DEAILED 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 .
Claim Status
Applicant’s submission filed 02/17/2026 has been received and entered. Claims 2, 14-21 and 30 have been cancelled. Claims 1, 8, 12, 13, 27 and 28 have been amended. Claims 31-40 have been new added. Accordingly, claims 1, 3-13, 22-29 and 31-40 are pending and under current examination.
Status of Prior Rejection/Response to Arguments
The objection to claim 8, 12 and 13 is withdrawn:
Applicant’s amendment to claims 8, 12 and 13 obviates the current objection on record. The objection is withdrawn.
The rejection to claims 14-21 and 27-28 under 35 U.S.C. §112(b) is withdrawn:
The cancellation of claims 14-21 renders the rejection thereto moot.
Applicant’s amendment to claim 1 adds the table regarding the score, claims 27 and 28 depend upon claim 1, are therefore definite in scope. The rejection is withdrawn.
The rejection to claim 2 under 35 U.S.C. §112(d) is withdrawn:
The cancellation of claim 2 renders the rejection thereto moot. The rejection is withdrawn.
The rejection to claim 30 under 35 U.S.C. §102(a)(1) and (a)(2) is withdrawn:
The cancellation of claim 30 renders the rejection thereto moot. The rejection is withdrawn.
The rejection to claims 1-4, 8-10 and 12-29 under 35 U.S.C. §103 over Hirschman et al. in view of Zhu et al., as evidenced by WHO is maintained:
The rejection to claims 1-10 and 12-29 under 35 U.S.C. §103 over Hirschman et al. in view of Zhu et al., as evidenced by WHO, further in view of Jiang et al., as evidenced by Greene et al. is maintained:
The rejection to claims 1-4 and 8-29 under 35 U.S.C. §103 over Hirschman et al. in view of Zhu et al., as evidenced by WHO, further in view of Dale et al., as evidenced by Herbinger et al. is maintained:
Applicant’s argumenta are fully considered but they are not persuasive.
Applicant has traversed the rejection, asserts that one of ordinary skill in the art would not have a reasonable expectation of success in combining the cited references to arrive at the claimed subject matter (Remarks, p9), for the reason that SARS-CoV-2 shares approximately 79.5% genomic homology with SARS-CoV, this similarity is not particularly high (Remarks, p9), and these viruses cause different diseases (SARS vs. COVID-19), and differ significantly in their pathogenesis, clinical course, and transmissibility (see Remarks, p10). In addition, while Hirschman may claim methods of treating SARS by administering EOM613, it lacks any experimental data indicating that EOM613 is effective for treating SARS, no mention SARS-CoV-2 (Remarks, p10). In response, the Examiner submits that it is not required that the expectation of success be a certainty; only one that is reasonable to a person of ordinary skill. In re Longi, 759 F.2d 887, 897 (Fed. Cir. 1985) (“Only a reasonable expectation of success, not absolute predictability, is necessary fora conclusion of obviousness”). In instant case, given that Zhu et al. teach that SARS-CoV-2 and SARS-CoV have similar cytokine and chemokine responses (p5, figure 2), clinical characteristics and laboratory findings (p7, table 2), chest X-ray/CT features (p9, table 3) and pulmonary pathology (p9, table 4), an ordinary skill in the art would use EOM613 which has been used for treating SARS to treat SARS-CoV-2 with a reasonable expectation of success. In addition, the Examiner submits that working examples are not required for a prior art reference, “[a] prior art reference provides an enabling disclosure and thus anticipates a claimed invention if the reference describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention; "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation." Impax Labs. Inc. v. Aventis Pharm. Inc., 468 F.3d 1366, 1383, 81 USPQ2d 1001, 1013 (Fed. Cir. 2006) (citing Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1326, 75 USPQ2d 1297, 1302 (Fed. Cir. 2005))”. See MPEP2121.III.
Applicant has further traversed the rejection, asserts that instant application has unexpected, superior results (see Remarks, p12-15, working examples as well as the submitted declaration), which are not predictable in view of the cited references (Remarks, p14). In response, the Examiner submits that while Applicant is asserting greater than expected results, there is no appropriate control for the showcase of the unexpected results. In instant case, the working examples are referring to individuals and there is no statistical analysis for a comparation between the control and experimental groups. In addition, the declaration shows that all the 23 patients are treated with EOM613, there is no control group which comprising subjects which has same sex, age, genetic background as well as underlying conditions, and the changes of sIL-2R levels and Troponin levels are only represent individuals but not groups, which is not sufficient to be demonstrated as the unexpected results. Moreover, The Examiner submits that the scope of the claims and the experimental conditions used to achieve any unexpected results must be commensurate in scope in order for a showing of unexpected results to support an argument of nonobviousness. See MPEP 716.02(d). In instant case, claims limit “selecting subjects having a COVID-19 severity score of 5 to 7”, however, the working examples only show the patient in example 4 having a score of 6, which is not sufficient to support the unexpected results as claimed.
