DETAILED ACTION
Notice of 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 .
Election/Restrictions
Applicant’s election without traverse of Group II in the reply filed on 8/21/2026 is acknowledged. The requirement is still deemed proper and is therefore made FINAL.
Claims 1-2, 75-76, 87-88, 101 and 109-116 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant’s election without traverse of a single method in the reply filed on 8/21/2026 is also acknowledged.
The elected species read upon claims 105-108.
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.
Claims 105-108 are rejected under 35 U.S.C. 112(a), because the specification is not considered enabled for treating or preventing a viral infection in a subject comprising administering a therapeutically effective amount of compound of Formula (I) to said subject. 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.
The standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below
Nature of the Invention: the claimed invention pertains to a method for treating or preventing a viral infection in a subject, or an illness resulting from the viral infection (more specifically, wherein the viral infection is SARS-CoV-2 and the illness resulting from the viral infection is SARS or COVID-19 (claims 107-108)), the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of claim 1 (i.e., a compound of Formula (I)) – which are alleged by the Specification to function as sigma 1 and/or sigma 2 receptor ligands (further noting that “improved Sigma receptor modulating compounds may be able to address an unmet need in the treatment of viruses” (Paragraph 0004)) – or a pharmaceutically acceptable salt, prodrug, or solvate thereof.
The development of antiviral drugs is extremely complicated. As discussed by Saxena et al (Electronic J Biol 6:26-31, 2010), “[d]evelopment of antiviral drugs is [a] very tedious process as it involves many stages like, target identification and screening, lead generation and optimization, pre-clinical and clinical studies, final registration of the drug etc.” (Abstract). As further taught by Saxena et al, “[i]n spite of modern tools and stringent quality control measures, only a few antiviral drugs are getting approved for human use” owing to “either side effects or the antiviral drug resistance” (Abstract). Indeed, as specifically stated by Saxena et al, “developing antiviral drugs is a difficult task” (Page 26, Column 1).
As such, the nature of the invention is highly complex.
Breadth of the Claims: the claims are extremely broad. At the outset, the compounds to be administered according to the method embrace hundreds of millions of structurally distinct compounds, including for example:
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240
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(Specification Page 52, Compound 2);
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390
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(Specification Page 54, Compound 10);
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158
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(Hypothetical Compound A) wherein X1 is absent; X2 is absent; R1 is H; R7 is C1 alkyl; R8 is C1 alkyl; and m, n and p are 0;
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426
750
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(Hypothetical Compound B) wherein X1 is C(O)NR3 wherein R3 is H; X2 is C(O)NR3 wherein R3 is H; R1 is a 5-membered heteroaryl substituted with two R5 wherein each R5 is independently C6 aryl; p is 2 and each R2 is independently a 6-membered heteroaryl substituted with two R6 wherein each R6 is independently C5 cycloalkyl; and m and n are each 2; and
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252
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(Hypothetical Compound C (taught by the prior art as CAS RN 21841-93-0 (entered into STN on 11/16/1984))) wherein X1 is CR3R4 wherein R3 and R3 are independently H; X2 is absent; R1 is C3 cycloalkyl; p is 1 and R2 is C6 aryl substituted with R6 wherein R6 is C1 alkoxy; and m is 1; and n is 2.
Additionally, the method embraces not only the treatment of any viral infection, without limitation, but also the prevention of any viral infection, without limitation, which would include future viral infections (claim 105), more specially, a coronavirus, HSV, HIV, influenza, or human papillomavirus (claim 106), even more specifically, SARS-CoV-2 and COVID-19 (claims 107-108).
Yet, as noted by Martin et al (Drug Discovery Today 30:12 pages, 2025), “truly pan-viral BSAAs [broad-spectrum antiviral agents] remain exceedingly rare and are typically discovered serendipitously rather than through rational design” (Page 2, Column 1).
As such, it is evident that the claims – which embrace the administration of hundreds of millions of structurally unrelated compounds for the treatment or prevention of any viral infection, without limitation – are extraordinarily broad, which exacerbates the complexity of the invention.
