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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Mar. 13, 2026. Claims 1-20 are pending. Claims 1-14 and 19-20 are withdrawn. Claims 15-18 are currently examined.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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.
(Previous Rejection – Maintained) Claims 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over vom Steeg et al. (Seminars in Immunopathology (2019) 41:189–194; submitted in IDS filed on Aug. 28, 2025) and Suber et al. (Am J Physiol Lung Cell Mol Physiol 313: L1087–L1095, 2017).
These claims are directed to a method of inhibiting virus dissemination in a subject infected with an influenza virus or coronavirus, comprising administering an aromatase inhibitor to said subject.
Aromatase, encoded by the CYP19A1 gene, is an enzyme that converts an androgen into an estrogen, playing a role in both normal physiological functions and disease. Aromatase inhibitors block the androgen to estrogen conversion.
vom Steeg reviews studies on impact of sex and sex steroids on influenza pathogenesis across the life course. It teaches that males and females differ in the outcome of influenza A virus (IAV) infections, which depends significantly on age. During a typical seasonal influenza epidemic, young children (< 10 years of age) and aged adults (65+ years of age) are at greatest risk for severe disease, and among these age groups, males tend to suffer a worse outcome from IAV infection than females. Following infection with either pandemic or outbreak strains of IAVs, females of reproductive ages (i.e., 15–49 years of age) experience a worse outcome than their male counterparts. Among females of reproductive ages, pregnancy is one factor linked to an increased risk of severe outcome of influenza, although it is not the sole factor explaining the female-preponderance of severe disease. Small animal models of influenza virus infection illustrate that inflammatory immune responses and repair of damaged tissue following IAV infection also differ between the sexes and impact the outcome of infection. There also is growing evidence that sex steroid hormones, including estrogens, progesterone, and testosterone, directly impact immune responses during IAV infection to alter outcomes. Greater consideration of the combined effects of sex and age as biological variables in epidemiological, clinical, and animal studies of influenza pathogenesis is needed. See Abstract.
vom Steeg teaches that, in a mouse model study, in male mice, lower concentrations of testosterone, either associated with aging (i.e., 16–18 months of age) or caused by surgical castration of young males, are associated with increased IAV-associated pulmonary inflammation and morbidity, with no effect on the control of virus replication. It teaches that, importantly, administration of exogenous testosterone to either aged male or castrated young male mice significantly improves the outcome of
IAV, independent of changes in pulmonary viral load. See page 192, para spanning the left and right columns.
Suber et al. teaches that, during the 1918 influenza pandemic, children experienced substantially lower mortality than adults, a striking but unexplained finding. Whether this was due to enhanced resistance (reduced virus load) or better tolerance (reduced impact of infection) has not been defined. The authors found that prepubertal mice infected with H1N1 influenza virus also showed greater survival than infected pubertal mice, despite similar virus loads. Transcriptome profiling of infected lungs identified estrogen as a regulator of susceptibility in both sexes and also linked better survival to late expression of IL-1b. Blocking puberty with gonadectomy or a gonadotropin-releasing hormone antagonist improved survival. Estrogen or testosterone (which can be converted to estrogen) restored susceptibility of gonadectomized pubertal mice to influenza mortality, but dihydrotestosterone (which cannot be converted to estrogen) did not. Estrogen receptor blockade with fulvestrant in both male and female pubertal mice resulted in improved survival, even when given 3 days after infection. Moreover, late, but not early, IL-1b neutralization after infection was also protective. These findings indicate that pubertal increases in estrogen in both sexes are associated with increased mortality during influenza. This helps explain the reduced mortality of children seen with influenza in 1918 and might also be relevant to childhood tolerance to many other infectious diseases. See Abstract.