Moreover, Applicant has also asserted that claim 1 as amended includes a step of selecting a subject having a severe SARS-CoV-2 infection (i.e., wherein the subject has a score of 5 or higher prior to initiation of treatment) for treatment. Merely teaching symptoms of SARS-CoV-1 does not equate to teaching a step of specifically selecting a subject having certain SARS-CoV-2 symptoms for treatment with EOM613. The cited references do not teach this step, nor do they provide a reasonable expectation of success in modifying Hirschman to treat severe a severe SARS-CoV-2 infection (Remarks, p11-12). In response, the Examiner submits that treat “a subject in need” (i.e., as recited in Hirschman et al.’s teaching) is inherently comprising the step of “selecting” the subject for treatment. In instant case, Hirschman et al. teach SARS is a type of atypical viral pneumonia, the infected individual may develop a dry, nonproductive cough, and the infected person may experience difficulty breathing (parag 0006), this symptom is corresponding to the COVID-19 having score of 5 or higher, which is non-invasive ventilation or high-flow oxygen. Hirschman et al. also teach a smaller group progress to a more severe form of SARS, many of whom develop acute respiratory distress syndrome and require mechanical ventilatory support (parag 0006), which is a symptom corresponding to the COVID-19 having score of 6 or higher, which is intubation and mechanical ventilation. In addition, Zhu et al. teach SARS-CoV-2 and SARS-CoV have similar cytokine and chemokine responses (p5, figure 2), clinical characteristics and laboratory findings (p7, table 2), chest X-ray/CT features (p9, table 3) and pulmonary pathology (p9, table 4). Therefore Hirschman et al.’s teaching of the method of treating SARS (including selecting and treating the symptoms corresponding to COVID-19 having score of 5 to 7), indicates that AVR118 (EOM613) can be used for the treatment (i.e., selecting and treating the subjects) of COVID-19 having a score of 5 to 7 as recited in instant claims. The rejection is maintained in modified form to address amended limitations.
New/modified grounds of rejection are set forth as necessitated by Applicant’s amendment.
New/Modified Claim Rejections
New Claim Objections
Claim 28 is newly objected to under 37 CFR 1.75 as being a substantial duplicate of claim 27. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Specifically, the independent claim 1 limits that the subjects having a COVID-19 severity score of 5 to 7, claim 27 further limits the score of claim 1 as 6 or 7, while claim 28 further limits the score of claim 1 as “6 or higher”, it has the same score of 6 or 7.
New Claim Rejections - 35 USC § 112(a)
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, 3-13, 22-29 and 31-40 are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The claims are newly rejected necessitated by Applicant’s amendment.
From M.P.E.P. § 2163, the analysis of whether the specification complies with the written description requirement calls for the examiner to compare the scope of the claim with the scope of the description to determine whether applicant has demonstrated possession of the claimed invention from the standpoint of one of skill in the art at the time the application was filed. For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. For claims drawn to a genus, possession may be shown (for example) through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus, and is an inverse function of the skill and knowledge in the art. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to
reflect the variation within the genus. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly. If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, para. 1.
Instant claims are directed to a method of treating a subject with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, comprising: selecting a subject having a COVID-19 severity score of 5 to 7, and administering a therapeutically effective amount of EOM613 to the subject. The claims demonstrate the description of the scores used. The claims encompass ALL subjects having COVID-19 and a severity score of 5 to 7 for the disease. The subjects are not limited in, for instance, human or non-human animal, sex, age, weight, genetic backgrounds or underlying conditions. Therefore the scope of the claim is very broad. The issue at hand is whether or not Applicants have possession of the full scope of the subject and a method of treating the subject at the time the application was filed.
In the instant case, Applicants have failed to provide disclosure of species which are representative of the full scope of the genus of the claimed subject. The dependent claims 9-10 limit the subject is human, and the subject is at least 75 years old. In the specification, only working example 4 refers the patient has a score of 6, other examples, for instance, example 5 is the patient with a score of 4, examples 2 and 3 do not refer to the scores. Therefore only one subject in the specification is accommodated in the scope of instant claims. Specification does not identify any other species of subject represent the scope of the claims, or a result of predictability in effect to the species (e.g., comparing with the subjects with same conditions without the treatment). As such, the instant specification does not provide a sufficient representative sampling of species of the subject and the method of treatment encompassed in claims.
