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 .
DETAILED ACTION
This Office Action is in response to Applicant’s Arguments and Amendment filed, 11/10/2025, wherein the Amendment amended claims 1 and 7.
Claims 1-8 are pending.
Priority
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Applicant’s amendment to claims 1 and 7 that delete “budesonide” and “prednisolone,” affords the instant claims an effective filing date of 05/11/2021.
Election/Restrictions
Applicant elected Group I, the composition comprising centhaquine and “(c),” in the reply filed on 05/01/2023.
In the course of the search, the species election was broadened to include corticosteroids in (b) and excipient in (f).
Claims 2-6, and 8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and subject matter, there being no allowable generic or linking claim.
It is noted that claim 8 was added in the amendment filed 11/14/2023. This claim is directed toward non-heparin anticoagulants, which are not elected species.
Claims 1 and 7 are examined on the merits herein.
REJECTIONS WITHDRAWN
The status for each rejection and/or objection in the previous Office Action is set out below.
35 U.S.C. § 112(a)-New Matter
Applicant’s amendment to claim 1 that deletes “supportive therapies to reduce fever consisting of steroids,” is sufficient to overcome this rejection.
35 USC § 103 over WO 2021/262799 to Tam in view of Gonzales-Zamora, and NCT05241067
As discussed above, Applicant’s deletion of “budesonide” and “prednisolone,” affords the instant claims an effective filing date of 05/11/2021. As such, NCT05241067, which has a publication date of 02/14/2022, is not prior art.
REJECTIONS—Maintained, Modified, & New
Applicant’s amendments to independent claim 1 and to claim 7 have resulted in the below new and modified rejections.
Claim Interpretation
Regarding claim 1, the transitional term “comprising” is an open-ended term that does not exclude additional, unrecited elements, while the transitional term “consisting of” is a closed transitional term that excludes any ingredient not specified in the claim. See MPEP 2111.03.
Claim 1 recites:
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Since the composition comprises a combination consisting of (a)-(d), the composition can contain additional, unrecited elements, i.e., components/ingredients other than that recited in (a)-(d). As such, the phrase “A pharmaceutical composition. . .comprising a combination consisting of. . .(a). . .and (d) an excipient,” is interpreted as “A pharmaceutical composition. . .comprising (a). . .and (d) an excipient.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
(Slightly modified) Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/262799 to Tam (effectively filed 06/23/2020, PTO-892 of 07/11/2025) in view of Gonzales-Zamora, (Successful treatment with Remdesivir and corticosteroids in a patient with COVID-19-associated pneumonia: A case report, Medwave, published 2020, PTO-892 of 07/11/2025), Hyoju (SARS-CoV-2 and the sympathetic immune response: Dampening inflammation with antihypertensive drugs (Clonidine and Propranolol), Medical Hypotheses, published 2020, PTO-892 of 07/11/2025), and Gulati (Resuscitative Effect of Centhaquine (Lyfaquin) in Hypovolemic Shock Patients: A Randomized Multicentric Controlled Trial, Adv Ther, published 05/10/2021, PTO-892 of 07/11/2025).
Tam teaches a composition comprising a) urolithin A or B, or ellagic acid, b) remdesivir, and c) a pharmaceutically acceptable carrier or excipient, wherein the composition can comprise at least one additional therapeutic agent selected from a second anti-viral agent, an anti-inflammatory agent, an anticoagulant, and an analgesic, such as those in Table 2, (pgs. 55-56, claims 41-43, 51-55). Tam teaches centhaquine and corticosteroids as additional therapeutic agents in Table 2 ([0047]; pg. 55, claim 43).
Tam teaches its compositions for the treatment of Covid-19 (Abstract.
pg. 52, claims 7-8; pg. 54, claims 26-27).
While Tam teaches a composition comprising remdesivir and excipient and further teaches corticosteroids, such as dexamethasone and centhaquine as compounds that can be further added to its composition, it differs from that of instant claim 1 in that it does not teach a composition comprising centhaquine, remdesivir, corticosteroid, and excipient.
