction, with higher nitric oxide production in the lungs and lung-derived neutrophils of mice infected with highly pathogenic H5N1 and 1918 H1N1 strains than with low-pathogenic seasonal H1N1 strain. (See the first paragraph of the left column of page 138.)
Laird teaches that E- and P-selectin expression on porcine cells are variably and differentially increased by exposure to human thrombin, TNF-α, IL-4, DDAVP, histamine and human serum. rhTNF-α and thrombin were the most potent upregulators of E-selectin in our model. (See first paragraph under Discussion at page 6.) Moreover, Larid teaches P-selectin antagonism has been shown by others to reduce monocyte recruitment, accelerate thrombolysis, inhibit platelet binding to injured vascular endothelium, and reduce ischemia-reperfusion injury in myocardial, renal, intestine, and hepatic models. Additionally, it prevented neutrophil migration in a mouse model of acute lung injury. (See Third paragraph of page 7.) Laird further concludes that porcine endothelium activated in response to inflammatory human cytokines exhibit significantly increased P- and E-selectin expression, which mediates subsequent neutrophil rolling. Novel E-selectin antagonist GMI 1271 and rPSGL-1. Fc, a P-selectin antagonist, inhibit selectin-mediated neutrophil rolling. (See Conclusion section.)
Yang teaches nfluenza A virus (IAV) infects the respiratory tract in humans and causes significant morbidity and mortality worldwide each year. Aggressive inflammation, known as a cytokine storm, is thought to cause most of the damage in the lungs during IAV infection. (See Abstract.) Moreover, Yang teaches the innate immune cell infiltration is regulated by ECs, which express adhesion molecules (P-selectin, E-selectin, ICAM-1 and VCAM-1) and facilitate the binding and migration of leukocytes during an influenza virus infection. (See Figure 2e.) An activated EC–platelet–leukocyte interaction feeds forward to amplify the overall inflammatory response. (See Figure 2e.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use the method taught by Lebensburger for treating systemic inflammatory response syndrome (SIRS) that is accompanied by an inflammatory response that occurs upon exposure to a virus in a subject with sepsis or severe sepsis where the virus is influenza to give Applicant’s claimed invention. One would have been motivated to do so, because not only Cummings teaches E-selectin to be detectable in increased quantities in patients with SIRS and sepsis, but particularly in patients with bacteremia or other microbiological confirmation of sepsis, but also because Florescu teaches more critically ill patients with severe sepsis caused directly by influenza viruses, or indirectly by influenza-induced secondary bacterial infections are being admitted to hospitals worldwide and also teaches severity of influenza virus infections is determined by nitric oxide induction, with higher nitric oxide production in the lungs and lung-derived neutrophils of mice infected with highly pathogenic H5N1 and 1918 H1N1 strains than with low-pathogenic seasonal H1N1 strain, and because Laird teaches inhibiting E-selectin directly inhibits neutrophil tethering and rolling on the endothelium, effectively reducing their recruitment to sites of inflammation, and lastly because Yang teaches the innate immune cell infiltration is regulated by ECs, which express adhesion molecules (P-selectin, E-selectin, ICAM-1 and VCAM-1) and facilitate the binding and migration of leukocytes during an influenza virus infection. One would reasonably expect the reduction of E-selectin with hydroxyurea to successfully treat influenza virus-induced sepsis by treating systemic inflammatory response that is accompanied by an inflammatory response that occurs upon exposure of influenza.
Claims 35, 37, 45, 47 are rejected under 35 U.S.C. 103 as being unpatentable over by by Lebensburger et al (Blood. 2011 Nov 30;119(8):1915–1921) in view of Cummings et al (Am J Respir Crit Care Med 1997; 156:431–437), Florescu et al (Virulence. 2013 Nov 19;5(1):137–142), and Laird et al (Xenotransplantation. 2018 Jan 23;25(2): e12381), as applied to claims 31-33, 38-39, 41-43, 48-50 in further view of Treanor et al (JAMA, 2000;283;(8):1016-1024)), and Yang et al (. 2016 Apr 4;13(4):432–442).
The teachings of Lebensburger, Cummings, Florescu, Laird, Treanor, and Yang have been discussed in the second rejection above.
Lebensburger, Cummings, Florescu, Laird, Treanor, and Yang collectively do not teach oseltamivir.