Furthermore, Applicant has failed to provide disclosure of relevant, identifying characteristics, such as the functional characteristics (i.e., change of cytokines related to COVID-19 severity) coupled with known or disclosed structure of EOM603. Applicant’s analysis of therapeutic effect (i.e., change of cytokines or their receptors) is based on individual patient, therefore it is not sufficient to support a structure-function relationship from Applicant’s disclosure. As such, Applicant has failed to establish a known structure- function relationship wherein the genus of structures of EOM603 is capable of treating a subject having a COVID-19 severity score of 5 to 7 by changing the levels of cytokines or their receptors (i.e., sIL-2R) or other markers with any predictability. Thus, one of ordinary skill in the art, in looking to the instant specification, would not be able to determine that Applicant was in possession of the invention, as claimed, at the time the invention was made.
New Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is newly rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The independent claim 1 is directed to a method of treating a subject with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the subject is having a COVID-19 severity score of 5 to 7. Given that SARS-CoV-2 is the specific coronavirus responsible for causing COVID-19. This recitation indicates that the subject has COVID-19. Therefore claim 3 fails to further limit the subject matter of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
New and Modified Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3-4, 8-10, 12-13, 22-29 stand rejected and claims 31-40 are newly rejected under 35 U.S.C. 103 as being unpatentable over Hirschman et al. (WO 2006/091222 A2, published in 2006, cited in IDS) in view of Zhu et al. (Respir Res. 2020 Aug 27;21(1):224), as evidenced by Friedland et al. (US 6,528,098 B2, patented in 2003) and Januzzi (Advances in Motion, published 06/05/2020). The rejection is modified as necessitated by Applicant’s amendment.
Hirschman et al. teach methods for treating Several Acute Respiratory Syndrome (SARS). Specifically, methods for treating patients having SARS comprising administering an effective amount of AVR118, alone or in combination with another medicament, are disclosed (Abstract).
Regarding claim 1, Hirschman et al. teach prophylactic and therapeutic protocols for the prevention, treatment, management or amelioration of a SARS- associated coronavirus infection or one or more symptoms thereof, comprising administering to a patient in need thereof an effective amount of AVR118 (parag 0013). AVR118 is alternative name of product EOM613 as recited in instant claim. Hirschman et al. teach the function of AVR118: AVR118 is an immunomodulator with a favorable safety profile affecting the production of pro-inflammatory chemokines and cytokines, driving the immune response towards a normal state. In particular, AVR118 modulates the expression of chemokines and cytokines. AVR118 stimulates macrophages to produce pro-inflammatory cytokines and chemokines, including MCP-1, IL-8 and IL-6. On the other hand, in highly activated macrophages, AVR118 inhibits the synthesis of these pro-inflammatory chemokines (parag 0011). Hirschman et al. teach prophylactic and therapeutic protocols for the prevention, treatment, management or amelioration of a SARS- associated coronavirus infection or one or more symptoms thereof, comprising administering to a patient in need thereof an effective amount of AVR118 (parag 0013). Herein administering to “patient in need” comprises the step of “selecting” a subject (which has a disease needs AVR118 administration) as recited in instant claim and give the subject a treatment. Hirschman et al. also teach SARS is a type of atypical viral pneumonia, the infected individual may develop a dry, nonproductive cough, and the infected person may experience difficulty breathing (parag 0006), this symptom is corresponding to the COVID-19 having score of 5 or higher, which is non-invasive ventilation or high-flow oxygen. Hirschman et al. also teach a smaller group progress to a more severe form of SARS, many of whom develop acute respiratory distress syndrome and require mechanical ventilatory support (parag 0006), which is a symptom corresponding to the COVID-19 having score of 6, which is intubation and mechanical ventilation. Therefore Hirschman et al. teach the method of treating SARS (including selecting and treating the symptoms corresponding to COVID-19 having score of 5 to 6).
Hirschman et al. teach using an effective amount of AVR118 (EOM613) for treating subjects having symptoms corresponding to COVID-19 having score of 5 to 6, but do not specifically teach using an effective amount of AVR118 (EOM613) for treating subjects having a COVID -19 severity score of 5 to 7. However, this is prima facie obvious in view of Zhu et al..
Zhu et al. summarize the cutting-edge knowledge and to provide an update of the major features of SARS-CoV, MERS-CoV, and SARS-CoV-2 in terms of animal hosts, morphology and genome
organization, cellular entry and viral transmission, and cytokine and chemokine responses (p2, right column).
