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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/22/2026 has been entered.
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
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 Claims 34, 36, 40, 44, and 46 are withdrawn.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
The rejection of claims 31, 33, 38, 39, 49, and 50 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, are withdraw in view of the amendment deleting “preventing” from the claims.
The rejection of claims 31-33, 38-39, 41-43, 48-50 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Laird et al (Xenotransplantation. 2018 Jan 23;25(2): e12381), and Yang et al (. 2016 Apr 4;13(4):432–442) is withdrawn and replaced with replaced with the new ground of rejection set forth below.
The rejection of claims 35, 37, 45, 47 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), are also withdrawn and replaced with the new ground of rejection set forth below.
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 cited as “Lebensburger”), in view of Florescu et al. (Virulence. 2013 Nov 19;5(1):137–142, cited as “Florescu”), Yang et al. (. 2016 Apr 4;13(4):432–442, cited as “Yang”), Kulkarni et al. (Mucosal Immunology (2019) 12:545–554, cited as “Kulkarni”).
This rejection encompasses the embodiment of treating or alleviating.
Lebensburger teaches administration an effective amount (50 mg/kg) by injection of hydroxyurea in an infectious-disease model involving pneumococcal infection and sepsis. Specifically, Lebensburger investigated hydroxurea treatment in a murine sickle-cell-anemia model challenged intranasally with Streptococcus pneumonia and demonstrated that hydroxyurea treatment inhibited progression of pneumococcal disease and improved survival. (See pp. 1915-1921, Abstract, Materials and Methods, Results, and Figs. 1-2). Lebensburger further teaches the protective effect of hydroxyurea was associated with reduction of inflammatory-cell trafficking, including reduced neutrophil extravasation into the infected lung, reduced pulmonary inflammation, and tissue injury, and down-modulation of E-selectin. (See pp. 1917-1920, and figs 2-4). Lebensburger therefore teaches administering an effective amount of hydroxyurea by injection to a subject experiencing infection-associated systemic/inflammatory disease and demonstrates an anti-inflammatory effect involving reduced neutrophil treatment.
Lebensburger does not expressly teach that the infectious agent is a virus, particularly influenza virus, or that the systemic inflammatory response/sepsis being treated occurs upon exposure.
Florescu teaches that, although severe sepsis is traditionally associated with principally with bacterial diseases, virus had become an increasingly recognized cause of sever sepsis and specifically identifies influenza virus as an important cause thereof. Florescu teaches that critically ill patients with severe sepsis may have sepsis caused directly by influenza virus or indirectly by influenza-induced secondary bacterial infection. (See Abstract, pp. 137-138) Florescu further teaches that the pathophysiology of severe sepsis includes a substantial host inflammatory component. In the initial response to infection, severe sepsis is characterized by a pro-inflammatory state involving inflammatory cytokines and endothelial activation. (See p. 137, Introduction). Florescu additionally discusses severe influenza infection and the inflammatory response accompanying highly pathogenic influenza infection. (See pp. 1370140). Thus, Florescu establishes that influenza infection was recognized in the art as capable of producing severe sepsis and a substantial systemic inflammatory response.
Yang teaches that severe influenza disease is attributable merely to viral replication but is associated with an aggressive host inflammatory response. Yang teaches that influenza A virus infests the respiratory tract and that aggressive inflammation or a “cytokine storm” is believed to account for substantial lung injury occurring during influenza infection. (See Abstract and pp. 432-434). Yang further teaches that endothelial cells participate in regulation of innate immune-cell infiltration during influenza infection by expression of adhesion molecules including P-selectin, E-selectin, ICAM-1, and VCAM-1, which facilitate leukocyte binding and migration, and that endothelial-cell/platelet/leukocyte interactions amplify the overall inflammatory response. (See pp. 434-437 and Fig. 2). Thus, Yang establishes that leukocyte recruitment through activated endothelium is a recognized component of the pathological inflammatory response occurring during influenza infection.