Gonzales-Zamora teaches the successful treatment of a patient with covid-19 associated pneumonia by administering remdesivir in combination with the corticosteroid methylprednisolone, to counteract the direct viral damage produced by COVID and at the same time, controlling the inflammatory response induced by the virus (abstract; “Conclusions”).
Hyoju teaches that a respiratory viral infection is a stress that activates the sympathetic nervous system resulting in release of norepinephrine, which exerts pro-inflammatory action via augmenting the production of macrophage derived TNFalpha through alpha2 adrenoceptors. Chronic exposure to norepinephrine during these stressed states can inhibit T cell proliferation and can enhance the production of inflammatory chemokine and cytokines, making people more vulnerable to viral infections (pg. 1, final paragraph-pg. 2, 1st paragraph). Hyoju teaches that attenuating the effects of sympathetic nervous system by beta2 adrenoreceptor antagonists or alpha2-adrenoreceptor agonists are plausible immunomodulatory options available to prevent over activation of immune system and its harmful effect (pg. 2, 1st paragraph). Hyoju teaches that people with chronic sympathetic hyperactive comorbid conditions who contract SARS-CoV-2 virus, can potentially drive the infection towards a fatal outcome, which can be attenuated by alpha 2 agonists to override T cell exhaustion, cytokine spillage and impaired clearance of virus (pg. 2, “The hypothesis”).
Gulati teaches centhaquine as an alpha adrenergic receptor agonist (pg. 3259, 1st full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to select centhaquine and the steroid, methylprednisolone, as additional therapeutic agents in the composition of Tam, to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such selections, with a reasonable expectation of success, because:
-Tam, Gonzales-Zamora, and Hyoju, all teach methods of treating COVID-19,
-Tam teaches centhaquine and corticosteroids as additional therapeutic agents for use in its compositions,
-Gonzales-Zamora teaches that combining corticosteroids with remdesivir counteracts the direct viral damage produced by COVID and at the same time, controls the inflammatory response induced by the virus,
-Hyoju teaches that people with chronic sympathetic hyperactive comorbid condition, who contract SARS-CoV-2 virus, can potentially drive the infection towards a fatal outcome, wherein this outcome can be attenuated by alpha 2 agonists to override T cell exhaustion, cytokine spillage and impaired clearance of virus,
-Hyoju teaches that patients harboring such comorbid conditions are the most vulnerable to SARS-CoV-2 (pg. 1, “Introduction”), and
-Gulati teaches centhaquine as an alpha2 adrenergic receptor agonist.
As such, an artisan having ordinary skill in the art would have been motivated to make such selections, to predictably arrive at a composition that effectively treats COVID-19 in subjects by controlling inflammation, and by attenuating T-cell exhaustion, cytokine spillage, and impaired clearance of virus.
The phrase “for treating acute respiratory distress syndrome” is interpreted as an intended use recitation. The intended use of a composition is being considered only to the extent that it limits the structure of the composition; it is not treated as a process of using claim. Since the combined composition of Tam, Gonzales-Zamora, Hyoju, and Gulati is capable of performing the intended use, it meets the limitations of the claim. See MPEP 2112.01 and 2111.02.
(Maintained) Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/262799 to Tam (effectively filed 06/23/2020, PTO-892 of 07/11/2025), Gonzales-Zamora, (Successful treatment with Remdesivir and corticosteroids in a patient with COVID-19-associated pneumonia: A case report, Medwave, published 2020, PTO-892 of 07/11/2025), Hyoju (SARS-CoV-2 and the sympathetic immune response: Dampening inflammation with antihypertensive drugs (Clonidine and Propranolol), Medical Hypotheses, published 2020, PTO-892 of 07/11/2025), and Gulati (Resuscitative Effect of Centhaquine (Lyfaquin) in Hypovolemic Shock Patients: A Randomized Multicentric Controlled Trial, Adv Ther, published 05/10/2021, PTO-892 of 07/11/2025), as applied to claim 1, above, and further in view of Prescott (Corticosteroids in COVID-19 ARDS, JAMA, published 2020, PTO-892 of 07/11/2025).
