DETAILED 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 .
Priority
This application, filed 17 November 2022, is a national stage application of PCT/US2021/063485, filed 20 May, 2021, which claims foreign priority of EP 20175739.0, filed 20 May, 2020.
Information Disclosure Statement
Two information disclosure statements (IDS), both submitted on 29 October, 2025, are acknowledged and have been considered.
Status of the Application
Receipt is acknowledged of Applicant’s claimed invention, filed 29 October, 2025, in the matter of Application N° 17/999,185. Said documents have been entered on the record.
Claims 22, 29, 31, 33-35, 37, 39-40, and 43-45 been amended. Claims 27-28, 30, 32, 38, and 42 are canceled. Claims 46-54 are new. No new matter has been introduced.
Thus, Claims 22-26, 29, 31, 33-37, 39-40, and 43-54 represent all claims currently under consideration.
Response to Amendments
Claims 27-28, 30, 32, 38, and 42 have been canceled. Therefore, the objections and rejections of these claims under 35 U.S.C. 112(b) and/or 103 are moot.
Applicant’s amendments are sufficient to overcome the previous remaining rejections of claims under 35 U.S.C. 112(b).
Response to Arguments
Applicant's arguments filed 29 October, 2025 have been fully considered but they are not persuasive regarding the remaining claims under 35 U.S.C. 103.
In response to applicant's arguments against the references individually, 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).
Applicant contends that “Both, Cai et al. and Kindrachuk et al. relate to different MEK inhibitors compared to PD- 0184264, and further do not provide any suggestion for the use of PD-0184264 in a human clinical situation.” That “Ludwig and Planz relates only general to the use of PD- 0184264 for the use in treating a viral disease, such as influenza virus, adding that influenza antivirals were later found to be ineffective for COVID-19. Moreover, the '947 publication does not relate to or disclose a cytokine storm let alone to a coronavirus induced COVID-19 cytokine storm in a subject.” And finally, that “NCT04385420 clinical trial document relates to a single ascending dose (SAD) study to evaluate the safety, tolerability, and PK of 3 oral doses of a MEK inhibitor and a multiple ascending dose (MAD) study of 3 oral doses of a MEK inhibitor in healthy individuals” (Remarks, Pg. 8.)
However, the previous rejections are based on the combined teachings of the references.
Cai teaches that suppression of coronavirus replication is achieved by inhibiting the MEK1/2-ERK1/2 signaling pathway, and demonstrates that MEK pathway inhibition suppresses replication of coronavirus (MHV), and this mechanistic teaching forms part of the motivation to combine. Whether Cai used a different MEK inhibitor is immaterial; the reference establishes the target and therapeutic rationale, not the identity of the compound.
Kindrachuk teaches that MEK1/2 and ERK1/2 are critical host factor nodes required for MERS-CoV infection and explicitly identifies MEK inhibitors as highly promising candidates for in vivo studies of coronavirus infection. This is a clear and direct suggestion to apply MEK inhibitors – including known MEK inhibitors such as PD-0184264 – as antiviral agents. As emphasized by KSR, substituting one known inhibitor of a shared pathway for another constitutes a predictable variation well within the ordinary skill in the art. Additionally, Kindrachuk teaches that MEK inhibitors down regulate TNF-α and IL-1, expressly meeting the biomarker-reduction limitations recited in the dependent claims.
The rejections rely on Ludwig and Planz (which share two inventors with the instantly claimed invention) for its teaching that PD-0184264 is a known MEK inhibitor with antiviral activity, clinical development, and defined dosage ranges, not for coronavirus-specific data. Once Cai and Kindruchak identify MEK inhibition as a conserved antiviral strategy for coronaviruses, a person of ordinary skill in the art would be motivated to evaluate known MEK inhibitors – such as PD-0184264 – for coronavirus infection.
Arguments based on differences between influenza and coronaviruses do not negate the clear motivation to repurpose host-targeted antivirals, especially during a pandemic when rapid evaluation of mechanistically justified candidates is routine.
Applicant’s reliance on a publication dated after the effective filing date is improper and cannot be used to discount the teachings of the prior art at the time of filing. “See, e.g., Tan et al., Bioorg. Chem. 2020 Nov;104:104257” (Remarks, Pg. 9.)