Kulkarni provides further influenza-specific evidence concerning the role of neutrophils in severe influenza disease. Kulkarni teaches that, although neutrophils participate in antiviral host defense, excessive neutrophil responses cause tissue injury and worsen influenza disease. (See p. 545, Abstract). Kulkarni experimentally demonstrated that aged mice infected with influenza virus exhibited increased pulmonary neutrophil accumulation and that excessive neutrophil recruitment contributed to influenza-associated mortality. (See pp. 545-548 and Fig.1). Significantly, Kulkarni teaches that the timing of neutrophil modulation determines its biological consequence. Depletion of neutrophils at the time of influenza inoculation increased mortality in young animals, demonstrating their protective early role, whereas depletion after influenza infection, beginning at day 6 post-infection, significantly increased survival in aged-infected animals. (See pp. 547-548, Fig. 2). In the aged animals, post-infection neutrophil depletion increased survival from approximately 40% to approximately 80%, Kulkarni further determined that this improvement occurred without impairing viral clearance, thereby demonstrating that excessive later-stage neutrophilic inflammation could be therapeutically reduced without preventing clearance of influenza virus. (See pp. 547-549 and Figs. 2-3).
Kulkarni accordingly concludes that excessive neutrophil recruitment contributes to influenza mortality and expressly suggests that therapies directed to mitigating this pathophysiological host immune response may improve the outcome of influenza and other respiratory infections. (See p. 545, Abstract; pp. 547-550).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer an effective amount of hydroxyurea by injection, as taught by Lebensburger, to a subject suffering from influenza-associated systemic inflammatory response/sepsis, as taught by Florescu, in order to reduce the excessive inflammatory/neutrophilic response associated with severe influenza disease, as further taught by Yand and Kulkarni.
One ordinary skill would have been motivated to do so because Lebensburger had already demonstrated that hydroxyurea could reduce neutrophil extravasation and inflammatory lung injury and improve outcome during an infectious inflammatory/sepsis condition; Florescu expressly identified influenza as a cause of severe sepsis; Yang established that severe influenza involves excessive inflammatory response associated with endothelial activation and leukocyte recruitment; and Kulkarni provided direct experimental evidence that excessive pulmonary neutrophil accumulation contributes to influenza-associated tissue injury and mortality and that reducing excessive neutrophils after establishment of influenza infection improves survival.
Accordingly, the proposed modification does not rest upon an assumption that bacterial sepsis and viral sepsis are identical. Rathe, the references collectively would have provided one of ordinary kill with reason to apply the known anti-inflammatory/neutrophil-modulating effect of hydroxyurea taught by Lebensburger to the excessive neutrophilic inflammatory component independently shown by the influence art to contribute to severe influenza pathology.
One of ordinary skill would also have possessed a reasonable expectation of success. Lebensburger provides experimental evidence that administration of hydroxyurea reduces neutrophil extravasation and inflammatory tissue injury in an infection-associated inflammatory condition. Yang identifies leukocyte/endothelial recruitment as a component of the inflammatory amplification occurring during influenza infection. Most ignorantly, Kulkarni experimentally demonstrates in influenza-infected animals that reduction of excessive neutrophils after infection has been established improves survival and reduces pathological inflammatory injury without compromising viral clearance. Thus, the art provided more than a general theoretical association between neutrophils and inflammation; it provided experimental evidence that excessive neutrophilic inflammation constituted a therapeutically modifiable contributor to severe influenza disease.
The skilled artisan therefore would reasonably have expected administration of hydroxyurea, which Lebensburger had shown to reduce neutrophil extravasation and inflammatory injury, to provide therapeutic benefit by reducing the pathological host inflammatory response. Absolute predictability of success is not required, only a reasonable expectation of success is required.
