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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 13, 2026, has been entered.
Status of the Claims
Claims 1-11 are pending and examined.
Response to Arguments
Applicant’s arguments are moot in view of the addition of Depfenhart and Maggio, below. They each independently teach the use of bromhexine as a sole active agent through multiple routes of administration to treat and prevent SARS-CoV-2, e.g., by inhibiting TMPRSS2 protease. A rejection is set forth below.
The examiner does not cite duplicative teachings, but does make the following material references of record:
Laporte et al., “Airway proteases: an emerging drug target for influenza and other respiratory virus infections,” Current Opinion in Virology 2017, 24:16–24; and
CN110898041.
Laporte and CN110898041 provide further insight into the state of the art prior to the filing of the instant application.
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, 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.
Claims 1-11 are rejected under 35 U.S.C. 103 as being unpatentable over Depfenhart et al., “Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy?,” May 26, 2020, in view of Maggio, “Repurposing the mucolytic cough suppressant and TMPRSS2 protease inhibitor bromhexine for the prevention and management of SARS-CoV-2 infection,” Pharmacological Research 157 (2020), in view of Väänänen et al., (US2021/0299230) (of record), in view of Fliri (US2023/0201215) (of record), and in view of Vetter et al., “Solubilizing agents in nasal formulations and their effect on ciliary beat frequency,” Toxicology in Vitro 26 (2012) 150-156.
Depfenhart teaches bromhexine or bromhexine hydrochloride at a dosage that selectively inhibits TMPRSS2- specific viral entry is likely to be effective against SARS-CoV-2. Depfenhart proposes bromhexine for prophylactic and treatment. See Abstract. Bromhexine has been identified as a TMPRSS2 inhibitor that can be applied orally and endonasally. See p804, last par. Drugs have been shown to prevent SARS-CoV-2 entry by TMPRSS2 knockdown. See p805, last par. Endonasal, sublingual, buccal, or inhalation can be good alternatives to bypass first pass metabolism. While bromhexine was shown to not show any significant prevention of cell entry of replication inhibition in influenza viruses, which utilize a different extracellular host protease. See p807, 1st full par. Bromhexine is shown to have a good effect on the treatment of COVID-19. See p807, 3rd full par. “An effective prophylactic medication to prevent viral entry has to contain, at least, either a TMPRSS2 inhibitor, e.g., bromhexine or a competitive virus ACE2-binding inhibitor, e.g., a peptide inhibitor.” See p809, 1st par.
Similarly, Maggio similarly teaches that bromhexine is a safe and potent inhibitor of TMPRSS2 that can be used to prevent and treating SARS-Cov-2, MERS, influenza, and other viruses and the trypsin-like proteases are expressed in the human respiratory tract.
Thus, Depfenhart and Maggio each independently provide teachings for the treatment and prevention of claimed subject with compositions that consist essentially of bromhexine.
Väänänen teaches that viruses often enter our bodies through the nasal mucosa, e.g. See par. 4. This includes SARS-Cov-2, COVID-19, and others. See par. 16 and prior art claim 46. Nasal administration by sprays, aerosols, gels, solutions, inhalers, and others to the nasopharyngeal tract are known. See par. 20. The nasal spray serves as prevention and treatment and can be administered to the nasal mucosa to prevent spread to the body. See par.’s 176-177, e.g. The composition can include bromhexine. See prior art claims 31, 32, and 35. Bromhexine is listed as one of 3 agents in claims 35 and 43. The amount of each compound include a dose as low as 0.1 to 5%. See par.’s 278-281, 356, and prior art claims 39 and 51. The prophylactic or therapeutic amount is a nasal dosage form, including a nasal drop, nasal spray, or inhaled aerosol. See prior art claims 36 and 37. Even further, the mechanism of action is inhibiting TMPRSS2. See par. 200.
Fliri teaches drug combinations that treat and prevent a viral infection. See Abstract. The embodiments described treating and preventing viral infections including influenza viruses, coronaviruses, MERS-CoV, SARS-CoV-2, and CoV-19, e.g. See par. 39. Further, the dosage form can be one for pulmonary or nasal administration. See par. 40. The composition can comprise an antiviral agent to include bromhexine hydrochloride. See prior art claims 9 and 14. For liquid preparations, PEG and propylene glycol can be used. See par. 41.
Vetter teaches the most common solubilizer for nasal formulations include PEG. See Abstract. Further, water is typically included in nasal formulations and is included in 6/7 examples in Table 1. PEG300 and PEG400 are includes as select solubilizing agents in Table 2.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). In this case, low doses of the same API are being taught for administration to treat a same subject population through a same route of administration. It would therefore be obvious to optimize the dosage of a known result-effect variable to arrive at the claimed product.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application to combine the prior art to arrive at the claimed methods. One would be motivated to do so because a formulation consisting essentially of bromhexine is taught by Depfenhart and Maggio, while additional references teach bromhexine as usable for nasal and inhalational means to prevent and treat viruses, including influenza viruses, coronaviruses, MERS-CoV, SARS-CoV-2, and CoV-19. Väänänen recognizes the same mechanism of action by which treatment occurs through bromhexine to include inhibition of TMPRSS2 protease. Further, solvents are taught for inclusion in the claimed compositions, including those claimed and the required concentrations of bromhexine is taught to be as low as 0.1%. This includes treating and preventing influenza viruses, coronaviruses, SARS-CoV-2, and CoV-19, e.g. As such, there is a reasonable and predictable expectation of success in administering the claimed API as a sole active agent through the claimed route of administration at a low and optimizable dosage to a subject to prevent and treat a claimed subject population. Such administration would be expected to potently inhibit TMPRSS2 to prevent viral entry. Optimization would be expected in view of the known mechanism of action by which prevention and treatment is expected to occur.
As such, no claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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