Regarding claim 1, Zhu et al. teach three documented highly pathogenic and lethal human coronaviruses (hCoVs), namely SARS-CoV, MERS CoV and SARS-CoV-2, because of their dreadful impacts on humans (p2, left column). SARS-CoV-2 shares approximately 79.5% genomic homology with SARS-CoV (p4, left column). Zhu et al. also teach SARS-CoV-2 and SARS-CoV have similar cytokine and chemokine responses (p5, figure 2), clinical characteristics and laboratory findings (p7, table 2), chest X-ray/CT features (p9, table 3) and pulmonary pathology (p9, table 4), also states that many researchers are focused on the application of cytokine-based interventions, including immune inhibitors (such as inhibitors of IL-6, IFN-. and TNF-a) in the therapy of COVID-19, and some of these inhibitors showed enthusiastic results (such as IL-6 inhibitor) (p5, right column-p6, left column).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Hirschman et al.’s method of treating SARS using EOM613 (AVR118), and use EOM613 (AVR118) for treating SARS-CoV-2 subjects such as subjects having a COVID-19 severity score of 5 to 7, based on the comparation study between SARS and COVID-19 as taught by Zhu et al.. The only difference between instant claim and Hirschman et al.’s method of treating SARS using EOM613 (AVR118) is instant claim use EOM613 (AVR118) for treating SARS-CoV-2 subjects such as subjects having a COVID-19 severity score of 5 to 7. Given that Hirschman et al. teach AVR118 is an immunomodulator with a favorable safety profile affecting the production of pro-inflammatory chemokines and cytokines, driving the immune response towards a normal state (i.e., adjust the expression of IL-6 to normal state, see parag 0011), and Zhu et al. teach SARS-CoV-2 and SARS are similar coronavirus which share approximately 79.5% genomic homology, and cause similar cytokine and chemokine responses (see p5) and adjust IL-6 level is effective for the treatment of COVID-19 (see p5, right column), one of ordinary skill in the art would have substituted Hirschman et al.’s method of treating SARS using EOM613 (AVR118), and use EOM613 (AVR118) for treating SARS-CoV-2 depends on their preference for the treatment. This simple substitution of one known element (using EOM613 (AVR118) for the treatment of SARS-Cov-2 subjects such as subjects having a COVID-19 severity score of 5 to 7) for another known element (using EOM613 (AVR118) for the treatment of SARS-Cov) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claim 3, Hirschman et al. teach AVR118 is administered to a subject prophylactically, when, for example, the subject is at increased risk of a SARS-associated coronavirus infection (parag 0057). In other embodiments, AVR118 is administered to a patient at an early phase of a SARS-associated coronavirus infection. In yet other embodiments, a pharmaceutical composition of the invention is administered to a patient at later stages of a SARS-associated coronavirus infection to, e.g., prevent the consequences of a progressive SARS-associated coronavirus infection in the subject affected (parag 0057).
Regarding claim 4, Hirschman et al. teach the objectives of AVR118 therapy in SARS include, but are not limited to, reduction in fever to less than 101 °F, disappearance of chills, mitigation of dyspnea, reversal of hypoxia, stabilization of blood pressure, reduction of tachycardia, and disappearance of general malaise (e.g., a return of energy and/or a return of appetite)(parag 0078). This teaching indicates that AVR118 is also eligible for treating i.e., hypoxia associated with SARS-CoV-2, as recited in instant claim. Moreover, it is inherent property that same method using same product would having same effect. [w]hen the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978). MPEP 2112.02.
Regarding claims 8 and 10, Hirschman et al. teach in certain embodiments, AVR118, alone or in combination with another medicament, is administered to an elderly human patient, an infant human patient, or an immunocompromised or immunosuppressed patient (parag 0055). This teaching indicates an elderly human patient which can be “a subject is at least 75 years old” in instant claim 10, and an immunosuppressed patient which has “suppressed immune system due to medical treatment” as recited in instant claim 8.