Accordingly, Ludwig and Planz contribute the identity, antiviral nature, and dosage parameters of PD-0184264, which combine predictably with the MEK-based antiviral rationale of Cai and Kindruchak.
Atriva (NCT04385420) is relied upon solely for its disclosure of the oral dosing ranges, safety profile, and pharmacokinetic behavior of PD-0184264 – information that is directly relevant to the claimed dosage amounts. It is well established that dosage selection is informed by clinical PK and safety data in healthy volunteers. Atriva therefore provides the exact dose ranges now recited in the claims and is properly used in combination with the antiviral motivation supplied by Cai, Kindruchak, and Ludwig and Planz.
Below can be found new grounds of rejection necessitated by amendments. Although all rejections are presented as new grounds due to amendment, they maintain the same references and substantive rationale.
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 49, 51 and 53 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 49 recites “is administered to the human subject on 5 to 18 or 7 to 14 consecutive days after hospitalization.” It is unclear whether the claim requires administration for either the 5-18 day window or the 7-14 day window, both windows, or whether the second range is intended to represent a subset of the first. Because the claim does not specify the relationship between these two dosing periods or provide a clear selection rule, one of ordinary skill in the art cannot ascertain the boundaries of the claimed method with reasonable certainty.
Claim 51 recites that the method comprises “reducing the level of one or more, two or more, three or more, four or more, five or more or all six” of a set of six biomarkers. The overlapping and nested alternatives render the scope of the claim unclear, as “one or more” already encompasses all subsequent alternatives (“two or more”, “three or more”, etc.), making it impossible to determine which embodiments are intended to be encompassed or excluded. Applicant may wish to amend the claim to consolidate the overlapping alternatives into a single clear expression. Examples include: “reducing the level of at least one biomarker selected from [list],” or “reducing the level of one to six biomarkers selected from [list].”
Claim 53 recites a dosage “from 300 to 900 mg, including any dosage amount in between such as 300, 600 or 900 mg.” The phrase “including any dosage amount in between” renders the scope unclear, as it is not apparent whether the claim is limited to the exemplified dosages or encompasses all possible intermediate values. Additionally, the examples provided (300, 600, and 900 mg) are not “in between” the end points of the range, introducing inconsistency within the limitation itself. Accordingly, the metes and bounds of the claim cannot be determined with reasonable certainty.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 22-26, 31, 34-37, 39-40, 43-44, 48, and 50-52 are rejected under 35 U.S.C. 103 as being unpatentable over Cai (Journal of Virology, Jan. 2007, Vol. 81, No. 2, Pg. 446-456, of previous record), and Kindrachuk (Antimicrobial Agents and Chemotherapy, February 2015, Vol. 59, No. 2, Pg. 1088-1099, of previous record), and further in view of Ludwig and Planz (WO 2019/076947 A1, published 25 April, 2019, of previous record.)
‘947 shares two inventors with the instantly claimed invention.
As the full obviousness rationale has already been articulated above and in the prior action, the following section provides only the claim-specific application of the references.
Regarding Claim 22, Cai teaches suppression of Coronavirus replication by inhibition of the MEK signaling pathway (2007, Title), and more specifically reports knockdown of MEK1/2 and ERK1/2 suppressed MHV replication implicating MEK1/2 receptor (2007, Abstract.) Kindrachuk also teaches that MEK1/2 and ERK1/2 may represent critical nodes of the biological responses of the host during MERS-CoV infection, from the same Coronavirus. Importantly, Kindrachuk explicitly identifies MEK inhibitors as highly promising therapeutic candidates and encourages further in vivo evaluation to determine clinical utility (2015, Pg. 1097, Col 2, Para 1.) Ludwig and Planz teach the specific MEK inhibitor PD-0184264, for use in the treatment or prevention of viral diseases (‘947, Pg. 2, Line 4-5.)
One would have had a reasonable expectation of success, based on the consistently strong in vitro antiviral activity of MEK inhibitors reported in both Cai and Kindrachuk, the explicit recommendation in Kindrachuk to pursue in vivo studies, and the prevailing scientific and regulatory practices during the pandemic that supported rapid translation of promising preclinical candidates – particularly for treating hospitalized patients suffering from severe disease.
