DETAILED ACTION
Examiner acknowledges receipt of the reply filed 10/21/2025, in response to the restriction requirement mailed 7/11/2025.
Claims 71 and 73-97 are pending. Claims 69, 70, and 72 have been cancelled.
Claims 71 and 73-97 are being examined on the merits in this office 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 .
Examiner Comment
The claims filed 10/21/2025 have the wrong application number in the page header. The page header refers to Appl Ser No 17/127631, not instant Appl No 17/908524.
Election/Restrictions
Applicant’s election of the following representative in the reply filed on 10/21/2025 is acknowledged. Election was made without traverse.
Second therapeutic agent – dexamethasone
Claims were amended to recite plitidepsin (compound enumerated in claim 70)
Applicant asserts that claims 71 and 73-97 read on the elected species (reply at p. 9).
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to for the following reasons. Figures 6-28, 32A-C, 34-37 have multiple parts. The figures should have separate figure legends and be identified in the specification. As written, the specification bundles the figure legends Figs 6-10, 1-14, 19-21, … 29-30.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
At least Figs 6-28 and 32A-C refer to color fluorescence, green, blue, etc. (Examples 2 and 4).
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See p. 59, l. 14.
Claim Objections
Claims 71, 74, 75, 77, 78, 83, 80, 84, and 88-94 are objected to because of the following informalities:
Claim 71 should be amended to recite “plitidepsin, a [[or]] pharmaceutically acceptable salt, or a stereoisomer
Claims 74 should be amended to recite “claim 71, wherein the CoV infection causes
Claims 75 should be amended to delete multiple references to “and/or” claim language.
Claim 77 should be amended to recite “one or more symptoms arising from i) a system selected from cardiovascular, respiratory, gastrointestinal, neurological, musculoskeletal, metabolic, renal, dermatological, otolaryngological, haematological and autonomic ii) psychiatric problems; iii)[[,]] generalised pain; iv)[[,]] fatigue; and v)
Claims 78 should be amended to delete multiple references to “and/or” claim language.
Claims 80, 84, 88, and 93 each recite the term “including”. The respective claims should be split into separate claims so that the “including” language is rewritten in independent claim form.
Claims 83 should be amended to delete multiple references to “and/or” claim language.
Claims 88 should be amended to delete multiple references to “and/or” and “or” claim language. Claim 88 should further be amended to delete reference to parenthetical information.
Claim 89 should be amended to delete to parenthetical information.
Claim 90 should be amended to delete to parenthetical information.
Claims 91 should be amended to delete multiple references to “and/or” claim language. Claim 91 should further be amended to delete parenthetical information.
Claim 92 should be amended to delete to parenthetical information.
Claim 93 should be separated into three distinct claims. Each of the clauses sets forth a fully developed and distinct claim set. Claim 93 should be amended to delete multiple references to “or” claim language.
Claim 94 should have a period at the end of the sentence.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 71 and 73-96 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 71 recites two consecutive "or" statements, and this grammatical arrangement raises substantial and material concerns regarding what possible combinations are required or optional in the claim scope because it is prima facie unclear if subsequent "or" statements are nested within earlier "and/or" statements, or merely intended to provide four alternative possibilities, from which at least one must be true. Applicant should clarify the claim scope by redrafting claim 71 to remove consecutive or potentially nested "or" statements.
Because claims 73-92 depend from indefinite claim 71 and do not clarify the point of confusion, they must also be rejected under 35 U.S.C. 112, second paragraph.
Examiner recommends that claim 71 be amended to recite “plitidepsin, a [[or]] pharmaceutically acceptable salt, or a stereoisomer
Claims 74 and 78 recite the limitation "the treatment". There is insufficient antecedent basis for this limitation in the claim.
Regarding claims 76, 78, 79, 81, 83, 84, 88, 89, 91, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Because claims 82 depends from indefinite claim 81 and do not clarify the point of confusion, they must also be rejected under 35 U.S.C. 112, second paragraph.
