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 .
Application Status
The claim set filed on 2/17/2024 is acknowledged. Claims 1-19 are currently pending and under consideration.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The criteria for enablement set out in the In re Wands, MPEP 2164.01(a), considers the following factors:
Breadth of the Claims
The instant claims are directed toward a method for reducing viral titer in a subject, comprising administering to the subject a composition comprising a sodium salt of Ethylenediaminetetracetic acid (EDTA), D-Mannitol and Ethanol. Neither the claims nor specification contemplate that the composition further comprise another antiviral agent. As such, it is presumed that either EDTA, D-Mannitol and Ethanol either alone or in combination are the active agent(s) for reducing viral liter in a subject. Thus, the claims encompass in vivo administration of the claimed composition in any amount and treating any and all viral titer in a subject.
Thus, the breadth of the claims is great.
Level of Skill in Art
The level of skill in the art is a clinician or an artisan with a PhD.
Working Examples
The instant specification provides a single in vitro example (Example 2) of the antiviral efficacy against SARS Cov-2 in two steps. The first step, referred to as a Virucidal assay, involved preparing an infection media containing the SARS Cov-2 virus at about 105 PFU/mL which was mixed with the test solution (presumed to be the present formulation described in Table 1) in 96 well plate and incubated for 3 minutes or 10 minutes at room temperature. Similarly, 70% ethanol (positive control) and media (only) were mixed with virus and incubated for the required contact time at room temperature. The viral load in each of the dilutions was determined by plaque assay (second step) for each of the samples. The plaque assay involves plating Vero E6 cells onto 96-well plates and incubating overnight, wherein after each incubation, each sample (test sample, virus-positive control, virus-negative negative control and cell only control) were exposed to Vero E6 cells for about 1 hour followed by shaking every 15 minutes. After exposure, medium containing the test material and the virus were removed from the well and mixture of growth, fixed and the number of plaque were counted in a dilution at which clear plaques are visible and the PFU/0.1ml was determined and residual viral load calculated. The results of the experiments were as follows:
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Thus, the specification teaches that the data shows that the viral load was completely eliminated when the sample was exposed to the formulation of the present disclosure for 3 minutes, as well as, 10 minutes. In particular, the specification teaches that the present formulation demonstrates a synergy of great than 2 log10.
Thus, the instant specification provides an in vitro example of antiviral activity in Vero-E6 cells.
Direction and Guidance
In view of the single example showing the in vitro effectiveness of the composition in Vero-E6 cells, there is minimal direction provided by the inventor regarding in vivo administration of claimed composition to a subject, wherein the viral titer is reduced.
State of the Prior Art
The state of the art at the time of filing regarding in vitro to in vivo models for predicting antiviral agents for viral infections such as SARS-CoV-2 has been unclear. For example, Rosa et al. (Viruses 2021; 313; 379) teaches that the emergence and rapid worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted the scientific community to rapidly develop in vitro and in vivo models that could be applied to COVID-19 research (Abstract). Moreover, Rosa et al. teach that in vitro models are based on two dimension (2D) or three-dimension (3D) cultures of primary cells or immortalized cells and tissues and while they are inexpensive, fast and allow for the study of specific cellular targets, they do not resemble the complexity of the whole organism and translatability of in vitro generated data to in vivo models can be particularly challenging (page 2 out of 29, 2. In Vitro Models). Regarding the two dimension (2D) in vitro models, Rosa et al. teach that the Vero cell line is the most largely used cell line for vaccine production and has been one of the most common cell lines for SARS-CoV-2 isolation around the world (page 2 out of 29, 2.1, 1st paragraph). In particular, Rosa et al. teach that a number of FDA drugs such as chloroquine/hydroxychloroquine and ivermectin have been tested against SARS-CoV-2 in Vero cells, wherein all three were found to reduce SARS-CoV-2 replication in Vero cells, but notes that there are some points that need to be taken into consideration regarding the use of these drugs and their respective studies including ivermectin’s low water solubility, lack of comparative standard drugs in antiviral tests, absent evaluation of treatment efficacy according to disease severity and the possible combination with other drugs to maximize antiviral efficacy (page 3 out of 29, paragraph beginning with Remdesivir). Similarly, Bradley, Poppy (Youth Stem Matters 2021; 1) referred to herein as Bradley compares In Vitro and In Vivo models as part of Pre-Clinical studies for COVID-19 medicines (Title). Regarding the In Vitro models, Bradley teaches that while Vero-E6 cell line is well established as an in vitro model for COVID-19, Vero-E6 cells do not always translate wholly to the clinic and may not fully represent how different tissues interact with the virus and the drug, rather than just one isolated tissue (page 3, 2nd column, 4th line from bottom and page 4, 2nd column, bridging paragraph ). For example, Bradley teaches that both Remdesivir and hydroxychloroquine, in Vero-6 cells, were found to be potent inhibitors of COVID-19. However, only Remdesivir was approved for COVID-19, wherein emergency market authorization were removed for hydroxychloroquine due to lack of efficacy (Page 4, Remdesivir and Hydroxychloroquine). Lastly, Kumar et al. (Antimicrobial Agents and Chemotherapy 2022; 66: e01543-21) discusses the inhibition of SARS-CoV-2 replication of moxidectin and ivermectin in Vero E6 cells, but not in human primary bronchial epithelial cells (Title). In particular, Kumar et al. teaches that these disappointing results call for a word of caution in the interpretation of anti-SARS-CoV-2 activity in drugs solely based on their activity in Vero Cells (abstract).