Regarding claim 9, Hirschman et al. teach the invention provides AVR118-based therapies for the prevention, treatment, management or amelioration of a SARS-associated coronavirus infection or one or more symptoms thereof. In preferred embodiments of the invention, the patient is a human (parag 0013).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Hirschman et al.’s method of treating SARS using EOM613 (AVR118), and use EOM613 (AVR118) for treating SARS-CoV-2 to a subject (i.e., human) having a score of 5 to 7, who is elderly patient (i.e., at least 75 years old) or having underlying medical conditions (i.e., immunosuppressed patient due to medical treatment), based on the comparation study between SARS and COVID-19 as taught by Zhu et al.. The only difference between instant claims and Hirschman et al.’s method of treating SARS using EOM613 (AVR118) is instant claims having subjects (i.e., human) who is elderly patient (i.e., at least 75 years old) or having underlying medical conditions (i.e., immunosuppressed patient due to medical treatment) infected with SARS-CoV-2, and use EOM613 (AVR118) for the treatment. Given that Hirschman et al. teach AVR118 is an immunomodulator with a favorable safety profile affecting the production of pro-inflammatory chemokines and cytokines, driving the immune response towards a normal state (i.e., adjust the expression of IL-6 to normal state, see parag 0011), and Zhu et al. teach SARS-CoV-2 and SARS are similar coronavirus which share approximately 79.5% genomic homology, and cause similar cytokine and chemokine responses (see p5) and adjust IL-6 level is effective for the treatment of COVID-19 (see p5, right column), one of ordinary skill in the art would have substituted Hirschman et al.’s method of treating SARS using EOM613 (AVR118), and use EOM613 (AVR118) for treating the subjects (i.e., human) who is elderly patient (i.e., at least 75 years old) or having underlying medical conditions (i.e., immunosuppressed patient due to medical treatment) infected with SARS-CoV-2, depends on their preference for the treatment. This simple substitution of one known element (using EOM613 (AVR118) for the treatment of SARS-Cov-2 to a subject having a score of 5 to 7, who is elderly patient or having underlying medical conditions) for another known element (using EOM613 (AVR118) for the treatment of SARS-Cov) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claims 12 and 13, Zhu et al. teach cytokine storm caused by COVID-19 (p6, figure 2), cytokines such as IL-6 increases. Zhu et al. also teach the laboratory findings of SARS and COVID-19 patients are greatly similar, of whom the commonest abnormal laboratory findings are lymphocytopenia and thrombocytopenia. In addition, the serum levels of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase and C-reactive protein are significantly elevated. Coagulation disorders characterized by elevated D-dimer level and prolonged prothrombin time are common, especially in severe patients (p8, right column). Therefore Zhu et al. teach the subject with SARS-Cov-2 has an elevated level of D-dimer, C-reactive protein and cytokine. Hirschman et al. do not directly teach the administering the therapeutically effective amount of EOM613 to the subject decreases the elevated level to a non-detectable or a normal level, however, Hirschman et al. teach AVR118 is an immunomodulator with a favorable safety profile affecting the production of pro-inflammatory chemokines and cytokines, driving the immune response towards a normal state (parag 0011). This teaching indicates administering the therapeutically effective amount of AVR118 (EOM613) to the subject is able to regulate inflammatory state towards a normal state, therefore decrease the elevated level of i.e., cytokines, or C-reactive protein which is known as a pro-inflammatory marker. Moreover, it is inherent property that same method using same product would having same effect. [w]hen the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978). MPEP 2112.02.
Regarding claim 22, Hirschman et al. teach in certain embodiments of the invention, AVR118 is administered parenterally, topically or systemically (parag 0014).
Regarding claim 23, Hirschman et al. teach for administration by inhalation, the compounds for use according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant (parag 0085).
Regarding claim 24, Hirschman et al. teach typical routes of administration for AVR118 may include, without limitation, oral, topical, parenteral, sublingual, rectal, vaginal, ocular, and intranasal.
Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intraperitoneal, intrapleural, intrastemal injection or infusion techniques (parag 0065).
Regarding claims 25-26, Hirschman et al. teach methods for preventing, treating, managing or ameliorating a SARS-associated coronavirus infection, said method comprising administering to a patient in need thereof (1) an effective amount of AVR118, and (2) an effective amount of another medicament (parag 0015). Examples of medicaments that can be used in combination with AVR118 to prevent, treat, manage or ameliorate a SARS-associated coronavirus infection, or a symptom thereof, include, but are not limited to, an antiviral agent, an antibiotic, an immunomodulatory agent, an anti-inflan1matory agent, and an antibody that immunospecifically binds to a SARS-associated coronavirus antigen (parag 0018).
Regarding claims 27 and 28, following the discussion above, Hirschman et al. teach prophylactic and therapeutic protocols for the prevention, treatment, management or amelioration of a SARS- associated coronavirus infection or one or more symptoms thereof, comprising administering to a patient in need thereof an effective amount of AVR118 (parag 0013). Hirschman et al. also teach a smaller group progress to a more severe form of SARS, many of whom develop acute respiratory distress syndrome and require mechanical ventilatory support (parag 0006), which is a symptom corresponding to the COVID-19 having score of 6 or 7, which is intubation and mechanical ventilation. Therefore Hirschman et al.’s teaching of the method of treating SARS (including the symptoms corresponding to COVID-19 having score of 6 or higher indicates that AVR118 (EOM613) can be used for the treatment of COVID-19 having score of 6 or 7, as recited in instant claims.