Claim 75 recites two consecutive "and/or" statements, and this grammatical arrangement raises substantial and material concerns regarding what possible combinations are required or optional in the claim scope because it is prima facie unclear if subsequent "and/or" statements are nested within earlier "and/or" statements, or merely intended to provide four alternative possibilities, from which at least one must be true. Applicant should clarify the claim scope by redrafting claim 75 to remove consecutive or potentially nested "and/or" statements.
Claim 76 recites “and/or” statements and the claim term “preferably”. The alternative claim language renders the metes and bounds of the claim indefinite. Applicant should redraft claim 76 to improve claim clarity.
Regarding claim 76, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 76 recites the broad recitation CoV infection, and the claim also recites COVID-19 which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Because claims 77 depends from indefinite claim 76 and do not clarify the point of confusion, they must also be rejected under 35 U.S.C. 112, second paragraph.
Claim 77 recites the limitation "the cardiovascular". There is insufficient antecedent basis for this limitation in the claim.
Claim 77 recites “and” and “and/or” within the claim rendering the metes and bounds of the claim indefinite. Claim 77 should be amended to remove alternative claim language and improve claim clarity. Examiner recommends that claim 77 be amended to recite “one or more symptoms arising from i) a system selected from cardiovascular, respiratory, gastrointestinal, neurological, musculoskeletal, metabolic, renal, dermatological, otolaryngological, haematological and autonomic ii) psychiatric problems; iii)[[,]] generalised pain; iv)[[,]] fatigue; and v)
Regarding claim 78, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 78 recites the broad recitation CoV infection, and the claim also recites COVID-19 which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 78 recites “and/or” statements and the claim term “preferably”. The alternative claim language renders the metes and bounds of the claim indefinite. Applicant should redraft claim 76 to improve claim clarity.
Regarding claim 78, the phrase "such" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 78 and 88-92, the use of parenthetical phrases render the claims indefinite because it is unclear whether the limitations following the phrases or in parentheses are part of the claimed invention. See MPEP § 2173.05(d).
Claim 79 recites the limitations "the prophylaxis", “the likelihood”, “the severity”, and “the treatment”. There is insufficient antecedent basis for the limitations in the claim.
Claim 79 further recites “and/or” statements and the claim term “preferably”. The alternative claim language renders the metes and bounds of the claim indefinite. Applicant should redraft claim 79 to improve claim clarity.
Claim 80 recites the limitations "the infectivity", “the patient”, and “the treatment”. There is insufficient antecedent basis for the limitations in the claim. Independent claim 71 refers to a individual in need thereof, not the patient.
Regarding claim 83, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 83 recites the broad recitation e.g., 2-5 days and 1-50 mg, and the claim also recites e.g., preferably 3 days and 4.5-7.5 mg which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 83 recites "and/or" and “or” statements, as well as the claim term “preferably. This grammatical arrangement raises substantial and material concerns regarding what possible combinations are required or optional in the claim scope because it is prima facie unclear if subsequent "and/or" statements are nested within earlier "and/or" statements, or merely intended to provide four alternative possibilities, from which at least one must be true. Applicant should clarify the claim scope by redrafting claim 83 to remove consecutive or potentially nested "and/or" and “or” statements, as well as eliminate indefinite claim language “preferably”.
Claim 84 further recites “or” statements and the claim terms “including” and “preferably”. The alternative claim language renders the metes and bounds of the claim indefinite. Applicant should redraft claim 84 to improve claim clarity.
Claim 86 recites the limitation "the dosage". There is insufficient antecedent basis for this limitation in the claim.
Claim 87 recites the limitation "the same day". There is insufficient antecedent basis for this limitation in the claim.
Because claims 88 depends from indefinite claim 87 and do not clarify the point of confusion, they must also be rejected under 35 U.S.C. 112, second paragraph.