The state of the art at the time of filing regarding the individual components of the composition and the treatment of viral infections such as COVID-19 is mixed. For example, Cashman (Medical Hypothesis 2020; 144: 110027) discusses the lower reported prevalence of asthma in patients diagnosed with COVID-19 validates repurposing EDTA solutions to prevent and manage/treat COVID-19 disease (Title). Specifically, Cashman teaches that searching for the viral mechanisms to elucidate why asthma patients appear resistant to COVID-19 infection uncovered evidence for the key role of calcium in SARS-CoV-2/COVID-19 infection, wherein analysis of nebulizer solutions typically used by asthma patients revealed the presence of an excipient called EDTA, a calcium chelating agent (page 4, Conclusion). However, Cashman only hypothesizes on the use of EDTA and does not provide any in vivo or in vitro data on its use for treating SARS-CoV-2/COVID-19 infection. Amoushahi et al. (Cureus 2022; 14(12):e32218) teaches that the in vitro antiviral effects of ethanol on solving the fat layer and destroying the glycoprotein of coronavirus have already been established, as well as, the antiviral effects of ethanol on extracellular surfaces (Introduction). As such, Amoushahi et al. discusses a randomized clinical trial detailing the efficacy and safety of inhalation of nebulized ethanol in COVID-19 treatment (Title). Regarding the administration of the ethanol, Amoushahi et al. teach that the ethanol spray was used in combination with the national standard treatment which included intramuscular dexamethasone and intravenous remdesivir (page 2 of 11, Intervention). Specifically, Amoushahi et al. teach that inhaled-nebulized ethanol is effective in rapidly improving the clinical status, reducing further treatment, and could be recommended as an adjunctive treatment for moderate COVID-19, wherein further research on curative effects in more serious and in prevention is advisable (Abstract, Conclusion). Thus, while Amoushahi et al. suggest that inhaled-nebulized ethanol improves clinical status and reduces further treatment, the article is silent on ethanol’s ability to reduce viral titers in a subject. Istanbul Universitesi Rektorlugu (WO2022055449A1. 2022-03-17, referred to herein as Istanbul) teaches the administration of active substances with antiviral, antimalarial and/or mucolytic properties for use in the treatment of viral lung diseases, especially COVID-19 by means of a soft mist inhaler or vibrating mesh technology (VMT) nebulizer through inhalation (Abstract). With regards to the antiviral and/or mucolytic, Istanbul teaches that antivirals include favipiravir, umifenovir, molnupiravir, pimodivir and remdesivir and mycolytic includes mannitol (page 18, lines 11-17). Thus, while Istanbul contemplates using mannitol for treating a viral lung disease with mannitol, mannitol is being used as a mucolytic agent and is silent on its ability to reduce viral titers.
Predictability in the Art
In view of the lack of predictability in correlating in vitro results performed in Vero-E6 cells to in vivo activity of compounds for treating viral infections such as COVID-19, as set forth above, as well as the lack of definitive examples of each of the individual agents being capable of reducing viral titers in a subject suffering from viral infections such as COVID-19, it is not predictable in the art to reduce viral titers in a subject suffering from a virus such as COVID-19 with the claimed composition. .
Quantity of Experimentation
In view of the unpredictability of the art, and the lack of direction in the specification, the amount of experimentation required to reduce viral titers in a subject having a virus such as COVID 19 with the claimed composition would be astronomical. A great deal of experimentation would be required starting with proof-of-concept, and proceeding through all levels of lead identification and optimization, which amounts to invention, not development; it is an undue amount of experimentation.
Conclusion
Therefore, No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
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BRANDON J. FETTEROLF, PHD
Primary Patent Examiner
Art Unit 1626
/BRANDON J FETTEROLF/Primary Examiner, Art Unit 1626
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