Claims 35, 37, 45, 47 are rejected under 35 U.S.C. 103 as being unpatentable over Lebensburger et al. (Blood. 2011 Nov 30;119(8):1915–1921 cited as “Lebensburger”), in view of Florescu et al. (Virulence. 2013 Nov 19;5(1):137–142, cited as “Florescu”), Yang et al. (. 2016 Apr 4;13(4):432–442, cited as “Yang”), Kulkarni et al. (Mucosal Immunology (2019) 12:545–554, cited as “Kulkarni”), as applied to claims 31, 33, 38-39, 41-43, 48-50 in further view Treanor et al. (JAMA, 2000;283;(8):1016-1024, cited as “Treanor”).
The teachings of Lebensburger, Florescu, Yang, and Kulkarni are incorporated herein as set forth in the rejection above.
As discussed above, the combined teachings of Lebensburger, Florescu, Yang, and Kulkarni render obvious administration of an effective amount of hydroxyurea to a subject from an influenza-associated inflammatory condition encompassed by claims 31 and 41. Lesensburger teaches the ability of hydroxyurea to reduce neutrophil recruitment/extravasation and inflammatory lung injury in an infection-disease setting, while Florescu, Yang, and Kulkarni establish that excessive host inflammatory responses, including excessive inflammatory-cell/neutrophil recruitment, contribute to the pathology of severe influenza. In particular, Kulkarni demonstrates that reduction of excessive neutrophils after establishment of influenza infection substantially increased survival in infested aged mice and reduced lung injury and inflammatory cytokines without significantly affecting viral clearance. (See pp. 545-548, Abstract, Results, Figs. 2-3).
Lebensburger, Florescu, Yang, and Kulkarni collectively do not expressly each the additionally recited administration of an antiviral agent, including oseltamivir.
Treanor teaches treatment of naturally acquired acute influenza with oseltamivir, an orally active neuraminidase inhibitor having antiviral activity against influenza virus. Treanor reports a randomized, double-blind, placebo-controlled study in subjects with naturally acquired influenza and teaches administration of oseltamivir for treatment thereof. Treanor further teaches that oseltamivir treatment reduces the duration and severity of each influenza illness and may decrease the incidence of secondary complications. (See p. 1016, Abstract; pp. 1017-1019, Methods; pp. 1019-1022, Results and Comment).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to further administer the antiviral agent oseltamivir, as taught by Treanor, in conjunction with the hydroxyurea treatment rendered obvious by Lebensburger, Florescu, Yang, and Kulkarni.
The motivation for the combination is expressly supported by Florescu. Florescu recognizes that severe influenza presents both a viral infection and a potentially harmful host inflammatory response. Florescu teaches that influenza virus can trigger deregulation of the innate immune system with excessive cytokine release and harmful consequences, including endothelial damage, altered microvascular permeability, tissue edema, shock, acute lung injury, and multiorgan failure. (See p. 137, Introduction and “Pathophysiology of acute influenza infection). Florescu further teaches that animal studies directed to suppressive the excessive host response during influenza demonstrated that suppression of cytokine production and innate immune-cell recruitment could increase survival without altering viral clearance. (See p. 138, left col.) Florescu additionally teaches that excessive accumulation of macrophage and neutrophils in the lung, together with massive cytokine and reactive-oxygen-intermediate release, culminates in vascular injury, parenchymal damage, loss of functional alveolar surface area, and ineffective gas exchange. (See p. 138.) Significantly, Florescu discusses antiviral therapy and host-derived immunomodulatory therapy in the same therapeutic context. Florescu teaches that in critically ill patents, treatment with oseltamivir may have a positive impact on survival, while also recognizing that pro-inflammatory cytokine levels correlate with outcomes in severe influenza. (See p. 139, “Outcomes”).
Fluorescu thereafter expressly teaches that patients with influenza might benefit from a largen umber of immunomodulatory agents that target the host rather than the viral pathogen. (See p. 140, left col.)