Tam, Gonzales-Zamora, Hyoju, and Gulati are applied as discussed above and incorporated herein.
While the combination of Tam, Gonzales-Zamora, Hyoju, and Gulati teaches a composition comprising centhaquine, remdesivir, corticosteroid, and excipient, it differs from that of instant claim 7 in that it does not teach dexamethasone.
Tam specifically teaches dexamethasone as a corticosteroid that can be added to its compositions in Table 2 ([0047]; pg. 55, claim 43).
Prescott teaches that corticosteroids, such as dexamethasone, have anti-inflammatory, antifibrotic, and vasoconstrictive effects (1st sentence). Prescott teaches that the association between administration of corticosteroids and reduced mortality in COVID-19 was similar for dexamethasone and hydrocortisone, suggesting the benefit is a general class effect of glucocorticoids and not specific to any particular corticosteroid (pg. 1293, Col. 2).
Prescott teaches that in a DEXA-ARDS (acute respiratory distress syndrome) trial in patients with moderate to severe ARDS, patients receiving high dose dexamethasone had lower 60 day all-cause mortality (pg. 1292, Col. 1).
Prescott teaches that in COVID-19 patients, dexamethasone reduced mortality by one third in patients receiving mechanical ventilation (pg. 1292, Col. 2).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the effectively filed application, to substitute the methylprednisolone in the combination of Tam, Gonzales-Zamora, Hyoju, and Gulati, with dexamethasone, to arrive at instant claim 7. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Tam specifically teaches dexamethasone as a corticosteroid that can be added to its compositions,
-Prescott teaches that corticosteroids, such as dexamethasone, have anti-inflammatory, antifibrotic, and vasoconstrictive effects,
-Prescott teaches dexamethasone as decreasing mortality in COVID-19 patients,
-Prescott teaches that the association between administration of corticosteroids and reduced mortality was similar for dexamethasone and hydrocortisone, suggesting the benefit is a general class effect of glucocorticoids and not specific to any particular corticosteroid, and
-substituting equivalents known for the same purpose is prima facie obvious, see MPEP 2144.06.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive at a composition that decreases mortality in COVID-19 patients and provides anti-inflammatory, antifibrotic, and vasoconstrictive effects,
Declaration
The Declaration under 37 CFR 1.132 filed 11/10/2025 is insufficient to overcome the rejection of claims 1 and 7 based upon the 35 USC 103 rejection as set forth in the last Office action.
In paragraphs 4 and 5, Declaration, Declarant details a comparative study conducted for evaluating the effects of a) centhaquine and b) centhaquine and steroid, on PO2/FiO2 ratio of patients with hypovolemic shock. 100mg hydrocortisone alone or 100mg hydrocortisone with 20mg prednisolone or 100mg hydrocortisone with 4mg methylprednisolone, are taught as the steroid.
In paragraph 6, Declaration, Declarant states that the difference in PO2/FiO2 value between baseline, which appears to be Day 1, and Day 2 for the centhaquine group, does not result in a statistically significant change, while the difference in PO2/FiO2 value between baseline and Day 2 for the centhaquine and steroid group, results in a statistically significant improvement, and states “These data confirm that centhaquine administration along with steroids can have unexpected improvement in response of steroids by centhaquine in the lung function in patients with shock.”