The Amount of Direction Provided by the Inventor / Existence of Working Examples: the Specification discloses 137 compounds, of which 25 were evaluated as ligands for the sigma 1 receptor and/or the sigma 2 receptor. Yet, of the 25 compounds which were evaluated, 11 showed little to no activity as sigma 1 receptor ligands, 9 showed little to no activity as sigma 2 receptor ligands, and 5 showed little to no activity as combined sigma 1 and sigma 2 receptor ligands (Pages 131-132, Table A).
The Specification further evaluated two compounds (compounds 2 and 10) along with PB28 (sigma 1 and sigma 2 receptor ligand), MIN-S006, and MIN101 (sigma 2 receptor ligand) against SARS-CoV-2 production in a “Vero-E6 cell line infected with SARS-CoV-2” in two infection conditions (Page 140; see also Figure 4 (low inoculum) and Figure 5 (high inoculum)). However, only compound 10 appears to demonstrate any antiviral effect, in particular in the high inoculum conditions (Figures 4-5).
The State of the Prior Art and the Level of Predictability in the Art: as indicated above, the claimed invention is drawn to a method for treating or preventing a viral infection in a subject, (more specifically, wherein the viral infection is SARS-CoV-2 and the illness resulting from the viral infection is SARS or COVID-19), the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (I) – which are alleged by the Specification to function as sigma 1 and/or sigma 2 receptor ligands, further noting that “improved Sigma receptor modulating compounds may be able to address an unmet need in the treatment of viruses” (Paragraph 0004)).
Yet, regarding the synthesis of sigma 1 and/or sigma 2 receptor ligands, at the time the instant application was filed, it would have been known by those of ordinary skill in the art that - due in large part to the strict requirement of complementarity between a compound and its corresponding binding site on a target receptor or enzyme - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. At the same time, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects. Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity, etc) would interact with the given target to elicit a related biological response.
Accordingly, at the time the invention was made, the relative skill of those in the art tasked with identifying compounds exerting an activity of interest would have been high, as the ordinarily skilled artisan would have had, at minimum, a Ph.D. and experience with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods. Deciding which technique to use would have been determined by the skilled artisan’s knowledge regarding the compound and target of interest. Ligand based drug design relies on knowledge of a compound or compounds of interest (i.e., ligands) to derive new compounds that will, in theory, similarly interact with the target of interest to elicit the activity of interest. Conversely, structure-based drug design relies on knowledge of the three-dimensional structure of the target of interest (i.e., receptor, ion channel, or enzyme) to derive new compounds that will, in theory, interact with the target of interest to elicit the activity of interest. In either case, the compounds derived from these techniques (applied alone or in combination) are then subjected to in vitro testing for validation.
Once a compound has been identified by ligand based and/or structure-based drug design methods as potentially binding to the target molecule, it must be evaluated. However, as discussed by Anderson (Chem and Biol 10:787-797, 2003), “it is important to consider that the ranking assigned by the scoring function is not always indicative of a true binding constant, since the model of the target:ligand interaction is inherently an approximation. Usually, several molecules which scored well during the docking run are evaluated in further tests since even the top scoring molecule could fail in vitro assays… Finally, leads are brought into the wet lab for biochemical evaluation” (Page 794, Column 1). By that point, as noted by Thiel (Nature Biotechnol 2:513-519, 2004), “libraries are small and hit rates are on the order of one in ten” (Page 517, Column 2). This low level of predictability is not surprising considering that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Indeed, modifying even a single atom in a compound can dramatically change the compound’s overall structure and - even though complementarity in one portion of the compound might be improved by the chemical revision - the overall binding or activity might be severely compromised.
This is certainly true in the case of sigma 1 and/or sigma 2 receptor ligands which, as demonstrated by the instant Specification, demonstrate significantly altered activity following minor modifications (compare, e.g., Compound 1, having sigma 1 and sigma 2 Ki values between 100 nM and 500 nM with Compound 2 (differing in the length of a single alkyl chain) having sigma 1 and sigma 2 Ki values between 5 nM and 50 nM).