Claim 88 recites multiple and variable endpoints. This is further complicated by multiple consecutive "and/or" statements. The grammatical arrangement raises substantial and material concerns regarding what possible combinations are required or optional in the claim scope because it is prima facie unclear if subsequent "and/or" statements are nested within earlier "and/or" statements, or merely intended to provide four alternative possibilities, from which at least one must be true. Claim 88 further recites the term “preferably” as well as parenthetical information. Applicant should clarify the claim scope by redrafting claim 88 to remove consecutive or potentially nested "and/or" statements.
Claim 89 recites the limitation "the patient". There is insufficient antecedent basis for this limitation in the claim. Independent claim 71 refers to a individual in need thereof, not the patient.
Further regarding claim 89, the claim recites parenthetical information, the term “preferably”. The claim further recites alternative claim language of “and” and “and/or” at lines 5 and 6.
Regarding claim 91, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 91 recites the broad recitation e.g., 1-10 mg, and the claim also recites e.g., preferably 7.5 mg which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 91 recites multiple and variable endpoints. This is further complicated by multiple consecutive "and/or" statements. The grammatical arrangement raises substantial and material concerns regarding what possible combinations are required or optional in the claim scope because it is prima facie unclear if subsequent "and/or" statements are nested within earlier "and/or" statements, or merely intended to provide four alternative possibilities, from which at least one must be true. Claim 91 further recites the term “preferably” as well as parenthetical information. Applicant should clarify the claim scope by redrafting claim 91 to remove consecutive or potentially nested "and/or" statements.
Claim 91 further recites the limitations “the single dose”, "the same day" and “the following prophylactic medications”. There is insufficient antecedent basis for the limitations in the claim.
Regarding claim 91, the phrase "particularly" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 93 recites the limitations "the patient" and “the symptoms. There is insufficient antecedent basis for the limitations in the claim. Please note that claim 93 refers to an individual in need thereof, not a patient.
The metes and bounds of claim 93 are deemed to be indefinite for several reasons. Claim 93 recites multiple "or" statements, and this grammatical arrangement raises substantial and material concerns regarding what possible combinations are required or optional in the claim scope because it is prima facie unclear if subsequent "or" statements are nested within earlier "or" statements, or merely intended to provide four alternative possibilities, from which at least one must be true.
Claim 93 recites three (3) distinct and fully developed claim clause/structures: preamble, transitional phrase, and body of the claim:
93 (Currently Amended) A method of prophylaxis, reduction or treatment of CoV persistent, long CoV or post-CoV syndrome, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of plitidepsin, or a pharmaceutically acceptable salt or stereoisomer thereof; or
a method of reducing the infectivity of CoV patients, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of plitidepsin, or a pharmaceutically acceptable salt or stereoisomer thereof; including wherein the patient is asymptomatic or not very symptomatic yet has a high viral load; or
a method of minimizing the symptoms of CoV infection, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of plitidepsin, or a pharmaceutically acceptable salt or stereoisomer thereof.
The phrase “the method” is deemed to be indefinite because it is unclear as to which specific method, “the method” is referring back to.
Because claims 94-96 depend from indefinite claim 93 and do not clarify the point of confusion, they must also be rejected under 35 U.S.C. 112, second paragraph.
To overcome this rejection, applicant should split claim 93 into 3 separate claims. Examiner recommends that claim 93 be amended to recite “plitidepsin, [[or]] a pharmaceutically acceptable salt, or a stereoisomer
Claim 95 recites the limitations “the likelihood” and “the severity”. There is insufficient antecedent basis for the limitations in the claim. Further regarding claim 95, the phrase "such" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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 71 and 73-97 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 attenuating, alleviating or inhibiting the progress of a coronavirus infection, does not reasonably provide enablement for prophylaxis, preventing or reversing a coronavirus infection. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Examiner expressly notes that the definition of treatment within the specification (further discussed below) encompasses prevention and prophylaxis. The specification is not enabled for treatment by definition of “treatment” per the specification. The specification is limited to enablement for attenuating, alleviating or inhibiting the progress of a coronavirus infection plitidepsin, but not prevention, prophylaxis, or reversing of a coronavirus infection.