Treanor teaches oral oseltamivir treatment reduces the duration and severity of acute influenza in healthy adults and may decrease the incidence of secondary complications. (See Conclusion Section of the Abstract.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invenvion was filed to modify the method taught by Lebensburger, Cummings, Florescu, Laird, Treanor, and Yang collectively by including oseltamivir as taught by Treanor for treating influenza virus-induced sepsis. One would have been motivated to do so, because Lin teaches sepsis can be caused by bacterial infection and by influenza and also because oral oseltamivir treatment reduces the duration and severity of acute influenza in healthy adults and may decrease the incidence of secondary complications. One would reasonably expect the addition of oseltamivir to hydroxyurea to successfully treat influenza virus-induced sepsis.
Acknowledgement is made of the receipt and entry of Applicant’s arguments/response filed on November 26, 2025.
Applicant argues that Lebensburger discloses that hydroxyurea administration increases survival only in sickle cell anemia (SCA) mice, not in all strains of mice induced with pneumonia, by intranasal administration of Streptococcus pneumoniae. Specifically, Figure 1A of Lebensburger demonstrates that hydroxyurea administration increases survival in mice transplanted with bone marrow cells from SCA mice (squares) compared to saline administration (circles). Figure 1B of Lebensburger discloses that there is no difference in survival rate between hydroxyurea administration (squares) and saline administration (circles) in normal mice transplanted with bone marrow cells from wild-type mice. Even in Figures 2E and 2F of Lebensburger, unlike in SCA mice, wild-type mice (i.e., Mock Tx) do not show an anti-inflammatory effect of hydroxyurea administration. In other words, Lebensburger only showed the ameliorating effect of sepsis associated with a specific disease, SCA. Therefore, a skilled person in the art would not be motivated by or predict from Lebensburger that sepsis caused by viral exposure can be treated with hydroxyurea.
In response, Applicant’s argument is not persuasive. Lesenburger may well teach that hydroxyurea administration increases survival in mice transplanted with bone marrow cells from SCA mice (squares) compared to saline administration (circles). Lesenbruger may also well teach unlike in SCA mice, wild-type mice (i.e., Mock Tx) do not show an anti-inflammatory effect of hydroxyurea administration. However, Lesenburger teaches treatment with hydroxyurea resulted in a significant delay in time to death (Figure 1A; P .0028), and the bacterial burden in the blood was significantly (P .01) reduced (sickle/ mock median 4.2 104 CFUs/mL vs sickle/hydroxyurea median below limit of detection of 103). Lesenburger also teaches these data in Figure 2E-F) clearly indicate that sickle mice receiving hydroxyurea therapy have significantly reduced lung inflammation and damage in response to bacterial infection and improved survival. Moreover, Lesenburger teaches the hydroxyurea is effective at reducing lung inflammation, neutrophils, and E-selectin. A person of ordinary skill would reasonably expect hydroxyurea to reduce neutrophils and P-selectin, which are activated or increased during sepsis and influenza infection in response to inflammatory cytokines.
Applicant argues that Lesenburger does not teach or suggest an increase of E-selectin in SIRS that is due to viral infection. Applicant further submits Exhibits 1 and 2, which likewise demonstrate that sepsis associated with viral infection does not typically involve an elevation of E-selectin:
Exhibit 1: Flavio Bruni, et al., Complement and endothelial cell activation in
COVID-19 patients compared to controls with suspected SARS-CoV-2 infection: A prospective cohort study, Front. Immunol. 13:941742, September 20, 2022
Exhibit 2: Madelein Hoffman, et al., E-Selectin and markers of HIV disease
severity, inflammation and coagulation in HIV-infected treatment-naive individuals, African Health Sciences, Vol. 18, Issue 4, December 2018.
EXHIBIT 1 reports that C5a and VCAM-1 concentrations were elevated and E-selectin concentrations decreased in COVID-19 cases compared to controls* (Table 2), in which 166 controls sufferred mainly from non-SARS-CoV-2 respiratory viral infections, non-infectious inflammatory conditions and bacterial pneumonia. EXHIBIT 1 also reports "... whereas an increase in E-selectin concentrations was mainly observed in patients with bacterial pneumonia
Was less pronounced in patient with other respiratory viral infections (Table S1, S2). The data of EXHIBIT 2 demonstrates that there is no significant difference in E-selectin levels between the HIV-infected group and the non-infected group. Analysis of 114 HIV- infected patients showed no significant difference in E-selectin levels between HIV-infected individuals and non-infected control subjects (p=0.84). Thus, one skilled in the art would clearly understand that E-selectin is not a reliable indicator of endothelial activation in the context of viral infection.