Regarding claim 29, following the discussion above, Hirschman et al. teach anti-viral agents useful in the methods and compositions of the invention include, but are not limited to, cytokines (e.g., IFN-a, IFN-J3, and IFN-y); inhibitors of reverse transcriptase (e.g., AZT (zidovudine), 3TC (lamivudine), d4T (stavudine), ddC (dideoxycytidine ), ddl (didanosine), abacavir, adefovir, delavirdine, efavirenz, nevirapine, and other dideoxynucleosides or dideoxyfluoronucleosides); inhibitors of viral mRNA
capping, such as ribavirin and ribavirin analogs; inhibitors of proteases such HIV protease inhibitors (e.g., amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir); amphotericin B; castanospermine as an inhibitor of glycoprotein processing; inhibitors of neuraminidase such as influenza virus neuraminidase inhibitors (e.g., oseltamivir and zanamivir); topoisomerase I inhibitors (e.g., camptothecins and analogs thereof); acyclovir, adefovir, dipoxil, amantadine, cidofavir, famciclovir, foscamet, ganciclovir, gangcyclovir, idoxuridine, rimantadine, trifluridine, vidarabine, and zalciltabine (parag 0019).
Regarding claims 31, Hirschman et al. teach method for preparing AVR118 (see parag 0096-0097): Hirschman et al. teach combining and dissolving casein, beef peptone, RNA, BSA and sodium hydroxide in step (i), autoclaving at about 9 lbs of pressure and 200-230 °F for about 4 hours, cooling for at least six hours at about 3-8° C in step (ii), filtering through 2 micron and 0.45 micron and then filtering again through 0.2 micron in step (iii), and a diluted filtrate with a nitrogen content between about 165-210 mg/100 ml, the pH was then adjusted to about 7.3-7.6, the diluted solution was then filtered again through 0.2 micron filters with inert gas at low pressure in steps (iv) and (v). The only difference between instant claim and Hirschman et al. is Hirschman et al. teach using weight (gram) of casein, beef peptone, RNA, BSA and sodium hydroxide in water, but not the amount in (%) as recited in step (i) of instant claims. However, Hirschman et al. referring that Friedland et al. (US patent 6,528,098, Hirschman as a co-inventor) disclose the preparation of AVR118, which provides evidence the use of amount in (%) of casein, beef peptone, RNA, BSA and sodium hydroxide.
Friedland et al. teach Product R, a novel therapeutic composition for treating viral infections and stimulating the immune system, comprises a unique peptide having 31 amino acids and another unique
peptide having 21 amino acids and connected with an oligo-nucleotide through a diphosphodiester or diphosphodithioate ester linkage (Abstract). Regarding claim 30, Friedland et al. teach preparing product R (the alternative name of EOM613 or AVR118, see Hirschman et al. parag 0010), the starting materials casein, beef peptone, RNA, BSA, and sodium hydroxide are suspended in proportions of, by weight, 35-50% (casein), 15-40% (beef peptone), 10-25% (RNA), 1-10% (BSA) and 5-25% (sodium hydroxide) in an appropriate volume of distilled water. yeast RNA is the most preferred. The ratio of total proteins versus the volume of distilled water is generally about 1.5-2.5 to about 100 by weight (parag 0035), this teaching reads on the step (i) as recited in instant claim. This teaching indicates that Hirschman et al. as evidenced by Friedland et al. teach the same method of preparation of EOM613 as recited in instant claim.