Pharmaceutical therapies in the absence of in vivo clinical data are unpredictable for the following reasons; (1) the protein may be inactivated before producing an effect, i.e. such as proteolytic degradation, immunological inactivation or due to an inherently short half-life of the protein; (2) the protein may not reach the target area because, i.e. the protein may not be able to cross the mucosa or the protein may be adsorbed by fluids, cells and tissues where the protein has no effect; and (3) other functional properties, known or unknown, may make the protein unsuitable for in vivo therapeutic use, i.e. such as adverse side effects prohibitive to the use of such treatment. See page 1338, footnote 7 of Ex parte Aggarwal, 23 USPQ2d 1334 (PTO Bd. Pat App. & Inter. 1992).
As stated in MPEP 2164.01(a), “there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
The factors to be considered when determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, were described in In re Wands, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) as:
1. the nature of the invention;
2. the breadth of the claims;
3. the state of the prior art;
4. the relative skill of those in the art;
5. the predictability or unpredictability of the art;
6. the amount of direction or guidance presented [by the inventor];
7. the presence or absence of working examples; and
8. the quantity of experimentation necessary [to make and/or use the invention.
(1) The Nature of the Invention and (2) The Breadth of the claims
Claims 71 and 73-92 are drawn to a method of method of treating coronavirus (CoV) infection, wherein the method comprises administering to an individual in need thereof a therapeutically effective amount of plitidepsin or pharmaceutically acceptable salts or stereoisomers thereof.
Claims 93-96 are drawn to a method of prophylaxis, reduction or treatment of CoV persistent, long CoV or post-CoV syndrome, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of plitidepsin, or a pharmaceutically acceptable salt or stereoisomer thereof; or a method of reducing the infectivity of CoV patients, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of plitidepsin, or a pharmaceutically acceptable salt or stereoisomer thereof; including wherein the patient is asymptomatic or not very symptomatic yet has a high viral load; or a method of minimizing the symptoms of CoV infection, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of plitidepsin, or a pharmaceutically acceptable salt or stereoisomer thereof.
Claim 97 is drawn to a method of treatment of CoV infection, the method comprising administering a combination therapy of plitidepsin or a pharmaceutically acceptable salt thereof and a corticosteroid to a patient in need thereof, thereby treating the CoV infection.
Claim 73 and 94 recite that the CoV is SARS-COV-2. Claims 79 and 91 further recite prophylaxis and “prophylactic medications”.
The specification defines:
The term “treating”, as used herein, unless otherwise indicated, means reversing, attenuating, alleviating or inhibiting the progress of the disease or condition to which such term applies, or one or more symptoms of such disorder or condition. The term treating as used herein may also include prophylactic treatment, that is treatment designed to prevent a disease from occurring or minimize the likelihood of a disease occurring.
“Treat”, “treating”, and “treatment” in the context of a viral infection may refer to one or more of the following: 1) reduction in the number of infected cells; 2) reduction in the number of virions present in the serum, including reduction in viral titre (which can be measured by qPCR); 3) inhibition (i.e., slowing to some extent, preferably stopping) the rate of viral replication; 4) reduction in the viral RNA load; 5) reduction in the viral infectivity titre (the number of virus particles capable of invading a host cell); and 6) relieving or reducing to some extent one or more of the symptoms associated with the viral infection. This may include inflammation associated with viral infection.
Specification at p. 12, ll. 10-22. Emphasis added.
Thus, the instant claim scope encompasses both treating and preventing/prophylaxis, regressing a coronavirus infection comprising administering plitidepsin, a pharmaceutically acceptable salt, or a stereoisomer thereof.