Suber teaches that, in a mouse model study, in males, protection by castration was reversed by both estrogen and testosterone. Testosterone can be converted to estrogen by aromatase. In contrast, dihydrotestosterone, which cannot be converted to estrogen, did not reverse the protective effect of castration (Fig. 3K). The role of aromatase conversion of testosterone to estrogen was also shown by the aromatase inhibitor anastrazole, which abrogated the ability of testosterone to reverse the protective effect of castration (Fig. 3L). See para bridging pages L1089 and L1090. Suber further teaches that administration of an aromatase inhibitor (anastrozole, 10 ug daily), which prevents conversion of testosterone to estradiol, showed greater tolerance to influenza virus infection compared with the high mortality seen in mice treated with testosterone alone (see legend of Fig. 3).
Accordingly, teachings of both vom Steeg and Suber indicate that there is a correlation between levels of sex hormones, especially those of testosterone and estrogen, and severity and/or clinical outcome of influenza A virus infection. Teachings of vom Steeg suggest that lower concentrations of testosterone are associated with increased IAV-associated pulmonary inflammation and morbidity, while Suber further teaches that administration of an aromatase inhibitor, anastrozole, improves tolerance to influenza virus infection compared with the high mortality seen in mice treated with testosterone alone, indicating the therapeutic effect of administration of an aromatase inhibitor to influenza virus infection.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of vom Steeg and Suber to arrive at the invention as claimed, i.e., administering an aromatase inhibitor to a subject with IAV infection. One would have been motivated to do so, e.g., to evaluate if an aromatase inhibitor, which is shown to improve tolerance to IAV infection in mouse model studies, would have the same effect in a subject in need thereof, e.g., a human subject with IAV infection. As to the claimed limitation of “inhibiting virus dissemination”, this effect is inherent with the administration of an aromatase inhibitor to an infected subject.
(Previous Rejection – Maintained) Claims 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over vom Steeg et al. (Seminars in Immunopathology (2019) 41:189–194; submitted in IDS filed on Aug. 28, 2025) and Suber et al. (Am J Physiol Lung Cell Mol Physiol 313: L1087–L1095, 2017), as applied above, in view of Pozzilli et al. (Metabolism Clinical and Experimental 108 (2020) 154252; submitted in IDS filed on Aug. 28, 2025).
Relevance of vom Steeg and Suber is set forth in the rejection above. However, they are silent on administration of an aromatase inhibitor to a subject with coronavirus infection.
Pozzilli provides comment on the possible role of testosterone with COVID19 pandemic. It is well established that plasma testosterone concentration is reduced by age and comorbidities like obesity, diabetes and obstructive sleep apnea (OSA), all comorbidities highly prevalent in COVID-19 patients. Several studies have shown that in men with chronic obstructive pulmonary disease (COPD) hypogonadism is associated with a prevalence ranging between 22% and 69%. In this context low testosterone levels can cause a reduction of respiratory muscles activity and overall strength and exercise capacity, whilst normal circulating testosterone levels show a protective effect on several respiratory outcomes (i.e. forced expiratory volume in one second-FEV1, and forced vital capacity - FVC). See page 1, left column, para 3.
Pozzilli teaches that the hypothesis arises that testosterone may have a role in the cascade of events leading to progression of COVID-19 infection due to the cytokine storm, that measuring testosterone levels may be recommended at the time of an identified COVID-19 positive patient, and that, if values are low, use of testosterone may be considered to reduce the associated pulmonary syndrome, thus preventing progression to severe COVID-19 disease where proinflammatory cytokines play a major role. See page 1, right column, para 2-4.
Accordingly, teachings of Pozzilli suggest that there is a possible association between sex hormone levels, especially the testosterone level, and disease outcomes of COVID19, a coronavirus infection. These teachings provide a nexus between the teachings of vom Steeg and Suber, which are focused on the role of sex hormones in IAV infection, and a coronavirus infection (both influenza virus and coronavirus infections affect pulmonary conditions).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of vom Steeg, Suber and Pozzilli to arrive at the invention as claimed. One would have been motivated to do so to evaluate if administration of an aromatase inhibitor, e.g., anastrozole, to a COVID-19 patient would alter the disease outcome to the subject, in a way similar to that shown in the studies of Suber for the influenza virus infection. As to the claimed limitation of “inhibiting virus dissemination”, this effect is inherent with the administration of an aromatase inhibitor to an infected subject.
