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 is a 371 of PCT/EP2021/059266 (04/09/2021)
and claims foreign priority to EP 20315150.1 (04/10/2020).
Claim Rejections - 35 USC § 103
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.
Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Leban et al. (WO2004/056747) in view of Xiong et al. (bioRxiv doi: 10.1101/2020.03.11.983056 (March 12,
2020)).
Leban teaches compounds of the formula
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for treating diseases such as viral infections, "where pyrimidine metabolism 1s beneficial," by inhibiting human dihydroorotate dehydrogenase (DHODH). The compounds specifically bind to the ubiquinone binding site of DHODH. Leban 2:2-4, 30: 10-11, and claims 1, 40 and 63-64. The compounds "can be used alone or in combination with other antiviral compounds such as ganciclovir and foscamet to treat such diseases." Leban 29:12-13. Compound 1 (a.k.a. vidofludimus) is representative of the DHODH inhibitors disclosed. Leban 4: 10 and claim 51.
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Leban does not teach treating a coronavirus infection with the DHODH inhibitor
compound 1.
Xiong teaches targeting the ubiquinone binding site of "DHODH offers broad-spectrum
antiviral efficacies against various RNA viruses, including the DAA-resistant influenza virus and
the newly emerged coronavirus SARS-CoV-2." Xiong 2. The "DHODH inhibitors are effective
in infected animals not only by inhibiting virus replication (Shown in Fig. 3 and Fig. 4) but also
by eliminating excessive cytokine/chemokine storm." Xiong 11. Xiong discovered two highly potent DHODH inhibitors, S312,
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, and S416
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(e.g., Fig. B) and reported "100% protection" from the pandemic H1N1 strain SC09 using a combination of S312 and Oseltamivir. Xiong 7-8.
Since Xiong teaches that coronavirus infection can be treated using DHODH inhibitors, a
PHOSITA would have been motivated to use Leban's DHODH inhibitors, such as compound 1,
in treating a coronavirus infection (e.g., SARS-CoV-2). The PHOSITA would have had a
reasonable expectation of success because Leban teaches that DHODH inhibitors of the formula
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bind to the ubiquinone site of DHODH and Xiong teaches that antiviral effects arise from binding at the ubiquinone pocket of DHODH. Furthermore, the PHOSITA would have been motivated to administer a therapeutically effective amount of Leban' s compound 1 (a.k.a. vidofludimus) in combination with another antiviral compound because both Leban and Xiong suggest combination antiviral therapy. Therefore, claims 1-3 would have been obvious.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Leban et al. (WO2004/056747) in view of Xiong et al. (bioRxiv doi: 10.1101/2020.03.11.983056 (March 12, 2020)) as applied to claims 1-3 above in further view of Arya et al. (chemRxiv doi: 10.26434/chemrxiv.11860011.v2 (February 20, 2020)).
Leban and Xiong render obvious the claimed method of treating a coronavirus infection
comprising administering a therapeutically effective amount of vidofludimus in combination
with another anti-viral compound, but Leban Xiong do not teach chloroquine as the other antiviral compound.
Arya conducted virtual screening and identified chloroquine as one of "[s]ixteen FDA
approved drugs showing the best affinity to SARS-CoV-2 PLpro." Arya 4. Chloroquine was
known "to block the SARS-CoV-2 infection at a low micro-molar concentration (EC50: 1.13
μM) in cell culture experiment" and was found to work "against the viral infection at the entry level, as well as post-entry stages" (citations omitted). Arya 6.
According to MPEP 2144.06, "[i]t is prima facie obvious to combine two compositions
each of which is taught by the prior art to be useful for the same purpose, in order to form a third
composition to be used for the very same purpose .... [T]he idea of combining them flows
logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d
846,850,205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).
Since Leban and Xiong suggest combining a DHODH inhibitor with a second antiviral
compound and Arya teaches the antiviral chloroquine has good affinity to SARS-CoV-2 PLpro
and has the ability to block SARS-CoV-2 infection, a PHOSITA would have been motivated to
combine the DHODH inhibitor vidofludimus (Leban's compound 1) with chloroquine for
treating coronavirus. The PHOSITA would have had a reasonable expectation of treatment
success because vidofludimus and chloroquine individually are taught/suggested as being useful for treating SARS-CoV-2. Thus, the PHOSITA would have expected that their combination would have resulted in an anti-corona viral therapy. Therefore, the claimed method of treating coronavirus with vidofludimus in combination with chloroquine would have been obvious.
With each of the claims, the level of skill in the art is very high such that one of ordinary skill in the art would consider routine the combination of elements from the teaching of the art. One of ordinary skill in the art would have recognized that the results of the combination would be predictable due to the well-known nature and optimizations routinely performed in the art. Thus, one of ordinary skill in the art would have arrived at the invention as claimed before the effective filing date with a reasonable expectation of success.
Response to Remarks - 35 USC § 103
Applicant argues “no combination of Leban and Xiong would make the claimed invention obvious” and “One of ordinary skill could not predict with a reasonable expectation of success that vidofludimus would be useful for treating coronavirus or any of the disorders disclosed by Leban.” Applicant also argues “one of ordinary skill in the art would recognize that no single drug would ever be useful for treating all of the differing diseases listed in Leban. Further, Leban does not provide a credible mechanistic nexus linking the activity of vidofludimus to treatment of any particular disease that was listed.”
These arguments are not persuasive because Leban identifies the compound as a DHODH inhibitor (Title, claim 1) which was known to be useful in treating viral infections and is in a class of compounds that have shown the same utility (p. 1-2, i.e., leflunomides). Leban also teaches the structure of the inhibitors when combined with human DHODH and supports the asserted utility (p. 2-3). Thus, one of ordinary skill in the art had a reasonable basis to conclude that the compound would be useful as specifically taught by Leban. In addition, one of ordinary skill in the art would have considered Xiong’s in vivo success with structurally related compounds and have had a reasonable expectation that other compounds known to be DHODH inhibitors would share the same utility and arrive at the invention as claimed.
Applicant argues based on Virji “vidofludimus had previously failed to meet the primary endpoint in a clinical trial for rheumatoid arthritis” thus would not be expected to be successful with viral infections and is a teaching away.
This argument is not persuasive because one of ordinary skill in the art following the teaching of Leban would have understood that clinical trials can fail to meet primary endpoints for a number of reasons not related to the activity of the compound as an inhibitor DHODH. Furthermore, the nature of the alleged teaching away is such that it is not related to the activity of the compound as an inhibitor or a therapeutic in treating a viral infection. Thus, the failure of a arthritis clinical trial “does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). MPEP 2145.
None of Applicant’s argument are persuasive and the rejection is maintained.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. 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 ROBERT H HAVLIN whose telephone number is (571)272-9066. The examiner can normally be reached 9am - 6pm.
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/ROBERT H HAVLIN/Primary Patent Examiner, Art Unit 1626