(3) The state of the art and (5) The predictability or unpredictability of the art
Rangel et al (Curr Prot Pept Sci 18: 72-91 (2017)) is a review article discussing marine depsipeptides. Didemnins showed great efficacy against a variety of virus at low doses: herpes simplex virus type 1 and 2, vaccinia virus, coxsackie virus A-21 and equine rhinovirus. Didemnins were also able to significantly reduce herpes virus lesions in rats when used as topical treatment, be sides presenting antitumor activity (p. 80). Aplidine Depsipeptide dehydrodidemnin B (aplidine, plitidepsin, Aplidin®) was isolated from the Mediterranean tunicate Aplidium albicans. Aplidine has a chemical structure very similar to didemnin B 2, a depsipeptide described in the 1980’s and also found in tunicates. Didemnin B presents antiviral activity (p. 74).
Alonso-Álvarez et al (Drug Design Dev Thera 11: 253–264 (2017)) is a review article discussing plitidepsin. Plitidepsin is a cyclic depsipeptide that was first isolated from a Mediterranean marine tunicate (Aplidium albicans) and, at present, is manufactured by total synthesis and commercialized as Aplidin® (abstract). Its antitumor activity, observed in preclinical in vitro and in vivo studies has prompted numerous clinical trials to be conducted over the last 17 years, alone or in combination with other anticancer agents. Single-agent plitidepsin has shown limited antitumor activity and a tolerable safety profile in several malignancies, such as noncutaneous peripheral T-cell lymphoma, melanoma, and multiple myeloma. Id. In patients with relapsed or refractory multiple myeloma, plitidepsin activity seems to be enhanced after addition of dexamethasone while remaining well tolerated, and a Phase III trial comparing plitidepsin plus dexamethasone vs dexamethasone alone is underway. Id.
Hu et al. (Nature Rev Microbiol. 19:141-154 (2021)) is a review article discussing characteristics of SARS-CoV-2 and COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus that emerged in late 2019 and has caused a pandemic of acute respiratory disease, named ‘coronavirus disease 2019’ (COVID-19) (abstract). As a novel betacoronavirus, SARS-CoV-2 shares 79% genome sequence identity with SARS-CoV and 50% with MERS-CoV24. Its genome organization is shared with other betacoronaviruses. The six functional open reading frames (ORFs) are arranged in order from 5′ to 3′: replicase (ORF1a/ORF1b), spike (S), envelope (E), membrane (M) and nucleocapsid (N) (p. 142). SARS-CoV-2 uses the same receptor as SARS-CoV, angiotensin-converting enzyme 2 (ACE2)11,47. Besides human ACE2 (hACE2), SARS-CoV-2 also recognizes ACE2 from pig, ferret, rhesus monkey, civet, cat, pangolin, rabbit and dog11,43,48,49. The broad receptor usage of SARS-CoV-2 implies that it may have a wide host range, and the varied efficiency of ACE2 usage in different animals may indicate their different susceptibilities to SARS-CoV-2 infection *p. 146). Similarly to other coronaviruses, SARS-CoV-2 needs proteolytic processing of the S protein to activate the endocytic route. It has been shown that host proteases participate in the cleavage of the S protein and activate the entry of SARS-CoV-2, including transmembrane protease serine protease 2 (TMPRSS2), cathepsin L and furin. Id. To date, there are no generally proven effective therapies for COVID-19 or antivirals against SARS-CoV-2, although some treatments have shown some benefits in certain subpopulations of patients or for certain end points (see later). Researchers and manufacturers are conducting large-scale clinical trials to evaluate various therapies for COVID-19 (p. 149). Fig. 5 indicates SARS-CoV-2 replication and potential therapeutic targets.
Yuki et al (Clin Immunol 215:108427 (2020)) teach SARS-coV-2 (a coronavirus) caused an acute atypical respiratory disease. The virus primarily affects the respiratory system, although other organ systems are also involved. Lower respiratory tract infection related symptoms include fever, dry cough and dyspnea (p. 1).