Response to Applicant’s Arguments
Applicant’s arguments filed on Mar. 13, 2026 have been fully considered and are addressed as follows.
Applicant argues that the preamble defines the patient population being treated and provides antecedent basis for the subject being treated in the claimed method, and, thus, the preamble cannot be ignored.
This argument is not persuasive. A preamble is generally not accorded any patentable weight where it merely recites the purpose of a process or the intended use of a structure, and where the body of the claim does not depend on the preamble for completeness but, instead, the process steps or structural limitations are able to stand alone. See In re Hirao, 535 F.2d 67, 190 USPQ 15 (CCPA 1976) and Kropa v. Robie, 187 F.2d 150, 152, 88 USPQ 478, 481 (CCPA 1951). Here, the process as claimed encompasses administering to a subject with a viral infection an aromatase inhibitor. The process itself is able to stand alone while the preamble only recites the purpose or intended use of the claimed process.
Applicant argues that the claims do not merely recite an association between an aromatase inhibitor and viral infection, that, rather, they relate to a specific method of treating a specific patient population with influenza virus or coronavirus infections. Applicant argues that the claimed invention is based on the data demonstrating that virus dissemination can be effectively controlled by administration of an aromatase inhibitor, as shown in example 6 of the present application, and that such a method is unexpected. Applicant argues that, in the experiment shown in example 6, male and female virus-infected golden hamsters were treated daily with the aromatase inhibitor letrozole or, alternatively, with a placebo; that viral loads were subsequently measured in multiple organs and fluids; that it was found that animals treated with letrozole showed significantly reduced viral titers in the organs and fluids compared to placebo; and that reduction of the viral titers demonstrates less dissemination of the virus.
Applicant argues that neither Suber nor vom Steeg discloses the use of an aromatase inhibitor for therapeutic purposes, much less the use of an aromatase inhibitor for inhibiting influenza virus dissemination. Applicant argues that vom Steeg teaches that high testosterone levels in patients infected with influenza A virus appear to protect against immune-driven lung inflammation, and that vom Steeg is focused on the effects of testosterone on inflammation in patients infected with influenza, and that there is no indication in vom Steeg that an aromatase inhibitor, or testosterone, could be used for controlling virus dissemination, i.e., the spread of the virus in the patient.
Applicant argues that Suber reported that prepubertal mice had significantly lower mortality, weight loss, and lung injury than pubertal mice, that the viral loads were similar between age groups, indicating that improved survival is due to tolerance, which Suber defines as impact of an infection, not enhanced viral clearance. Applicant argues that Suber identifies estrogen signaling as a major regulator associated with higher mortality in pubertal mice of both sexes, and that a skilled person could have merely derived from this document that estrogen receptor blockade improves survival in influenza patients, which means that estrogen is a possible target for reducing the mortality in influenza. Applicant argues that Suber repeatedly distinguishes tolerance of a virus, i.e. impact of an infection, from resistance, i.e., reduced viral load, and that, thus, Suber suggests a completely different approach for treating influenza infections from the claimed invention.
Applicant argues that Pozzilli does not discuss the therapeutic use of aromatase inhibitors, nor does Pozzilli recommend or suggest that an aromatase inhibitor would have an impact on viral dissemination, and that, thus, it also cannot be said that there would be a reasonable expectation of success in a method of inhibiting virus dissemination, based upon the information presented in vom Steeg, Suber, and Pozzilli.
Applicant’s arguments are not persuasive.