In response, Applicant’s argument is not persuasive. While the Examiner acknowledges and considers Exhibit 1 and Exhibit 2, the Examiner contends that Exhibit 1 cannot be relied on to show unpredictability in the art because it is a postdating art. Predictability is at the time of the invention. (See MPEP 2143.02 (III).) With respect to Exhibit 2, the Examiner contends that the influenza virus establishes the basis for the rejection and not HIV.
Applicant argues that the data of Cummings only demonstrates an increase in E-selectin in bacterial sepsis. In bacterial sepsis (culture-positive), E-selectin levels were high at 15.39 ng/mL, but in culture- negative sepsis and non-infectious SIRS, levels were low, below 4.87 ng/mL. This clearly shows that the increase in E-selectin is a phenomenon that only appears in the specific pathological condition of bacterial infection. Lin describes viral sepsis and suggests that increased levels of substances such as E- selectin can induce neutrophil extravasation, but does not discuss whether hydroxyurea can directly improve sepsis. Treanor only demonstrates the therapeutic effect of oseltamivir against influenza, not the therapeutic effect of hydroxyurea. Accordingly, one skilled in the art would not be motivated to combine the teachings of the asserted references to arrive at the claimed methods with reasonable expectation of success.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the present case, Lebensburger teaches (50 mg/kg) hydroxyurea by injection to the subject by inhibiting E-selectin and by reducing neutrophil extravasation, leukocytosis and lung inflammation. Cummings teaches E-selectin to be detectable in increased quantities in patients with SIRS and sepsis, but particularly in patients with bacteremia or other microbiological confirmation of sepsis. Florescu teaches more critically ill patients with severe sepsis caused directly by influenza viruses, or indirectly by influenza-induced secondary bacterial infections are being admitted to hospitals worldwide. Florescu also teaches severity of influenza virus infections is determined by nitric oxide induction, with higher nitric oxide production in the lungs and lung-derived neutrophils of mice infected with highly pathogenic H5N1 and 1918 H1N1 strains than with low-pathogenic seasonal H1N1 strain. Laird teaches inhibiting E-selectin directly inhibits neutrophil tethering and rolling on the endothelium, effectively reducing their recruitment to sites of inflammation. Yang teaches the innate immune cell infiltration is regulated by ECs, which express adhesion molecules (P-selectin, E-selectin, ICAM-1 and VCAM-1) and facilitate the binding and migration of leukocytes during an influenza virus infection. One would reasonably expect the reduction of E-selectin with hydroxyurea to successfully treat influenza virus-induced sepsis by treating systemic inflammatory response that is accompanied by an inflammatory response that occurs upon exposure of influenza.
Applicant argues that Experimental Example 4 of the present application directly demonstrates through experimental results that hydroxyurea reduces the severity of systemic inflammation and pustular formation following viral infection. Therefore, it is respectfully submitted that Lebensburger, Cummings, Lin, and Treanor, individually or in combinations, do not render present claims 39, 41, and 49, and their dependent claims obvious under 35 U.S.C. 103.
In response, Applicant’s argument is not persuasive. It may well be true that Example 4 of the present application directly demonstrates through experimental results that hydroxyurea reduces the severity of systemic inflammation and pustular formation following viral infection. However, example 4 clearly uses 30 mg/kg/day hydroxyurea and 80 mg/kg/day hydroxyurea, a monkey model where absolute neutrophils count, white blood cell count, and absolute lymphocyte count were reduced. In contrast, the claim recites a broad subject, a broad therapeutically effective amount, a broad systemic inflammatory response. 30 mg/kg/day hydroxyurea and 80 mg/kg/day hydroxyurea as the effective amount, a monkey model as the subject, and neutrophils count, white blood cell, and lymphocyte as systemic inflammatory response. Therefore, the asserted unexpected experimental results are not commensurate in scope with the claim. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). See MPEP 716.02(d). Furthermore, assuming the unexpected experimental results are commensurate in scope with the claim, the asserted unexpected experimental results are expected by the fact that hydroxyurea can reduce E-selectin and by reducing neutrophil extravasation, leukocytosis and lung inflammation as taught by Lebensburger.
Conclusion
Claims 31, 33, 35, 37-39, 41-43, 45, and 47-50 are not allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628