These statements and data have been fully considered, but are not persuasive to overcome the instant rejections. It is first noted that the patient population of the declaration is “patients in shock” while the instant claims are directed toward “A pharmaceutical composition for treating acute respiratory distress syndrome,” wherein shock and acute respiratory distress syndrome are distinct patient populations. Moreover, Declarant has provided no data for the difference in PO2/FiO2 value between baseline and Day 2 for the steroid group alone. As such, it is not possible to evaluate if the administration of a combination of centhaquine and steroid have a synergistic effect on PO2/FiO2 value or if the PO2/FiO2 value is due to the administration of the steroid, alone. Additionally, it is not possible to evaluate if the effects are due to the administration of hydrocortisone, or hydrocortisone + prednisolone, or hydrocortisone + methylprednisolone, or if all of these steroids produce the same result. Lastly, it is not known if the same amount of centhaquine was administered in the “centhaquine” group and the “centhaquine + steroid” groups.
Declarant is further reminded that unexpected results a) are greater than expected results, b) show superiority of a property shared with the prior art, c) exhibit the presence of an unexpected property, and/or d) exhibit the absence of an expected property. MPEP 716.02 additionally states that unexpected results must be commensurate in scope with the claimed invention and provide a comparison with the closest prior art.
The instant data is not commensurate in scope with the instant claims. The instant claims are directed toward a composition comprising four components, wherein component (b) can be any one of twelve antiviral therapies or combinations thereof, and (d) can be an supportive therapy to reduce fever or any steroid, and (e) can be any excipient. However, the instant declaration is directed toward the administration of either:
-a single instantly claimed component:
centhaquine (a), or
-two instantly claimed components,
centhaquine and hydrocortisone (a) and (c),
centhaquine + hydrocortisone + prednisolone (a) and (c), or
centhaquine + hydrocortisone + methylprednisolone (a) and (c).
Moreover, it is not clear if the two instantly claimed components are administered in a
composition or if they are administered separately.
As such, the instant Declaration is not sufficient to overcome the instant prior art rejections.
Response to Arguments
On pgs. 5-6, Remarks, Applicant argues that the instant claims require a composition comprising a combination consisting of instant (a)-(d), and that the primary reference Tam, requires a compound from its Tables 1 or 3, which are not instant (a)-(d).
This argument has been fully considered, but is not found persuasive. Tam teaches a composition comprising a) urolithin A or B, or ellagic acid, b) remdesivir, and c) a pharmaceutically acceptable carrier or excipient, wherein the composition can comprise at least one additional therapeutic agent selected from a second anti-viral agent, an anti-inflammatory agent, an anticoagulant, and an analgesic, such as those in Table 2, (pgs. 55-56, claims 41-43, 51-55). Tam teaches centhaquine and corticosteroids as additional therapeutic agents in Table 2 ([0047]; pg. 55, claim 43).
As discussed in the above claim interpretation, the term “comprising” is open ended and does not exclude additional unrecited elements. Thus, the instantly claimed composition, as recited in claim 1, can contain additional, components/ingredients.
Secondary references Gonzales-Zamora, Hyoju and Gulati are relied upon to provide motivation to specifically select centhaquine and corticosteroid as the additional components in its compositions.
As such, this argument is not persuasive to overcome the rejection.
On pg. 6, Remarks, Applicant specifically argues that “The secondary references. . .fail to supplement the deficiency of Tam, i.e., the four-component pharmaceutical composition of presently pending claim 1 and 7. Gonzales-Zamora discloses a combination therapy, but only of remdesivir and a corticosteroid, to treat covid-19 patients. Hyoju merely discloses that alpha2 adrenergic agonists can be used to treat Covid, and Gulati discloses that centhaquine is an alpha2 adrenergic receptor agonist. Prescott discloses that dexamethasone decreases mortality in COVID-19 patients.”
This argument has been fully considered, but is not found persuasive.