Furthermore, regarding the treatment of viral infections (including SARS-CoV-2, COVID-19) by administering a sigma 1 and/or sigma 2 receptor ligand, as taught Tummino et al (Science 373:541-547, 2021), which – “motivated by the discovery that human sigma receptors were candidates for modulating SARS-CoV-2 infection and that drugs and reagents like chloroquine, haloperidol, slemastine, and PB28 - all with nanomolar affinity against one or both sigma receptors – had cellular antiviral half-maximal inhibitory concentration (IC50) values in the 300-nM to 5-µM range” – “investigated more than 50 different molecules with a wide range of affinities at these receptors”, “there was little correlation between receptor potency and antiviral efficacy in cells” (Page 1 of 7, Column 1). Moreover, Tummino et al report that “four of the... drugs most potent against SARS-CoV-2 in vitro – amiodarone [sigma 1 receptor ligand], sertraline [sigma 1 receptor ligand], PB28 [sigma 1 and sigma 2 receptor ligand], and tamoxifen [sigma 2 receptor ligand]” which were tested “for efficacy in a murine model of COVID-19... had little effect on viral propagation in the mice” (Page 4 of 7, Column 2).
Additionally, as taught by The RECOVERY Collaborative Group (N Engl J Med 282:2030-2040, 2020), in a “randomized, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19” where “1561 patients [were randomly assigned] to receive hydroxhloroquine [a sigma 1 ligand] and 3155 to receive the usual care... those who received hydroxychloroquine did not have a lower incidence of death and 28 days that those who received usual care” (Abstract).
Amount of Experimentation Necessary: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to compounds of Formula (I), which are alleged by the Specification to act as sigma 1 and/or sigma 2 receptor ligands for use in the treatment of prevention of viral infections.
Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the broadness of Formula (I) with respect to the disclosure since Formula (I) encompasses hundreds of millions of compound species, and potentially billions of compound species, whereas the instant Specification discloses only approximately 20 compounds exhibiting activity as a sigma 1 and/or sigma 2 receptor ligand, and a single compound which appears to demonstrate antiviral activity in vivo.
Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan (armed with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods) could not reasonably predict which of the hundreds of millions of other compounds encompassed by Formula (I) would exert the alleged activity based on the limited disclosure of approximately 20 active compounds. Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similarly activity, the skilled artisan would have also known that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Indeed, as demonstrated by the instant Specification, sigma 1 and/or sigma 2 receptor ligands, in particular, demonstrate significant unpredictability since even minor modifications result in drastic changes in activity. Thus, in order to identify usable compounds of Formula (I), the skilled artisan (at minimum) would have to carry out ligand based drug design methods using the approximately 20 disclosed compounds as a starting point and, assuming the structure of the target receptor was known, combine the findings with data derived from structure based drug design methods to arrive at a small library of “lead” compounds believed to possess the activity of interest. The skilled artisan would then synthesize lead compounds that are within Formula (I) for in vitro testing. At this point, however, even "the top scoring molecule could fail in vitro assays” (Page 794, Column 1) and “hit rates are on the order of one in ten” (Page 517, Column 2). Given the unpredictability of sigma 1 and/or sigma 2 receptor ligands, in particular, it is highly unpredictable whether any compound within the subgenus of compounds of Formula (I) identified by rational drug design based on the instant disclosure would, in fact, be usable. Whether the other compounds of Formula (I) (i.e., those not identified by rational drug design based on the instant disclosure) would be usable is even less predictable. As such, the only way to ascertain which of the hundreds of millions, and potentially billions, of claimed compounds encompassed by Formula (I) are usable based on the limited disclosure would require undue experimentation. That is, the only way one skilled in the art is enabled to use the entire scope of the claim based on the instant disclosure entails undue experimentation.
Yet, even assuming arguendo that one of ordinary skill in the art could reasonably ascertain which of the hundreds of millions, and potentially billions, of claimed compounds encompassed by Formula (I) show activity as sigma 1 and/or sigma 2 receptor ligands, there would have been no expectation that any of these compounds would function in the treatment or prevention of SARS-CoV-2/COVID-19, let alone in the treatment or prevention of any and all other viral infections, including future viral infections. As discussed above, the state of the prior art and predictability of the prior art clearly establish that the only way to determined whether a single sigma 1 and/or sigma 2 receptor ligand will show efficacy in the treatment of SARS-CoV-2/COVID-19 viral infection is to test that ligand, with virtually no expectation of success.
For all the foregoing reasons, claims 105-108 are rejected. To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CRAIG D RICCI whose telephone number is (571) 270-5864. The examiner can normally be reached on Monday through Thursday, and every other Friday, 7:30 am - 5:00 pm ET. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached on (571) 272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611
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