Thus, the reason for combining the teachings is not based merely upon the fact that oseltamivir and hydroxyurea could be administered to an influenza patient. Rather, Florescu itself provides the skilled artisan with reason to address bot components of severe influenza disease: (1) the underlying viral infection using antiviral therapy, such as oseltamitir; and (2) the excessive and potentially damaging host inflammatory response using host-directed immunomodulatory therapy.
Accordingly, the prior art would have provided a reasonable expectation that the antiviral agent would retain its established activity against the underlying influenza infection while the host-directed treatment would address the excessive inflammatory component contribution to severe disease. The proposed combination therefore represents the predictable use of known or suggested therapies to address complementary aspects of influenza pathophysiology.
Response to Amendment
The Declaration by Dr. Tae-Ho Hwang under 37 CFR 1.132 filed 05/22/2026 is insufficient to overcome the rejection of claims 35, 37-39, 41-43, 45, and 47-50 based upon the new ground of rejection set forth above. Likewise, Applicant’s arguments with respect to claims 31, 33, 35, 37-39, 41-43, 45, and 47-50 have been considered. To the extent the arguments are directed specifically to the references and rationale underlying the previously applied grounds of rejection, such arguments are moot in view of the withdrawal of those grounds. To the extent the arguments and supporting Declaration remain applicable to the newly constituted grounds of rejection, they have been considered and are not persuasive for the reasons set forth above.
Response to Applicant’s arguments and evidence under 37 C.F.R § 1.131.
Applicant’s arguments and the Declaration submitted under 37 C.F.R § 1.131 have been fully considered but are not fully persuasive of patentability for the reasons discussed below.
Applicant argues, relying principally upon the Declaration, that the prior art fails to provide a reason to administer hydroxyurea for viral-induced SIRS or sepsis because the mechanisms underlying bacterial and viral sepsis differ; that E-selectin is principally associated with bacterial sepsis; that Lebensburger concerns pneumococcal infection in a sickle-cell-anemia model rather than viral infection; and that inhibition or depletion of neutrophils during viral infection would have been contrary to the knowledge in the art because neutrophils participate in antiviral host defense.
The Examiner acknowledges that Lebensburger evaluates hydroxyurea in an SCA model of pneumococcal infection and does not itself teach treatment of viral sepsis. The rejection, however, does not rely upon Lebensburger alone or upon a finding that bacterial and viral sepsis are mechanistically identical. Rather, Lebensburger is relied upon for its experimental teaching that hydroxyurea reduced neutrophil adhesion/extravasation and recruitment to infected lung tissue, attenuated lung injury, and improved survival in the disclosed infectious inflammatory model. See Lebensburger, pp. 1917–1920, Figs. 1–4.
The remaining references provide the influenza-specific teachings. Florescu expressly teaches that influenza can directly cause severe sepsis and that influenza can produce dysregulated innate immunity characterized by excessive cytokine release, endothelial injury, shock, acute lung injury, and multiorgan failure. Florescu further teaches that excessive accumulation of macrophages and neutrophils in influenza-infected lungs contributes to vascular and parenchymal injury and reports that suppression of cytokine induction and innate immune-cell recruitment improved survival in influenza models without altering viral clearance.
Yang independently teaches that overactivated innate immune cells contribute to morbidity and mortality in influenza-induced ARDS and that endothelial expression of P-selectin, E-selectin, ICAM-1, and VCAM-1 facilitates leukocyte binding and migration during influenza infection, thereby amplifying the inflammatory response. See Yang, pp. 432–435. Thus, Applicant’s argument that the proposed modification depends upon treating bacterial and viral sepsis as mechanistically identical, or upon E-selectin being exclusively or characteristically associated with bacterial disease, does not address the rejection as presently constituted.
Applicant and the declarant further rely upon the recognized protective functions of neutrophils and contend that reducing neutrophils during viral infection would have been expected to impair viral clearance. The Examiner agrees that the art recognizes a protective role for neutrophils and has considered this evidence. However, the evidence does not establish that the skilled artisan would have avoided modulation of an excessive pathological neutrophil response.