Regarding claims 32-34, following the discussion above, Hirschman et al. teach the same method of producing AVR118. Hirschman et al. teach in certain embodiments, the amount of AVR118 effective for the prevention, treatment, management or amelioration of SARS is in a range from about 0.5 microliters to about 100 microliters per kilogram of body weight per day, or from about 2.5 microliters to about 40 microliter per kilogram of body weight per day, or from about 10 microliters to
about 25 microliters per kilogram of body weight per day (parag 0014). Moreover, it is not inventive to find optimal workable ranges by routine experimentation. See Jn re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claims 35-39, following the discussion above, Hirschman et al. teach the dose of AVR118 for treatment of SARS is four ml (2 vials) per day. This can be administered as a dose of two ml subcutaneous every 12 hours or 1 ml subcutaneous every six hours (parag 00109). The duration of therapy in patients with SARS should be ten days. The minimum treatment should be five days if all symptoms of SARS abate in the patient (parag 00111). Moreover, it is not inventive to find optimal workable ranges by routine experimentation. See Jn re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 40, following the discussion above, Hirschman et al. teach in certain embodiments of the invention, AVR118 is administered parenterally, topically or systemically (parag 0014). Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intraperitoneal, intrapleural, intrasternal injection or infusion techniques (parag 0065). Hirschman et al. also teach the desired dose may be administered once a day or in two, three or more sub-doses at appropriate intervals, generally equally spread in time, throughout the day (parag 0064). Hirschman et al. do not teach the subject has elevated troponin levels prior to treatment and treatment with EOM613 decreases troponin levels to a non-detectable or a normal level. However, given that Hirschman et al. in view of Zhu et al. renders obvious to the method of treating COVID-19, and Januzzi provide evidence that COVID-19 patient has an elevated troponin, this teaching reads on the subject has elevated troponin levels prior to treatment. Regarding the effect of treatment with EOM613 decreases troponin levels to a non-detectable or a normal level, it is considered as inherent property that same method using same product would having same effect. [w]hen the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978). See MPEP 2112.02.
Claims 1, 3-10, 12-13, 22-29 stand rejected and claims 31-40 are newly rejected under 35 U.S.C. 103 as being unpatentable over Hirschman et al. (WO 2006/091222 A2, published in 2006, cited in IDS) in view of Zhu et al. (Respir Res. 2020 Aug 27;21(1):224), as evidenced by Friedland et al. (US 6,528,098 B2, patented in 2003) and Januzzi (Advances in Motion, published 06/05/2020), as applied to claims 1, 3-4, 8-10, 12-12, 22-29 and 31-40 above, and further in view of Jiang et al. (Lancet Infect Dis 2020;20: e276–88, published Online August 17, 2020), as evidenced by Greene et al. (Am J Emerg Med. 2020 Nov;38(11):2492.e5-2492.e6, published online June 6). The rejection is modified as necessitated by Applicant’s amendment.
The teaching of Hirschman et al. and Zhu et al. is set forth above.
Regarding claims 5-7, Hirschman et al. and Zhu et al. do not teach administering to the subject an amount of EOM613 effective to inhibit SARS-CoV-2 induced multisystem inflammatory syndrome. However, this is prima facie obvious in view of Jiang et al..
Jiang et al. review the epidemiology, causes, clinical features, and current treatment protocols for multisystem inflammatory syndrome in children and adolescents associated with COVID-19, discuss the possible underlying pathophysiological mechanisms for COVID-19-induced inflammatory processes, which can lead to organ damage in pediatric patients who are severely ill (Abstract).
Regarding claim 5, Jiang et al. teach COVID-19-associated multisystem inflammatory syndrome in children and adolescents is referred to interchangeably as pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) or multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 (p e276). Because clinical and laboratory features of MIS-C overlap with those of Kawasaki disease, Kawasaki disease shock syndrome, and macrophage activation syndromes, patients with severe MIS-C have received immunomodulatory agents such as infliximab
(anti-tumour necrosis factor drug), tocilizumab (IL-6 antagonist), and anakinra (IL-1 receptor
antagonist), which have been shown to be effective in similar diseases (p e282).
