DETAILED ACTION
This action is in response to papers filed on 11/21/2025. Claims 8, 10-19, and 21-28 are pending examination on the merits. Claims 8, 10-18 are allowable, and claims 19 and 21-28 are rejected.
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 .
Priority
Acknowledgment is made of applicant's claim for benefit of provisional application 63/218,318 filed on 07/04/2021 and is also a CIP of 17/315,249 filed on 05/07/2021. Upon reconsideration, the Examiner agrees with Applicant that the earliest priority date of the parent CIP application is that of May 07, 2020.
Election/Restrictions
Election of Species Requirement
Applicant responded to an Election of Species Requirement mailed on October 19, 2023, in a response filed on January 25, 2024. Applicant elected, with traverse, the following species:
Species of an ACE2 externalizer: diminazene, drawn to claims 8, 19 and 29.
Applicant’s election of species – diminazene as ACE2 externalizer is acknowledged. Accordingly, this Election of Species is made final.
Withdrawn Rejections
The following rejections are withdrawn:
The rejection of claims 8, 10-19 and 21-28 under 35 U.S.C. 103 as being unpatentable over Rigatto et al., European Journal of Pharmacology, Volume 713, Issues 1-3, 5 August 2013, pages 89-93 (“Rigatto”), in view of Yun et. al., (e-Published: 31 August 2020), The Journal of Biomedical Research, 2020, 34(6): 458-469, (“Yun”) is withdrawn in view of the earliest priority date of the parent CIP application being May 07, 2020.
Maintained Claim Rejection - 35 USC § 112 – Scope of Enablement
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 19 and 21-28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating as per claims 8, 10-18, does not reasonably provide enablement for a method of preventing COVID-19 as per claim 19, 21-28. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
[In re Sichert, 196 USPQ 209 (CCPA 1977)]
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
The breadth of the claims;
The nature of the invention;
The state of the prior art;
The level of one of ordinary skill;
The level of predictability in the art;
The amount of direction provided by the inventor;
The existence of working examples; and
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
MPEP. § 2164.01(a); In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988); In re Wright, 999 F.2d 1557, 27 USPQ2d 1510 (Fed. Cir. 1993). When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. A discussion of these factors as they relate to the pending claims follows.
The above factors, regarding the present invention, are summarized as follows:
The breadth of the claims;
The claims are thus very broad insofar as they recite a “method of preventing COVID-19 infection” in a patient comprising administering to the patient an ACE2 externalizer, wherein the ACE2 externalizer increases ACE2 surface expression; wherein the ACE2 externalizer is one of diminazene, diminazene aceturate, or a pharmaceutically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, or prodrug thereof.
The nature of the invention;
The invention relates to “A method of preventing COVID-19 infection in a patient comprising administering to the patient an ACE2 externalizer, wherein the ACE2 externalizer increases ACE2 surface expression; wherein the ACE2 externalizer is one of diminazene, diminazene aceturate, or a pharmaceutically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, or prodrug thereof.”. However, the state of the art recognizes that even monoclonal vaccines are ineffective in preventing COVID-19 exposure for example.
The state of the prior art; and (E) The level of predictability in the art;
Hammond et al., Therapeutics for COVID-19. Nat Microbiol 8, 771–786 (2023) that the state of the art is such that no non-immunological therapy is known to be effective in preventing, for example, the exposure of COVID-19 (Applicant’s Specification at para. [0044]. Hammond teaches that even with monoclonal antibodies that target the spike protein of SARS-CoV-2, and block the attachment of the spike protein to the human ACE2 receptors and inhibit viral entry, that “Although this proved to be an efficacious mechanism in preventing disease progression in this population, the utility of specific monoclonal antibodies was limited by the emergence of variants with a mutation of the spike protein that rendered this class of drugs ineffective. Thus, new monoclonal antibodies would be needed once a new variant of concern becomes the predominant strain.” Hammond at page 779. This suggests that the mere prevention of exposure to COVID-19 is elusive, even with the most effective method of treating COVID-19 to date. Hammond at page 779.
