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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 Aug. 7, 2026 has been entered.
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Aug. 7, 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 Claims 1-14 and 19-20 are withdrawn.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.
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.
(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 comments 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.
(New Rejection) Claims 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Brueggemeier et al. (Endocrine Reviews, 2005, 26(3):331–345) and Eisen et al. (Cancer Treatment Reviews (2008) 34, 157– 174) in view of Cooksley et al. (Cancer 2005;104:618 –28) and/or Chellapuram et al. (Cancer Res Stat Treat 2020;3:35‑9; Published: 25‑Apr‑2020).
Brueggemeier reviews studies on aromatase inhibitors in the treatment of breast cancer. Brueggemeier teaches that inhibition of aromatase is an important approach for reducing growth-stimulatory effects of estrogens in estrogen-dependent breast cancer. Both steroidal and nonsteroidal aromatase inhibitors have shown clinical efficacy in the treatment of breast cancer. The potent and selective third generation aromatase inhibitors, anastrozole, letrozole, and exemestane, were introduced into the market as endocrine therapy in postmenopausal patients failing antiestrogen therapy alone or multiple hormonal therapies. These agents are currently approved as first-line therapy for the treatment of postmenopausal women with metastatic estrogen-dependent breast cancer. Several clinical studies of aromatase inhibitors are currently focusing on the use of these agents in the adjuvant setting for the treatment of early breast cancer. Use of an aromatase inhibitor as initial therapy or after treatment with tamoxifen is now recommended as adjuvant hormonal therapy for a postmenopausal woman with hormone-dependent breast cancer. See Abstract.
Eisen reviews the evidence for the use of third generation aromatase inhibitors (anastrozole, letrozole and exemestane) as adjuvant therapy for post-menopausal women with early-stage, hormone receptor-positive breast cancer and to develop and support recommendations for their use, with regard to three areas: aromatase inhibitors compared to tamoxifen, aromatase inhibitors in sequence with tamoxifen for a total of five years, and aromatase inhibitors given after five years of tamoxifen therapy. See Abstract.
Eisen teaches that in the mid-1990s, a new class of oral hormone agents, the third-generation aromatase inhibitors, became available for use in post-menopausal women with metastatic breast cancer. These agents comprise two categories: (1) the reversible inhibitors anastrozole (Arimidex, AstraZeneca Pharmaceuticals LP) and letrozole (Femara, Novartis Pharmaceuticals Corporation) and (2) the irreversible inhibitor exemestane (Aromasin, Pfizer Inc). Evidence from phase III clinical trials suggests that anastrozole and letrozole are modestly superior to tamoxifen as first-line therapy for post-menopausal women with metastatic breast cancer. By extension, the hypothesis that aromatase inhibitors may also be superior to tamoxifen in the adjuvant setting was generated. See “Introduction”.
Eisen teaches that the Arimadex, Tamoxifen, Alone or in Combination (ATAC) trial compared three treatment regimens: five years of tamoxifen, five years of anastrozole, or five years of both agents given in combination. The primary outcome was disease-free survival (DFS; defined as the time to the earliest occurrence of either local or distant recurrence, new primary contralateral breast cancer [invasive or ductal carcinoma in situ], or death). At 68 months of follow-up, the intent-to-treat analysis showed significantly improved DFS, time to recurrence (TTR), and time to distant recurrence (TDR; see Fig. 1) for anastrozole over tamoxifen while overall survival (OS) was similar. See page 160, left column, para 3.
Accordingly, both Brueggemeier and Eisen teach treatment of breast cancers with aromatase inhibitors, with both teachings indicating that duration of aromatase inhibitor treatments may last as long as five years. However, Brueggemeier and Eisen are silent on the teaching of giving aromatase inhibitor treatments to subjects with influenza virus or coronavirus infection.