The instant claims recite only one active step of administrating an aromatase inhibitor to a subject with influenza virus or coronavirus infection. As indicated in the rejection body above, teachings of both vom Steeg and Suber indicate that there is a correlation between levels of sex hormones, especially those of testosterone and estrogen, and severity and/or clinical outcome of influenza A virus infection. Teachings of vom Steeg suggest that lower concentrations of testosterone are associated with increased IAV-associated pulmonary inflammation and morbidity, while Suber further teaches that administration of an aromatase inhibitor, anastrozole, improves tolerance to influenza virus infection compared with the high mortality seen in mice treated with testosterone alone. Therefore, teachings of vom Steeg and Suber indicate that there is a correlation between sex hormone levels and severity of the influenza virus infection. One of skill in the art would have found it obvious to evaluate the effect of administration of an aromatase inhibitor, which is known to shift sex hormone levels, in affecting viral infection process, especially considering that Suber further teaches that administration of an aromatase inhibitor, anastrozole, improves tolerance to influenza virus infection compared with the high mortality seen in mice treated with testosterone alone. As to the claimed limitation of “inhibiting virus dissemination”, this effect is inherent with the administration of an aromatase inhibitor to an infected subject.
Teachings of Pozzilli suggest that there is a possible association between sex hormone levels, especially the testosterone level, and disease outcomes of COVID19, a coronavirus infection. These teachings provide a nexus between the teachings of vom Steeg and Suber, which are focused on the role of sex hormones in IAV infection, and a coronavirus infection (both influenza virus and coronavirus infections affect pulmonary conditions). One would have been motivated to evaluate if administration of an aromatase inhibitor, e.g., anastrozole, to a COVID-19 patient would alter the disease outcome to the subject, in a way similar to that shown in the studies of Suber for the influenza virus infection.
As to applicant’s arguments about unexpected results, as an initial matter, “the burden of showing unexpected results rests on he who asserts them. Thus it is not enough to show that results are obtained which differ from those obtained in the prior art: that difference must be shown to be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (citation omitted). Moreover, “[i]t is well settled that unexpected results must be established by factual evidence. Mere argument or conclusory statements in the specification does not suffice.” In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984) (citation omitted).
Here, Applicant refers to data presented in Example 6, showing that treatment mice treated with the aromatase inhibitor letrozole showed reduced viral loads in multiple organs and fluids compared to mice treated with placebo. MPEP 2145 II teaches that prima facie obviousness is not rebutted by merely recognizing additional advantages or latent properties present but not recognized in the prior art.
Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) (Claims were directed to grooved carbon disc brakes wherein the grooves were provided to vent steam or vapor during a braking action. A prior art reference taught noncarbon disc brakes which were grooved for the purpose of cooling the faces of the braking members and eliminating dust. The court held the prior art references when combined would overcome the problems of dust and overheating solved by the prior art and would inherently overcome the steam or vapor cause of the problem relied upon for patentability by applicants. Granting a patent on the discovery of an unknown but inherent function (here venting steam or vapor) “would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art.” 596 F.2d at 1022, 201 USPQ at 661.); In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991) (Appellant argued that the presence of DEHP as the plasticizer in a blood collection bag unexpectedly suppressed hemolysis and therefore rebutted any prima facie showing of obviousness, however the closest prior art utilizing a DEHP plasticized blood collection bag inherently achieved same result, although this fact was unknown in the prior art.).
Here the combined teachings of vom Steeg and Suber suggest the claimed invention of administering an aromatase inhibitor to a subject for the treatment of an influenza virus infection. The viral load reduction is a latent property that is silent in the cited references and does not rebuttal the obviousness of the claimed invention.
Applicant’s attention is directed to MPEP 716.02(b)-(e) for how unexpected results can be established. E.g., to evaluate if the claimed invention produces unexpected results, one must also consider if the results produced by the claimed invention are commensurate in scope with the claims and how the results compare with the closest prior art. See MPEP Section 716.02(d) and (e).
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671
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