Hammond et al., Therapeutics for COVID-19. Nat Microbiol 8, 771–786 (2023) also summarizes in Table 1, COVID-19 therapeutics that have been FDA approved or authorized. Hammond teaches that although popular antibacterial Azithromycin showed in vitro antiviral activity, possibly limiting viral replication, and hydroxychloroquine also demonstrated antiviral activity against SARS-CoV-2 in vitro by blocking viral entry; and when combined in vitro, they were observed to have a synergistic effect on SARS-CoV-2 infection; hydroxychloroquine and azithromycin were not effective in clinical trials and are not recommended for the treatment or prevention of COVID-19 by the National Institutes of Health (NIH) Treatment Guidelines Panel (c.f., page 772, Treatment early in the pandemic). As discussed by Hammond on page 772, “These combinations were routinely used early in the pandemic. With later data showing that these regimens yield no clinical benefit, it provides a caution as to how limited in vitro data can be misinterpreted…”. Consequently, the level of predictability is low.
Moreover, no clinical nexus between administration of an “ACE2 externalizer” is known in the art, and Applicants have not established any such connection in the prevention of COVID-19.
The level of one of ordinary skill;
The relative skill of those in the art is high, that of an MD or PHD. That factor is outweighed, however, by the unpredictable nature of the art.
The amount of direction provided by the inventor; and (G) The existence of working examples;
The amount of guidance or direction needed to enable the invention is inversely related to the degree of predictability in the art. In re Fisher, 839, 166 USPQ 24. Thus, although a single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements, in cases involving unpredictable factors, such as most chemical reactions and physiological activity, more teaching or guidance is required. In re Fisher, 427 F.2d 839, 166 USPQ 24; Ex Parte Hitzeman, 9 USPQ 2d 1823. For example, the Federal Circuit determined that, given the unpredictability of the physiological activity of RNA viruses, a specification requires more than a general description and a single embodiment to provide an enabling disclosure for a method of protecting an organism against RNA viruses. In re Wright, 999 F.2d 1562-63, 27 USPQ2d 1575.
In order to practice the full scope of this invention, a skilled artisan would have to conduct several levels of experimentation, starting from the most fundamental proof-of-concept, proceeding through establishing a cellular model, conduct a high-throughput screening for reliable therapeutics, through several levels of animal-model experiments. This amount to development, not invention. It is an undue amount and kind of experimentation.
Based on the evidence regarding each of the above factors, a conclusion of lack of enablement means that the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of claim 19 without undue experimentation; {In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)}. The specification fails to provide sufficient support of the broad use of a method of preventing COVID-19 in a patient in need thereof comprising administering to the patient “an ACE2 externalizer”. Moreover, the term “ACE2 externalizer” is not conventional in the art, and is not clearly defined in Applicants’ disclosure.
The specification also fails to provide any working examples for prevention by administration of the elected species, diminazene. Applicant’s Specification in para. [0044] recites:
The term "prevent," as used herein, includes prophylactic treatment or treatment
that prevents one or more symptoms or conditions of a disease, disorder, or conditions described herein (e.g., exposure to the SARS-CoV-2 virus, subsequent infection, and/or COVID-19). Treatment can be initiated, for example, prior to ("pre-exposure prophylaxis") or following ("post-exposure prophylaxis") an event that precedes the onset of the disease, disorder, or conditions. Treatment that includes administration of a compound of the invention, or a pharmaceutical composition thereof, can be acute, short-term, or chronic. The doses administered may be varied during the course of preventive treatment.
The sole experimental data concern treatment of cells in culture with diminazene (see, Specification, pp. 12-13). A summary of the description of the figures in the specification on pp.12-13 and discloses:
Diminazene aceturate effects on the externalization of ACE2 and the increase of ACE2-mediated binding and signal of VSV virus-expressing COVID- spike protein in target cells. (Fig 1., paragraph [0053]).
Confirmed externalization of ACE2 on the cell surface of human brain endothelial cells exposed to diminazene (Fig. 2, paragraph [0054]).
The LD50 for diminazene is then determined based on a dose-dependent reduction in the infectivity of cells as disclosed by Fig. 3, paragraph [0055], whereby there is a claimed infectious ratio of 1:100 viruses per cell.