Cooksley teaches that to describe the epidemiology of those in the cancer population whose influenza-related infections were severe enough to require hospitalization, the authors obtained national public-use hospital inpatient data of patient level discharges for the years 1998–2001 and 5-year cancer prevalence estimates for the U.S. From these data, the authors described the affected cancer population and estimated the magnitude of influenza-related hospitalizations in terms of expense, resource utilization, and inpatient mortality. See page 619, right column, para 1. To verify that the above random subpopulation accurately reflected reported data, the authors evaluated all of the discharge records for the type of principal admitting diagnosis before selecting the random subpopulation. This evaluation revealed variability in diagnostic patterns by type of cancer. Individuals with breast carcinoma had a principal admitting diagnosis of confirmed influenza, whereas individuals with lung carcinoma or hematologic malignancy had a predominant principal admitting diagnosis of pneumonia caused by an unspecified origin. See page 621, left column, para 2.
Chellapuram teaches that the global community is currently facing the unprecedented challenge of the coronavirus disease 2019 (COVID‑19) pandemic. More than 1 million cases have been reported until now. Increased mortality is reported in patients who are older and have cancer and multiple comorbidities. Few retrospective analyses of COVID‑19 in cancer patients showed a higher mortality of about 28.6%; additionally, severe events are more in patients who develop infection within 2 weeks of receiving anticancer treatment. Clinical data separately analyzing breast cancer patients are lacking. Until an effective drug/vaccine develops, the clinical management is supportive, and pandemic control lies in non-pharmacologic interventions such as social distancing, testing, tracing, isolation, and quarantine. These measures hinder the proper care of breast cancer patients in all the three domains of clinical care, education, and research. These desperate circumstances need desperate measures. In this review, the authors highlight the medical management of breast cancer during this pandemic. An adoptive strategy is the need of the hour to balance both cancer care and COVID‑19 management. See Abstract.
Accordingly, teachings of Cooksley and Chellapuram indicate, respectively, that the infections by influenza virus or coronavirus (including SARS-CoV-2) may happen to cancer patients, including patients with breast cancer.
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 Brueggemeier, Eisen, Cooksley and Chellapuram to arrive at the invention as claimed, which reads on administering an aromatase inhibitor to a breast cancer patient who is also experiencing an influenza virus or SARS-CoV-2 infection. One would have been motivated to do so to continue the aromatase inhibitor treatment for patients who are already on the treatment before the viral infection so that the cancer treatment is not disrupted. It is noted that the only active step of the claims is administration of an aromatase inhibitor to a subject with influenza or coronavirus infection, and that this active step stands alone while the preamble of the claims merely represents the purpose or intended use of the active administration step.
Response to Applicant’s Arguments
Applicant’s arguments filed on Aug. 7, 2026 have been fully considered and are addressed as follows.
To the 103 rejections, Applicant makes the following arguments:
1) Applicant argues that the examiner’s reliance on In re Hirao and Kropa v. Robie (in the examiner’s response to applicant’s arguments in the previous Office action) is misplaced and/or unclear, citing MPEP 2141.02 and MPEP 2111.02, that the former case concerned issues that were not actually related to whether the preamble per se was limiting for the purpose of patentability, and the situation of the latter case does not apply here as the claims are drawn neither to a product nor do they recite an inherent property of a product. Applicant argues that, what is well established in the law is that “the determination of whether a preamble limits a claim is made on a case-by-case basis in the light of the facts in each case; there is no litmus test defining when a preamble limits the scope of a claim”, and that it must be taken into account when assessing the patentability of the subject matter as a whole in accordance with legal precedent. Applicant argues that the claim is not merely directed to the administration of an aromatase inhibitor, but to administration of an aromatase for a specific purpose, namely inhibiting viral dissemination in an already infected subject, which limits the scope of the claimed method.