Kulkarni expressly recognizes both sides of this biological relationship. Kulkarni teaches that neutrophils participate in influenza viral clearance, but that excessive neutrophil responses cause tissue injury and worsen disease. showPdf.pdf Experimentally, depletion of neutrophils at the time of infection increased mortality in young mice, whereas depletion after infection significantly increased survival in aged influenza-infected mice from approximately 40% to 80%. See Kulkarni, pp. 546–547, Fig. 2. Post-infection neutrophil depletion also reduced lung damage and inflammatory cytokines without significantly affecting viral clearance. See Kulkarni, pp. 547–548, Fig. 3. Kulkarni therefore directly supports the proposition that the protective role of neutrophils did not teach away from therapeutically reducing an excessive neutrophilic response during established influenza infection.
Applicant additionally argues that the HYDREA prescribing information would have discouraged the claimed treatment because hydroxyurea can cause myelosuppression and because the labeling contains warnings concerning vaccination and administration with certain antiviral therapies. This evidence has been considered but does not constitute a teaching away from the presently proposed modification. The cited safety information identifies recognized risks requiring clinical management; it does not establish that hydroxyurea should not be administered to a subject having influenza or that modulation of excessive inflammatory-cell recruitment would lack therapeutic benefit. Moreover, the warning concerning live-virus vaccination does not equate administration of a live attenuated vaccine with treatment of an established naturally acquired viral infection.
Applicant’s hindsight argument is likewise unpersuasive. The rationale does not originate from Applicant’s disclosure. Florescu expressly teaches both that severe influenza involves harmful host inflammation and that patients with influenza may benefit from host-directed immunomodulatory agents. Yang identifies leukocyte/endothelial recruitment as part of the influenza inflammatory pathway, and Kulkarni experimentally demonstrates that reducing excessive neutrophilic inflammation during established influenza can improve outcome without compromising viral clearance. Accordingly, the reason for modifying the treatment of Lebensburger arises from the prior art itself.
The experimental evidence presented in the Declaration, including the influenza and vaccinia-virus studies, has been considered and accorded appropriate weight.
The Examiner acknowledges that the submitted experiments constitute evidence relevant to nonobviousness. However, the evidence must be weighed against the evidence of obviousness as a whole. In particular, the presently applied prior art establishes before the effective filing date that excessive host inflammatory responses contribute to severe influenza pathology, that excessive neutrophil accumulation can contribute to influenza-associated lung injury and mortality, and that reducing the excessive neutrophilic response after infection can improve survival without impairing viral clearance. Kulkarni expressly concludes that controlling excessive neutrophil levels may improve outcomes in subjects infected with influenza.
Accordingly, the submitted influenza results do not establish a result wholly contrary to what the prior art would have led the skilled artisan to expect. Rather, the direction of the reported therapeutic effect—amelioration of influenza-associated pathology through modulation of an excessive inflammatory/neutrophilic response—is consistent with the therapeutic approach suggested by Florescu and Kulkarni.
Further, to the extent the Declaration relies upon the influenza and vaccinia experiments as evidence of unexpected results across the full scope of claims encompassing numerous viral infections and inflammatory conditions, the evidence has not been shown to be reasonably commensurate in scope with all of the claimed alternatives. The declarant’s conclusion that the tested viruses are representative has been considered, but the limited experimental showing does not establish unexpected results throughout the entire breadth of the claimed viral genera/species and associated conditions.
Accordingly, when the Declaration and Applicant’s arguments are considered together with the prior art evidence as a whole, the evidence is insufficient to outweigh the evidence supporting the prima facie case of obviousness. The rejections under 35 U.S.C. 103 are therefore maintained as newly constituted above.
Conclusion
Claims 31, 33, 35, 37-39, 41-43, 45, and 47-50 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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