Furthermore, in a mathematical assumption, Applicant discloses in paragraph [0056] that “Assuming 100% biological distribution in a 70kg human, 10-4M is a dose of 3.5g and 10-5M is 350mg. The LD50 for Diminazene is ~350mg/kg or 24 grams”, in order to determine a theoretical dose of diminazene.
Similarly, Applicant discloses in Fig 5., paragraph [0057] that “… at an infectious ratio of 10:100 viruses per cell…”, “… Assuming 100% biological distribution in a 70kg human, 10-4M is a dose of 3.5g and 10-5M is 350mg. The LD50 for Diminazene is ~350mg/kg or 24 grams”.
The final figure, Fig. 6 is described as showing “the appearance of ACE2 expressing cell monolayers at an infectious ratio of 5:100 viruses per cell, and that “This is equivalent to a high dose of 515mg/kg (1mM) to the lowest dose of 5.15mg/kg”, without any further details.
Figures 3-5, in particular, disclose experiments related to the observation of luminescence, over a total area, by cells that are treated with the claimed diminazene over time. This increase in luminescence, according to Applicant’s specification, is due to the administration of the claimed diminazene compound and its ability to force the externalization of ACE2 protein; wherein said ACE2 protein “… also happens to be the receptor for COVID-19…” (p.19, paragraph [0076]).
Applicant goes on further to state on p. 19, paragraph [0076], that they have discovered that diminazene functions similarly to other angiotensin type 1 receptor antagonists, and ezetimibe and cholesterol synthesis inhibitors, in that it promotes or forces the externalization of ACE2. Applicant then uses prophetic assertions to support the claimed rationale that an increase in the externalization of ACE2, following the administration of diminazene, would be able prevent COVID-19 (p. 19, paragraph [0076]):
“Maintaining patients on combination therapy with one or more ACE2 externalizers and one or more ACE2 internalization preventors, will promote at least two specific clinical benefits: 1) the beneficial balance of surface ACE2 will be restored, ACE2 being an anti-coagulant, anti-inflammatory and vasorelaxant, effects which are diminished or lost in COVID infection, 2) secondly, this combination of drugs will 'lock out' the SARS-CoV-2 virus against penetration into the cytoplasm of the cell, thereby preventing propagation and infection spread.”
There is no description of an actual reduction to practice supporting the administration of diminazene, diminazene aceturate, or a pharmaceutically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, or prodrug thereof, according to the claims, to prevent COVID-19 in a patient in need thereof.
All statements regarding treatment variables, from the composition of formulations to the route of administration and suitable dosage amounts and frequency lack specificity. The therapeutic dosage disclosed for treatment varies over several orders of magnitude, and are generic for an “active agent” (c.f., paragraph 101). There is no description of the preparation of the cells, or results data showing the prevention of COVID-19. The specification also does not provide any assurance of success in terms of the administration diminazene in preventing COVID-19. There is no discussion of the cell type employed and its connection with the actual disease. There is no discussion of an animal model, and no nexus between Applicants’ results and COVID-19 infection is established. In addition, all of the claims are broadly generic as to the active agent -- “ACE2 externalizer” term which lacks a definition in the specification to compensate for the absence of a precise meaning as used in the art.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that every instantly claimed method could be predictably used for the prevention of COVID-19 inferred by the claims and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is “undue”, not “experimentation”.
In sum, the enablement prong of 35 U.S.C. §112(a) requires that a patent specification teach a skilled artisan to use – not to make and test – the full scope of the claimed invention without undue experimentation. For a method of preventing (claims 19 and 21-28) COVID-19, the specification provides none of the indicia set forth above in sufficient detail that one skilled in the art can reasonably use the claimed invention without undue experimentation. The Specification is largely theoretical (e.g., “…would be expected to experience relief...”) (see, p. 16, paragraph [0068]), or hypothetical, or allude to experimental results that are neither referenced nor provided. Therefore, the connection between Applicants’ results and COVID-19 infection is at best hypothetical.
In view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to prevent COVID-19 in a patient in need thereof per the claimed invention, with no assurance of success in preventing COVID-19.
