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
Claims 1-4, 9-14, and 24-30 are currently pending.
Election/Restriction
Applicant’s election with traverse of Group II (Claims 1-4 and 24-30, drawn to methods of treating viral infection) and SARS-CoV-2 as the elected disease in the reply filed on 6/10/2026 is acknowledged.
Claims 9-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected Group I or unelected species, there being no allowable generic or linking claim.
Claims 1-4, 9-14, and 24-30 are currently pending in the application. However, due to restriction requirement, Claims 9-14 are withdrawn from further consideration and Claims 1-4 and 24-30 are being examined on the merits herein. Again, election was made with traverse in the reply filed on 6/10/2026.
Applicant argues that the required restriction/election is improper because newly added Claims 29-30 include the subject matter of withdrawn Claim 9 and therefore, search and examination of the new claims requires a search of the subject matter of Claim 9.
However, applicant’s arguments are not persuasive as Claim 9 is necessarily broader than the scopes of either Claim 29 or 30 because both Claims 29-30 require the limitation of administering the composition to treat/prevent a viral infection. Further, there is no special technical feature common to both groups as explained in the restriction requirement mailed 4/16/2026. Applicant does not specifically traverse the arguments offered in the restriction requirement citing Huber, teaching (S)-crizotinib and compositions thereof. Lastly, search burden is not a consideration of unity of invention for a 371 national stage application. Thus, the requirement is deemed proper and is therefore made final.
Claim Objections
Claims 1, 4, 24, 28-30 are objected to because of the following informalities:
Claims 1, 4, 24, 28-30 recite “pharmaceutically-acceptable” and should be amended to remove the hyphen as follows: “pharmaceutically acceptable”.
Appropriate correction is required.
Claim Interpretation
Regarding the “includes” language of Claims 4, 25, and 28-30, “includes” is interpreted as “comprising” rather than exemplary language of acceptable embodiments. The limitations that follow “includes” are required but not exclusive. For example, Claim 28 requires oral administration but does not preclude other forms of administration in combination with the required oral administration. The “includes” limitations are not interpreted as a Markush grouping “that is by its nature closed”. See MPEP 2111.03.
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.
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.
Claims 24 is rejected under 35 U.S.C. 103 as being unpatentable over Wang (Oncogene (2020) 39:603–616; 2/02/2024 IDS).
Wang teaches “Treatment with the MTH1 inhibitors TH588 and (S)-Crizotinib selectively induced DNA damage and apoptosis in EBV-positive cell lines and prevented the establishment of EBV transformed lymphoblastoid cell lines from freshly infected B-lymphocytes, suggesting that activation of the cellular defense against oxidative stress plays a central role in promoting the growth transformation and survival of EBV infected cells” (Page 604). Epstein-Barr virus positive cancer is tantamount to viral infection and the treatment of the viral cancer associated with EBV is tantamount to the treatment of the infection.
Wang does not explicitly teach administering (S)-crizotinib to a patient in an amount sufficient to “inhibit MTH1 expression” or “inhibiting viral nucleic acid replication” via said administration as claimed.
Wang does however teach (S)-crizotinib is a MTH1 inhibitor and “that EBNA1 or other viral products may counteract the antiproliferative effects of oxidative DNA damage” (Page 604). “Expression of EBNA1…induced a reversible dose-dependent increase of MTH1”, which “sanitizes oxidized purines from the free nucleotide pool” thereby counteracting antiproliferative effects of the oxidized nucleotides (Page 604). In a clinical setting, one of skill in the art would therefore find it obvious to administer an effective amount of (S)-crizotinib to inhibit MTH1 expression because such inhibition introduces damaged nucleotides to the pool thereof and can “counteract the antiproliferative effects” of EBV infection as stated. Additionally, viral replication requires nucleotides which would be expected to suffer similarly from oxidative damage of nucleotides, further treating the infection of EBV cells in a patient. One of skill in the art would expect success in doing so before the effective filing date because Wang details the pathway of EBV infection and its role in cancer as well as MTH1 inhibitor activity in an effort to assess potential clinical therapies (Page 613, Last Para) as described in the examined claims.
Further regarding the limitation “inhibiting viral nucleic acid replication in the patient”, in Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a "‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention." Id. However, the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). See MPEP 2111.04. the “inhibiting” limitation merely recites the intended effect achieved by the process step positively recited: “administering to the patient a dose of (S)-crizotinib…sufficient to inhibit MTH1 expression”, which is rendered obvious for the reasons explained above.
Claims 26-28 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Wang as applied to Claim 24 above in further view of FDA (XALKORI® (crizotinib) Capsules, oral Initial U.S. Approval: Jan 2021. 1-37).
The teachings of Wang are set forth above and incorporated by reference herein.
Wang fails to teach particular dosing arrangements for (S)-crizotinib.
FDA teaches approved methods of dosing (R)-crizotinib including 250mg or 280 mg/m2 oral doses twice per day (Page 1, DOSAGE AND AMIN…; Pages 23-24, DESCRIPTION). The oral form is comprised of excipients including “colloidal silicon dioxide, microcrystalline cellulose, anhydrous dibasic calcium phosphate, sodium starch glycolate, magnesium stearate, and hard gelatin capsule shells” (Page 23-24, DESCRIPTION).
Regarding (R) vs (S) enantiomers of crizotinib in dosing and formulation, compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See MPEP 2144.09.