It is noted that pharmaceutical and biological art is generally unpredictable, requiring each embodiment to be individually assessed for physiological activity. Given this fact, historically the development of new drugs has been difficult and time-consuming. Adding to the unpredictability is that many treatment options may show promise in animal models, but may fail to show therapeutic improvement in clinical trials. There is no absolute predictability, even in view of the high level of skill in the art.
The invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
Examiner notes that in order to prevent an infection, the skilled artisan must be apprised of patients that are at risk of developing a coronavirus infection. In contrast, the examples relate to treatment following infection. There are no examples of prophylaxis/prevention of infection.
(4) The relative skill of those in the art
MPEP 2141.03 states (in part)” A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR International Co. v. Teleflex Inc., 127 S.Ct. 1727, 167 LEd2d 705, 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At 1396, 82 USPQ2d at 1396. The “hypothetical person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988) (disagreeing with the examiner’s definition of one of ordinary skill in the art (i.e. a doctorate level engineer or scientist working at least 40 hours per week in semiconductor research or development), and finding that the hypothetical person is not definable by way of credentials, and that the evidence in the application did not support the conclusion that such a person would require a doctorate or equivalent knowledge in science or engineering). In the instant case, the skill in the art high with respect to physicians and scientists. The level of skill in the art (physicians and scientists) would be high.
(6) The amount of direction or guidance presented (by the inventor) and (7) The presence or absence of working examples
Example 1 is in an in vitro assay indicating a reduction in HIV replication (antiviral activity) in the presence of plitidepsin. Example 2 assessed antiviral activity of plitidepsin in Huh-7 cells (human hepatoma cell line) infected with HCoV-229E. Example 2 states: HCoV-229E has a multiplication and propagation mechanism very similar to SARS-COV-2. The N protein of HCoV-229E has a protein homology greater than 90% with the homologous N protein in SARS-CoV-2. It is believed that all coronaviruses need their N (nucleocapsid) protein to bind to EF1A in order to replicate effectively and synthesize viral proteins. Reducing or abolishing the binding of N to EF1A reduces the viability for the spread of the virus. Example 3 discloses a clinical trial in which COVID-19 patients were administered plitidepsin. Patients exhibited a reduction in viral replication. Examples 4 and 5 disclose antiviral activity of plitidepsin against SARS-CoV-2 was in an in vitro assay using vero cells. Examples 6 and 7 are prophetic example of a clinical trial of patients with COVID-19.
Examiner expressly notes there are no examples of prophylaxis/prevention of a coronavirus infection set forth in the specification. Examiner further notes that in order to prevent an infection, the skilled artisan must first be able to identify and predict patients at risk for developing a coronavirus infection, as well as effective amounts, routes of administration, and dosing regimen sufficient for prophylaxis/preventing a coronavirus infection.
There is no evidence that the specification offers a solution to the problem set forth in the specification of providing alternative therapies for prophylaxis/preventing a coronavirus infection. Though not controlling, the lack of working examples, is, nevertheless, a factor to be considered in a case involving both physiological activity and an undeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, he runs the risk that unless one with ordinary skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them. Ex parte Sudilovsky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971).
In essence, the specification merely presents an idea of, and leaves it entirely up to the practitioner to determine whether the method would produce a therapeutically relevant effect, and if so, how to carry out the claimed method. It has been established by legal decision that a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion. Tossing out the germ of an idea does not constitute an enabling disclosure. While every aspect of a generic claim need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable the skilled artisan to understand and carry out the invention. It is true that a specification need not disclose what is well known in the art. However, that general, oft-repeated statement is merely a rule of supplementation, not a substitute for a basic enabling disclosure. It means that the omission of minor details does not cause a specification to fail to meet the enablement requirement under 35 USC 112, first paragraph. When there is no disclosure of the specific starting materials or conditions under which the process can be carried out, there is a failure to meet the enablement requirement. See Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (Fed. Cir. 1997).