Therefore, 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 treat a disease caused by coronavirus in a human population that is hospitalized by administering a MEK inhibitor, wherein the MEK inhibitor is PD-0184264.
Regarding Claims 23-24, Kindrachuk teaches multiple licensed kinase inhibitors targeting the ERK/MAPK or PI3K/AKT/mTOR signaling pathway inhibited MERS-CoV infection (2015, Pg. 1097, Col 1, Para 2.)
Regarding Claim 25, as Cai and Kindrachuk identify the MEK1/2-ERL1/2 pathway as a conserved host-factor target for multiple coronaviruses, and Kindrachuk explicitly teaches MEK inhibitors as “promising candidates” for treating coronavirus infection, applying PD-0184264 to SARS-CoV-2 infection would be a routine and predictable use of a known MEK inhibitor.
Regarding Claim 26, the additional limitation reciting that the subject’s COVID-19 is “stage II” does not impart a further meaningful limitation to the claim. The claims upon which this rely already require that the subject is suffering from COVID-19, is hospitalized, and has acute respiratory disease. Under the standard clinical staging systems for COVID-19 used at the time of filing, hospitalized COVID-19 patients exhibiting acute respiratory involvement necessarily fall within Stage II of disease progression. Furthermore, the limitation does not introduce an additional method step, but merely describes the condition of the patient receiving the same administration of PD-0184264 to treat a coronavirus in a hospitalized human subject. Treatment of patients at any stage would have been an obvious and predictable application of the same therapy.
Regarding Claim 31, 40 and 48, the additional limitations reciting that the subject is infected with “a variant of SARS-CoV-2,” including the further limitation that the variant is selected from specific lineages such as B.1.1.7, B.1.351, P.1, and others, do not impart patentable distinction. These limitations merely describe the viral lineage infecting the patient and do not alter the therapeutic method step of administering PD-0184264. A person skilled in the art would have reasonably expected the same host-targeted therapeutic approach to apply to any SARS-CoV-2 strain or variant, as all rely on the same cellular pathways for replication. Moreover, the majority of the specifically recited variants (e.g., B.1.1.7, B.1.351, P.1, etc.) arose after the effective filing date and cannot be relied upon to establish non-obviousness. Even if they had been known, applying the same therapeutic method to newly arising viral variants represents a routine and predictable use of the known treatment taught by the prior art.
Regarding Claim 34, Ludwig and Planz teach PD-0184264 may be administered orally (‘947, Pg. 14, Line 15)
Regarding Claims 35 and 50, similarly to above, the additional limitations reciting that the infecting SARS-CoV-2 is “resistant to previous antiviral treatment,” including the further limitation that the prior treatment was Remdesivir, do not impart patentable distinction. These limitations merely describe the clinical treatment history or resistance profile of the virus infecting the subject and do not alter the therapeutic step of administering PD-0184264. Because the antiviral activity of the MEK inhibition is host-targeted rather than virus-targeted, resistance to a virus-directed antiviral such as Remdesivir would not change the expectation that PD-0184264 would remain effective. Furthermore, treating infections caused by drug-resistant strains is a routine and predictable extension of treating drug-sensitive strains, and a persona skilled in the art would have recognized that host-pathway inhibitors (e.g., MEK inhibitors) retain efficacy even when RNA-dependent RNA polymerase inhibitors like Remdesivir fail. Thus, the recitation of prior antiviral resistance does not meaningfully limit the method and does not overcome the obviousness of administering PD-0184264 as taught by the combination of Cai, Kindrachuk, and Ludwig and Planz.
Regarding Claim 36, the high-risk nature of hospitalized populations, including older adults and individuals with underlying comorbidities, would have made them an obvious and ethically appropriate target group for a routine and predictable extension of the treatment, as this limitation neither modifies the steps of the method nor changes the mechanism by which PD-0184264 acts.