One of skill in the art seeking to dose (S)-crizotinib for the purposes disclosed in Wang would find it obvious to do so with the pharmaceutical considerations of the FDA to achieve safe administration and bioavailability. One of skill in the art would expect success in dosing the formulation according to the FDA for the treatment described in Wang before the effective filing date of the claimed invention because Wang details the pathway of MTH1 and the expected activity of MTH1 inhibitor (S)-crizotinib whereas the FDA provides an effective dosing strategy for the position isomer thereof.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Adhami (BMC Biotechnol 21, 22 (2021). 1-11. Version of record: 12 March 2021; 2/02/2024 IDS) as evidenced by FDA (XALKORI® (crizotinib) Capsules, oral Initial U.S. Approval: Jan 2021. 1-37).
Adhami teaches “the most remarkably identified candidate drugs for COVID-19 were PACLITAXEL with four interactions and BORTEZOMIB, CAR BOPLATIN, CRIZOTINIB, CYTARABINE, DAUNORUBI CIN, and VORINOSTAT with three interactions with the genes associated with the coronavirus infection” (Page 5, Right Col.). “[N]o study was found to report CARBOPLATIN, CRIZOTINIB, and CYTA RABINE, which were introduced in the current study. Therefore, these novel potential drugs should be investigated as a therapy for COVID-19” (Page 9, Right Col.). COVID-19 is the resultant disease of SARS-CoV-2 viral infection (Page 2, Left Col.).
FDA teaches “crizotinib” is an (R) enantiomer (Pages 23-24, DESCRIPTION).
Adhami does not teach treatment of the condition with the (S)-enantiomer.
However, compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.).
Therefore, one seeking to treat Covid-19 with crizotinib as suggested by Adhami would find it obvious to choose the (S) stereoisomer to do so before the effective filing date of the instant application because enantiomers, which are position isomers, “are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties”. The same artisan would expect successful treatment because the (R) isomer is associated “with three interactions with the genes associated with the coronavirus infection… [and] should be investigated as a therapy for COVID-19” as taught by Adhami and the two enantiomers are presumed to have similar interactions with said genes.
Claims 4 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Adhami as applied to Claim 1 in further view of FDA (XALKORI® (crizotinib) Capsules, oral Initial U.S. Approval: Jan 2021. 1-37).
The teachings of Adhami and FDA are set forth above and incorporated by reference herein.
Adhami fails to teach pharmaceutical compositions comprising the crizotinib and a pharmaceutically acceptable excipient or carrier for oral administration.
FDA teaches orally dosing (R)-crizotinib (Page 1, DOSAGE AND AMIN…; Pages 23-24, DESCRIPTION). Crizotinib is taught to be formulated with “colloidal silicon dioxide, microcrystalline cellulose, anhydrous dibasic calcium phosphate, sodium starch glycolate, magnesium stearate, and hard gelatin capsule shells as inactive ingredients” (Page 24, DESCRIPTION). Therefore, one of skill in the art seeking to treat Covid-19 as suggested by Adhami before the filing date of the examined invention would find it obvious to formulate crizotinib with the excipients taught for oral administration to a patient in need thereof because the FDA teaches the formation of oral capsules of said API. One of skill in the art would expect success in forming such compositions for oral administration because the FDA approved of such formulations for the same delivery route.
Regarding Claims 2-3, 24-28, and 30 unrejected over Adhami et al., applicant teaches surprising and unexpected results of (S)-crizotinib to inhibit pseudoviral entry with greatly increased efficacy as opposed to the (R) enantiomer in Figs. 1 and 2:
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Reduced cytotoxicity through (S)-specific administration is also shown in Fig. 3:
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Applicant attributes such results to the following (Specification: Page 5):
The present invention relates to the discovery that crizotinib is effective in preventing
infection by SARS-CoV-2, and, surprisingly, that (S)-crizotinib is significantly more effective than (R)-crizotinib in doing so. This may be attributable to (S)-crizotinib's ability to inhibit MTH1. During viral replication, inhibition of MTH1 results in the incorporation of oxidatively damaged nucleotide bases, resulting in high error correction and less efficient RNA synthesis.
Therefore, disruption of the nucleotide pool necessary for viral replication generally is taught to be disrupted by MTH1 inhibition, yielding the unexpected results in combatting viral infection. Applicant claims in Claim 24 that the dose of the (S) crizotinib to be administered is “sufficient to inhibit MTH1 expression in the patient”, which is a limitation also required by dependent Claims 25-28 and 30. Regarding Claims 2-3 which are not rejected, the same claims require the dose amounts described in Claims 26-27 which are necessarily “sufficient to inhibit MTH1 expression in the patient” because said limitation of Claim 24 is incorporated into Claims 26-27, reciting the dose amounts. Therefore, the amount recited in Claims 2-3 is also sufficient for commensurate in scope with the same surprising results.
The rejected claims fail to incorporate the requirement that MTH1 expression be inhibited, which applicant teaches is the cause of the unexpected results on Page 5 of the Specification. No particular minimum dose threshold is disclosed for achieving the increased efficacy, no dose amount is required by the rejected claims, and no requirement for MTH1 inhibition is present in the rejected claims. Therefore, the scope of Claims 1, 4, and 29 is not commensurate in scope with the results offered by applicant. Further, Adhami teaches other mechanisms by which crizotinib is an effective treatment against Covid-19 infection (“three interactions with the genes associated with the coronavirus infection” Page 5, Right Col.), which are not necessarily limited to an amount “sufficient to inhibit MTH1 expression”.
Conclusion
Claims 1, 4, 24, 28-30 are objected to. Claims 1, 4, 24, and 26-30 are rejected. Claim 25 is allowable.
Claims 2-3 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Richard G. Peckham whose telephone number is (703)756-4621. The examiner can normally be reached 8:30am - 4:30pm EST.
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/RICHARD GRANT PECKHAM/Examiner, Art Unit 1627
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