(8) The quantity of experimentation necessary (to make and/or use the invention)
Owing to the factors listed above, especially in points 1-7, the amount of experimentation needed will be extensive in view of the lack of guidance by the inventor. MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, 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 the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 71, 73-77, 81-88, 93-85, and 97 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 130-150 of copending Application No. 17/908526 (hereinafter referred to as “the ‘526 application”). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons. The ‘526 application has the same priority claim/earliest effective filing date as the instant application.
Regarding claims 71, 93, and 97, claims 130, 134, 135, 137-140 of the ‘526 application teach a method of treating inflammation in a patient in need thereof, comprising administering a therapeutically effective amount of plitidepsin by IV infusion. The denoted claims further recite that the method can treat a coronavirus infection.
Regarding claim 73 and 94, the CoV can be SARS-CoV-2 (claims with 137-138, 141, 143, 145, and 152 of the ‘526 application).
Regarding claims 74-76 and 95, the method can be used to treat post-COVID-19 syndrome, COVID persistent or long COVID (claim 151 of the ‘526 application).
Regarding claim 77, the method can be used to treat pneumonia or acute respiratory distress (ARDS), reads on respiratory system (claim 132 of the ‘526 application).
Regarding claims 81 and 82, plitidepsin can be administered in combination with a corticosteroid, on the same day (claims 148-149 of the ‘526 application).
Regarding claims 83 and 84, claims 146 147 of the ‘526 application recites the same subject matter- dosing regimen, infusion.
Regarding claims 87 and 88, claims 148-150 of the ‘526 application recite overlapping subject matter- corticosteroid, dosing regimen.
Regarding claims 90-91, claims 153 and 154 of the ‘526 application recite that plitidepsin is administered at a dose of1.5 mg/day once a day for three consecutive days.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 71, 73-82, 87, 89, and 93-97 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-55 of copending Application No. 17/908531 (hereinafter referred to as “the ‘531 application”). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons. The ‘531 application has the same priority claim/earliest effective filing date as the instant application.
Regarding claims 71, 93, and 97, claim 30 of the ‘531 application teach a method of treating coronavirus infection comprising administering to a patient in need thereof, PLD in combination with Remdesivir.
Regarding claim 73 and 94, the CoV can be SARS-CoV-2 (claim with 37 of the ‘531 application).
Regarding claims 74-79 and 95, the method reduces the risk of CoV infection, reduces the infectivity, treats COVID-19, mild infection of CoV, acute infection, and/or post-Covid syndrome, Covid persistent, or long Covid and includes one or more symptoms arising from the cardiovascular, respiratory, gastrointestinal, neurological, etc (claims 36-41, 43, 44, of the ‘531 application).
Regarding claims 80 and 96, claim 48 of the ‘531 application recites a method of reducing viral load and a cell reducing the infection efficacy of a virus in a cell comprising a administering plitidepsin (PLD).
Regarding claims 81, 82, and 87, plitidepsin can be administered in combination with a corticosteroid, concurrently, sequentially, or separately (claims 33-34 of the ‘531 application).
Regarding claim 89, claim 35 of the ‘531 application recites the same subject matter- ondanesteron, diphenhydramine hydrochloride, ranitidine.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Relevant Art not Relied Upon
Rinehart et al (WO 1991/004985 – cited in IDS filed 1/07/2026) teach dehydrodidemnin B (plitidepsin) in its biological activity. The peptide was found to have activity against herpes simplex virus type 1 (HSV-1) (p. 6, Ex 2). Herpes simplex virus is a double stranded DNA virus.
However, the reference does not teach or suggest treatment of a coronavirus (positive-sense, single-stranded RNA).
Accordingly, the instant claims are free of the prior art.
Conclusion
No claims are allowed.
Claims 71 and 73-97 are pending and rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA M HELLMAN whose telephone number is (571)272-2836. The examiner can normally be reached M-F 9:00 am-5:30 pm.
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, LIANKO GARYU can be reached at 571-270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KRISTINA M HELLMAN/Examiner, Art Unit 1654