Applicant’s Arguments
Applicant argues that the Specification is enabling for the prevention of COVID-19 per claims 19 and 21-28 in a patient. Applicant argues the mechanism by which they believe prevention occurs in a patient, and according to Applicant, this is by promoting ACE2 externalization on the surface of the cell without activating ACE2 and without the need for direct interference with ACE2-spike interaction. Applicant’s Remarks at page 6.
Examiner’s Response
Applicant’s arguments have been considered, but are not found to be persuasive. In view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to prevent COVID-19 in a patient in need thereof per the Applicant’s claimed invention, with no assurance of success in preventing COVID-19. Applicant fails to demonstrate or show how the method is enabling for the prevention of COVID-19 and instead argues the mechanism of action of the claimed compound.
For a method of preventing COVID-19 the specification provides no description of an actual reduction to practice, no showing that the invention is ready for patenting, and no description of distinguishing characteristics of a method of treating COVID. All statements regarding treatment variables, from composition of formulations to route of administration to dosage amounts and frequency lack specificity; they are boilerplate. The therapeutic dosage disclosed for treatment varies over several orders of magnitude, and the treatment cycle varies from a single treatment to the rest of the subject’s life. In addition, all of the claims are broadly generic as to one or both of the active agents -- “ACE2 externalizer” and an “ACE2 internalization preventer,” terms which themselves lack a definition in the specification to compensate for the absence of a precise meaning as used in the art. The specification does not provide information regarding administration of sufficient species of either of these genera to represent the full genus.
The specification also fails to provide any working examples for prevention by administration of the elected species, diminazene. Applicant has not demonstrated any method that prevents one or more symptoms or conditions of COVID-19. The claims are not enabled for the prevention of COVID-19. The rejection is maintained.
Subject Matter Free of the Art
Claims 8, 10-19 and 21-28 were previously rejected under 35 U.S.C. 103 as being unpatentable over Rigatto et al., European Journal of Pharmacology, Volume 713, Issues 1-3, 5 August 2013, pages 89-93 (“Rigatto”), in view of Yun et. al., (e-Published: 31 August 2020), The Journal of Biomedical Research, 2020, 34(6): 458-469, (“Yun”). Upon reconsideration, the Examiner agrees with Applicant that the earliest priority date of the parent CIP application is that of May 07, 2020. Hence, Yun et al., does not qualify as prior art and the rejection has been withdrawn.
In summary, Rigatto teaches the administration of diminazene aceturate (DIZE) to a subset of rats at 15 mg/kg/day for a period of 21 days. (Abstract).
While Rigatto does not teach the use of DIZE in a method of treating and/or preventing COVID-19 as per independent claims 8 and 19, Yun teaches in the Abstract that “coronavirus harnesses spike protein to invade host cells through angiotensin converting enzyme 2 (ACE2)” and on p. 459, that the disclosure is based a need “to screen and understand the mechanism of known drugs for COVID-19 for the purpose of designing new drugs with higher efficacy”.
As disclosed by Yun on p. 462, a virtual, primary, high-throughput screening resulted in 238 compounds (i.e., out of an initial 2080 FDA-approved molecules that were screened as COVID-19 inhibitors; see p. 460), dose dependently bound to the spike-ACE2 interaction interface, and this included diminazene aceturate and pravastin (see also, p. 5-6, of the Supplementary Data, Table 1).
The results of the primary high-throughput screen identified multiple compounds, including Diminazene Aceturate and pravastatin, as potential therapeutics for the treatment of COVID-19 (p. 5-6, of the Supplementary Data, Table 1). The results from this high-throughput screen teaches the claimed invention, as the finding suggests that one of ordinary skill in the art would be motivated to use any of the identified compounds, including Diminazene Aceturate, as potential therapeutics for the treatment of COVID-19 in “a method of treating COVID-19 in a patient in need thereof comprising: administering to the patient an ACE2 externalizer, wherein the ACE2 externalizer comprises diminazene, diminazene aceturate, or a pharmaceutically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, or prodrug thereof” as required by independent claims 8 and 19.
It is also noted that the neither independent claim 8 (treatment) nor independent claim 19 (prevention) require the administration of any particular dose of diminazene, which would presumably be necessary to achieve the recited result. Nonetheless, the subject matter is free of the prior art.
Conclusion
THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
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/C A/ Examiner, Art Unit 1622
March 4, 2026
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622