Regarding claims 6 and 7, following the discussion above, Jiang et al. teach immunomodulatory agents that adjust IL-6 is effective to COVID-19 caused MIS-C, which is evidenced by Greene et al.. Greene et al. teach a case of MIS-C in a child who presented to Emergency Department (ED) twice and on the second visit was found to have signs of distributive shock, multi-organ injury and systemic inflammation associated with COVID-19 (Abstract). Greene et al. teach full-dose anticoagulation with enoxaparin was initiated and the patient was also given Vitamin K to correct elevated PT and INR. IL-6 was elevated to 1449 (0.0–15.5 pg/mL) and tocilizumab, an IL-6 inhibitor, was started along with convalescent plasma and remdesivir. The patient received steroids and IVIG for possible incomplete Kawasaki. She improved dramatically; within <24 h, she no longer required pressors and was afebrile without tachycardia (p2492.e6). This teaching indicated the treatment including adjusting level of IL-6 reduce the organ damage to the heart (disappear of tachycardia) as recited in instant claim 6 in the subject, which is a child as recited in instant claim 7.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Hirschman et al.’s method of treating SARS using EOM613 (AVR118), and use EOM613 (AVR118) for treating a subject (i.e., a child) has a COVID score of 5 to 7, who is having multisystem inflammatory syndrome caused by COVID-19, as taught by Jiang et al. and Greene et al.. The only difference between instant claims and Hirschman et al.’s method of treating SARS using EOM613 (AVR118) is instant claims use EOM613 (AVR118) for treating a subject (i.e., a child) who is having multisystem inflammatory syndrome caused by COVID-19. Given that Hirschman et al. teach AVR118 is an immunomodulator with a favorable safety profile affecting the production of pro-inflammatory chemokines and cytokines, driving the immune response towards a normal state (i.e., adjust the expression of IL-6 to normal state, see parag 0011), and Jiang et al. and Greene et al. teach patients with severe MIS-C have received immunomodulatory agents such as tocilizumab (IL-6 antagonist) has been shown to be effective in similar diseases, one of ordinary skill in the art would have substituted Hirschman et al.’s method of treating SARS using EOM613 (AVR118), and use EOM613 (AVR118) for treating the subjects (i.e., a child) who is having multisystem inflammatory syndrome caused by COVID-19, depends on their preference for the treatment. This simple substitution of one known element (using EOM613 (AVR118) for the treatment of SARS-Cov-2 caused multisystem inflammatory syndrome) for another known element (using EOM613 (AVR118) for the treatment of SARS-Cov) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Claims 1, 3-4, 8-13, 22-29 stand rejected and claims 31-40 are newly under 35 U.S.C. 103 as being unpatentable over Hirschman et al. (WO 2006/091222 A2, published in 2006, cited in IDS) in view of Zhu et al. (Respir Res. 2020 Aug 27;21(1):224), as evidenced by Friedland et al. (US 6,528,098 B2, patented in 2003) and Januzzi (Advances in Motion, published 06/05/2020), as applied to claims 1, 3-4, 8-10, 12-13, 22-29 and 31-40 above, and further in view of Dale et al. (WO 2012/158707 A1), as evidenced by Herbinger et al. (Am. J. Trop. Med. Hyg., 94(6), 2016, pp. 1385–1391). The rejection is modified as necessitated by Applicant’s amendment.
The teaching of Hirschman et al. and Zhu et al. is set forth above.
Regarding claim 11, Zhu et al. teach clinical characteristics and laboratory findings of COVID-19 (p7, table 2), wherein the lymphopenia (<1.5 X 109/L) happens in 55.3% of the COVID patients. Hirschman et al. and Zhu et al. do not teach administering the therapeutically effective amount of EOM613 to the subject increases lymphocyte count in the subject to a range of 20-40% of white blood cells. However, this was disclosed by Dale et al. at the time of instant invention.
Dale et al. teach methods and compositions for treating or preventing WHIM syndrome and certain other disorders or conditions with a certain CXCR4 antagonist (Abstract).
Regarding claim 11, Dale et al. teach subcutaneous administration of single doses of CXCR4 antagonists plerixafor can transiently correct neutropenia and lymphocytopenia in patients with
myelokathexis/WHIM syndrome (parag 00109). Dale et al. also teach suitable CXCR4 antagonists for the instantly disclosed methods and compositions also include the CXCR4 antagonist AVR118 (parag 0048). This teaching indicates AVR118 also be able to correct neutropenia and lymphocytopenia, which means increase lymphocyte count in the subject to a range of 20-40% of white blood cells (a normal range of lymphocyte count as evidenced by Herbinger et al., see p1385, left column) as recited in instant claim. Moreover, it is inherent property that same method using same product would having same effect. [w]hen the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978). MPEP 2112.02.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Hirschman et al.’s method of treating SARS using EOM613 (AVR118), and use EOM613 (AVR118) for treating a subject has a COVID score of 5 to 7, who has lymphocytopenia due to the SARS-CoV-2 infection, as taught by Zhu et al. and Dale et al.. The only difference between instant claims and Hirschman et al.’s method of treating SARS using EOM613 (AVR118) is instant claims use EOM613 (AVR118) for treating a subject a subject has lymphocytopenia due to the SARS-CoV-2 infection. Given that Zhu et al. teach lymphopenia (<1.5 X 109/L) happens in 55.3% of the COVID patients, and Dale et al. teach AVR118 is able to correct neutropenia and lymphocytopenia, one of ordinary skill in the art would have substituted Hirschman et al.’s method of treating SARS using EOM613 (AVR118) as an immunomodulator, and use EOM613 (AVR118) for treating the subjects has lymphocytopenia due to the SARS-CoV-2 infection. This simple substitution of one known element (using EOM613 (AVR118) for the treatment of SARS-Cov-2 caused lymphocytopenia) for another known element (using EOM613 (AVR118) for the treatment of SARS-Cov) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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