As discussed in the above rejection, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to select centhaquine and the steroid, methylprednisolone, as additional therapeutic agents in the composition of Tam, to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such selections, with a reasonable expectation of success, because:
-Tam, Gonzales-Zamora, and Hyoju, all teach methods of treating COVID-19,
-Tam teaches centhaquine and corticosteroids as additional therapeutic agents for use in its compositions,
-Gonzales-Zamora teaches that combining corticosteroids with remdesivir counteracts the direct viral damage produced by COVID and at the same time, controls the inflammatory response induced by the virus,
-Hyoju teaches that people with chronic sympathetic hyperactive comorbid condition, who contract SARS-CoV-2 virus, can potentially drive the infection towards a fatal outcome, wherein this outcome can be attenuated by alpha 2 agonists to override T cell exhaustion, cytokine spillage and impaired clearance of virus,
-Hyoju teaches that patients harboring such comorbid conditions are the most vulnerable to SARS-CoV-2 (pg. 1, “Introduction”), and
-Gulati teaches centhaquine as an alpha2 adrenergic receptor agonist.
As such, an artisan having ordinary skill in the art would have been motivated to make such selections, to predictably arrive at a composition that effectively treats COVID-19 in subjects by controlling inflammation, and by attenuating T-cell exhaustion, cytokine spillage, and impaired clearance of virus.
On pgs. 6-7, Remarks, Applicant argues that the references merely provide a large number of possible choices for development of anti-coronavirus compositions while failing to give any indication of which parameters were critical or direction as to which of many possible choices would be successful for an improved treatment of covid-19. Applicant further argues that “Tam discloses an extensive list of compound that may be combined for the treatment of coronavirus infection, however, if one were to vary each of all possible combinations of compounds, the number of different combinations would be exponentially large.”
These arguments have been fully considered, but are not found persuasive. The instant rejection does not rely on Tam, alone, to teach the instantly claimed composition, but relies on the combination of Tam, Gonzales-Zamora, Hyoju, and Gulati, wherein Gonzales-Zamora, Hyoju, and Gulati, provide motivation to specifically choose centhaquine and corticosteroid, in the composition comprising remdesivir and excipient of Tam, to arrive at the instantly claimed composition. Applicant is respectfully reminded that:
-Tam, Gonzales-Zamora, and Hyoju, all teach methods of treating COVID-19,
-Tam teaches centhaquine and corticosteroids as additional therapeutic agents for use in its compositions,
-Gonzales-Zamora teaches that combining corticosteroids with remdesivir counteracts the direct viral damage produced by COVID and at the same time, controls the inflammatory response induced by the virus,
-Hyoju teaches that people with chronic sympathetic hyperactive comorbid condition, who contract SARS-CoV-2 virus, can potentially drive the infection towards a fatal outcome, wherein this outcome can be attenuated by alpha 2 agonists to override T cell exhaustion, cytokine spillage and impaired clearance of virus,
-Hyoju teaches that patients harboring such comorbid conditions are the most vulnerable to SARS-CoV-2 (pg. 1, “Introduction”), and
-Gulati teaches centhaquine as an alpha2 adrenergic receptor agonist.
Further regarding the arguments directed solely toward Tam, Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Regarding the arguments on pg. 7, Remarks, the instant rejection is not based on an obviousness rationale to explore a new technology or a general approach that seemed to be a promising field of experimentation. None of Tam, Gonzales-Zamora, Hyoju, or Gulati are directed toward new technologies or promising fields of experimentation. Each of these references provide teachings and not prophetic examples or ideas.
Further regarding the arguments on pg. 7, Remarks, the instant rejection is not arrived at by varying all parameters each of numerous choices until one possibly arrives at a successful result, where the prior art gave no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful. As detailed in the above rejection, Gonzales-Zamora, Hyoju, and Gulati provide motivation to select the corticosteroid and centhaquine taught by Tam, as the additional active ingredients in its compositions.
On pg. 7, Remarks, Applicant argues that the instant rejection was based on improper hindsight. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
On pg. 7, Remarks, Applicant argues that unexpected results have been achieved and submitted in a Rule 132 Declaration.
This Declaration is fully addressed and responded to above.
For these reasons, the arguments are not persuasive to overcome the instant rejections.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
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/LAUREN WELLS/Examiner, Art Unit 1622