2) Applicant argues that vom Steeg and Suber provide only indirect and vague conclusions on the relationship between sex hormone levels and infection which, even worse, contradict each other, and 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 it is not plausible to assume that a skilled person, after reading vom Steeg, would consider the use of an aromatase inhibitor, since the use of such aromatase inhibitor would reduce estradiol levels, thereby weakening or eliminating protection according to the teachings of vom Steeg, and that it can also be taken from the vom Steeg article that estradiol reduces the inflammatory responses associated with tissue damage. Applicant argues that vom Steeg provides no reasonable expectation that administration of an aromatase inhibitor would improve morbidity after influenza infection, and it certainly does not provide any hint that that administration of an aromatase inhibitor can inhibit virus dissemination in an infected subject.
3) Applicant argues that Suber does not remedy the deficiencies of vom Steeg, and that the conclusion of Suber is that modulation of estrogen signaling can affect the host's pathological response to infection, not that it reduces viral replication or dissemination. Applicant argues that in Suber anastrozole was used in castrated male mice treated with testosterone to prevent conversion of testosterone into estrogen, that the reported effect was greater tolerance to influenza infection compared with the high mortality observed in mice treated with testosterone alone, that the overall teaching of Suber is that sex-hormone manipulation affected mortality and lung injury despite similar lung viral loads, and that Suber would have directed the skilled person toward modulating host tolerance or inflammatory injury, not toward inhibiting viral dissemination. Applicant argues that the teaching of Suber regarding testosterone alone is inconsistent with the teaching of vom Steeg, which demonstrates that administration of exogenous testosterone improves the outcome of influenza virus infection in aged or castrated male mice, and that it cannot be said there "would have been a reasonable expectation of success".
4) Applicant contends the examiner’s standing that “Pozzilli suggests that there is a possible association between sex hormone levels, especially testosterone level, and disease outcomes of COVID19” and argues that Pozzilli does not add anything to the teachings of vom Steeg and Suber, does not discuss the therapeutic use of aromatase inhibitors, nor does Pozzili recommend or suggest that an aromatase inhibitor would have an impact on viral dissemination.
Applicant’s arguments are not persuasive.
Regarding argument 1), even though the cases of In re Hirao and Kropa v. Robie do not relate to the same situations as the claimed invention, the court rulings provide guidance for other cases on the consideration of patentability weight to the preamble of a claim, i.e., it should be considered on a case-by-case basis. If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. See MPEP 2111.02 II.
Here, the limitation “of inhibiting virus in a subject infected with an influenza virus or coronavirus” in the preamble of claim 15 represents a purpose or intended use of the claimed method. The active step “administering an aromatase inhibitor to said subject” is equivalent to “administering an aromatase inhibitor to a subject infected with an influenza virus or coronavirus”, and thus, stands alone. In other words, the process of “administering an aromatase inhibitor to a subject infected with an influenza virus or coronavirus” would inherently serve the purpose of “inhibiting virus dissemination”, since the claims do not require any additional elements.
Regarding arguments 2) and 3), it is first worth noting that aromatase inhibitors block the androgen to estrogen conversion, i.e., shifting sex balance of hormones. Teachings of vom Steeg suggest that there is a correlation between severity or disease outcome of influenza virus infection with levels of sex steroid hormones. Suber explicitly teaches administration of an aromatase inhibitor (anastrozole, 10 ug daily), which prevents conversion of testosterone to estradiol, to test animals, showing greater tolerance to influenza virus infection compared with the high mortality seen in test animals treated with testosterone alone (see legend of Fig. 3). Teachings of both vom Steeg and Suber together 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. Therefore, one of skill in the art would have found it obvious to test an aromatase inhibitor on a subject with influenza virus infection based on the teachings of vom Steeg and Suber to further the studies disclosed in the two references, especially based on the teachings Suber, which explicitly teaches administration of an aromatase inhibitor (anastrozole) to a subject to study its effect on influenza virus infection.
Regarding argument 4), 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 discussion in the rejection body above. Therefore, teachings of Pozzilli 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.
Conclusion
No claims are allowed.
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 ALLEN, 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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