Regarding Claims 37, 39 and 51, Kindrachuk teaches that multiple proinflammatory signaling pathways (tumor necrosis factor alpha [TNF-a] and interleukin-I [IL-1]) and innate immune response signaling pathways (Toll-like receptor [TLR] signaling) were downregulated (2015, Pg. 1091, Col 2.) A person skilled in the art would have recognized that treating SARS-CoV-2 infection using MEK inhibition would inherently treat or prevent the hyperinflammatory cytokine-storm response associated with severe COVID-19, since MEK inhibition modulates downstream inflammatory mediators.
Regarding Claim 43, Kindrachuk discloses MEK inhibitors inhibited MERS-CoV infection when added prior to or following viral infection (2015, Pg. 1097, Col 1, Para 2.)
Regarding Claims 44 and 52, Ludwig and Planz teach PD-0184264 at a dosage in the range of 10 to 100 mg/kg PD-0184264, preferably in the range of 25 to 75 mg/kg PD-0184264 (‘947, Pg. 16, Line 1-2.)
Therefore, Claims 22-26, 31, 34-37, 39-40, 43-44, 48, and 50-52 are prima facie obvious over Cai and Kindrachuk, in view of Ludwig and Planz.
Claims 33, 45-47, and 53-54 is rejected under 35 U.S.C. 103 as being unpatentable over Ludwig and Planz (WO 2019/076947 A1, published 25 April, 2019, cited in IDS), and further in view of Atriva Therapeutics GmbH (NIH Clinical Trial NCT04385420, last updated 13 May, 2020), hereinafter Atriva.
The teachings of Ludwig and Planz are set forth in the above 35 U.S.C. 103 Rejections and are incorporated herein.
Ludwig and Planz teach PD-0184264 for use in the treatment or prevention of viral diseases, but fail to teach the specific dose for a pharmaceutical composition.
However, Atriva evaluates the safety, tolerability, and PK of ATR-002 (also known as PD-0184264) at oral doses of 100 mg, 300 mg, 600 mg, and 900 mg for seven days (Study Details, Pg. 1-2.)
It would have been prima facie obvious before the effective filing date of the claimed invention to administer PD-0184264/ATR-002 at the clinically established dosage disclosed in Atriva, given that Ludwig and Planz already teaches the therapeutic use of the PD-0184264/ATR-002. One would have been motivated to use the known human, oral dosage from Atriva, and would have had a reasonable expectation of success based on the demonstrated safety in clinical evaluation.
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 22-26, 29, 34, 44-47 and 52-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1, 3, 10-13 and 15-20 of copending Application No. 18/443,904 in view of Cai (Journal of Virology, Jan. 2007, Vol. 81, No. 2, Pg. 446-456, of previous record), and Kindrachuk (Antimicrobial Agents and Chemotherapy, February 2015, Vol. 59, No. 2, Pg. 1088-1099, of previous record), and further in view of Ludwig and Planz (WO 2019/076947 A1, published 25 April, 2019, of previous record.).
Cai teaches suppression of Coronavirus replication by inhibition of the MEK signaling pathway (2007, Title), and more specifically reports knockdown of MEK1/2 and ERK1/2 suppressed MHV replication implicating MEK1/2 receptor (2007, Abstract.) Kindrachuk also teaches that MEK1/2 and ERK1/2 may represent critical nodes of the biological responses of the host during MERS-CoV infection, from the same Coronavirus. Importantly, Kindrachuk explicitly identifies MEK inhibitors as highly promising therapeutic candidates and encourages further in vivo evaluation to determine clinical utility (2015, Pg. 1097, Col 2, Para 1.) Ludwig and Planz teach the specific MEK inhibitor PD-0184264, for use in the treatment or prevention of viral diseases (‘947, Pg. 2, Line 4-5.)
One would have had a reasonable expectation of success, based on the consistently strong in vitro antiviral activity of MEK inhibitors reported in both Cai and Kindrachuk, the explicit recommendation in Kindrachuk to pursue in vivo studies, and the prevailing scientific and regulatory practices during the pandemic that supported rapid translation of promising preclinical candidates – particularly for treating hospitalized patients suffering from severe disease.
Therefore, 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 treat a disease caused by coronavirus in a human population that is hospitalized by administering a MEK inhibitor, wherein the MEK inhibitor is PD-0184264.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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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/D.M.N./ Examiner, Art Unit 1627
/SARAH PIHONAK/ Primary Examiner, Art Unit 1627