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
Status of the Claims
Claims 51 and 57-60 are pending and are examined on their merits.
Information Disclosure Statement
The Information Disclosure Statement filed on October 22nd 2025 is in compliance with the provisions of 37 CFR 1.97 and has been considered in full. A signed copy of references cited from the IDS is included with this Office Action.
35 U.S.C. § 103 Rejections Maintained
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 rejections of claims 51 and 57-60 under 35 U.S.C. 103 as being unpatentable over Fathi (WO 2017/060771 A2 published on April 13th 2017 in view of Levade (WO 2017/129769 A1 effectively filed on January 28th 2016) and Domagala (Domagala et al., Int J Mol Sci. 2018 Aug 1;19(8):2256) are maintained.
Response to Arguments
Applicant’s arguments in the response filed on October 22nd 2025 are acknowledged. Applicant argues that one of ordinary skill in the art would not reasonably use the combination of opaganib and an anti-CTLA-4 antibody for the treatment of lung cancer because SK1 and SK2 act on different pathways, derive from distinct genes, have different subcellular localizations, and different biological functions. As evidence, Applicant cites Zdislaw (US 2012/0035268):
“Although both produce S1P, it appears that SK1 and SK2 can serve opposite cellular functions. SK1 appears to mainly promote proliferation and migration, whereas SK2 favors a proapoptotic response."
and Maceyka (Maceyka et al., The Journal of Biological Chemistry Vol. 280, No. 44, p 37118-37129, Nov 4 2005):
“The potent sphingolipid metabolite sphingosine 1-phosphate is produced by phosphorylation of sphingosine catalyzed by sphingosine kinase (SphK) types 1 and 2. In contrast to pro-survival SphK1, the putative BH3-only protein SphK2 inhibits cell growth and enhances apoptosis. [...] Our results demonstrate that SphK1 and SphK2 have opposing roles in the regulation of ceramide biosynthesis and suggest that the location of sphingosine 1-phosphate production dictates its functions.”
" [...] These two isoenzymes have different kinetic properties and also differ in developmental and tissue expression, implying that they may have distinct physiological functions. Indeed, rather than promoting growth and survival, SphK2 suppressed growth and enhanced apoptosis that was preceded by cytochrome c release and activation of caspase-3. Moreover, SphK2-induced apoptosis was independent of activation of SIP receptors.”
Applicant’ then states that “One of ordinary skill in the art would not expect that a selective inhibitor of SK2, such as opaganib, would exhibit a comparable antiproliferative effect against lung cancers as a selective inhibitor of SK1,” and the combination of opaganib and an anti-CTLA4 antibody is therefore nonobvious.
Regarding these arguments, while the separate biological functions presented in Maceyka are acknowledged, Maceyka does not address how the inhibition of these processes would impact lung cancer cells. Specifically, the argument presented in the last action was not that sphingosine-kinase 1 and sphingosine-kinase 2 are known to act in a similar manner, but that the inhibition of sphingosine-kinase 1 and sphingosine-kinase 2 both induce lysosomal membrane permeabilization in cancer cells, leading to induced cell death, and it would be reasonable for one of ordinary skill in the art to substitute one such LMP-inducing compound for another in combination with a CTLA4 antibody.
That is:
The treatment of lung cancers with Opaganib in combination with immune checkpoint inhibitors is known in the art (see Levade)
The treatment of lung cancers with SK1 inhibitors in combination with anti-CTLA4 antibodies (immune checkpoint inhibitors) is known in the art (see Fathi)
Both Sk1 inhibitors AND Opaganib are known in the art to induce lysosomal membrane permeabilization in lung cancer cells (see Domagala)
One of ordinary skill in the art would therefore reasonably substitute one LMP-inducing compound (opaganib) for another (SK1 inhibitor) in the combination treatment presented by Fathi, especially as all compounds presented are already known in the art to be used in the treatment of lung cancers.
As one of ordinary skill in the art would reasonably treat lung cancer with applicant’s combination, claims 51 and 57-60 are prima facie obvious.
Rejections Reiterated
Claim 51 is directed towards a method of treating lung cancer comprising administration of a combination treatment of opaganib and an anti-CTLA4 antibody.
Fathi teaches the treatment of lung carcinoma (Fathi, pg. 84, claim 10), via administration of a combination treatment that includes the sphingosine-kinase 2 inhibitor opaganib (Fathi, pg. 82, claim 1, compound 2), and an immune checkpoint inhibitor (Fathi, pg. 84, claim 13). Fathi does not explicitly teach that the immune checkpoint inhibitor is an anti-CTLA4 antibody, but one of ordinary skill in the art would have a reasonable expectation of success in using an anti-CTLA4 antibody as the immune checkpoint inhibitor, because:
Other sphingosine kinase inhibitors are known in the art to be used in combinations with CTLA4 inhibitors.
Regarding the combination of sphingosine kinase inhibitors with anti-CTLA4 antibodies, Levade teaches such a combination of sphingosine-kinase 1 inhibitors (Levade, pg. 41, claim 11). Levade does not explicitly teach sphingosine-kinase 2 inhibitors in combination with anti-CTLA4 antibodies, but one of ordinary skill in the art would have a reasonable expectation of success in making this combination, because drugs that target sphingolipid metabolism, including both inhibitors of sphingosine-kinase 1 and sphingosine-kinase 2, are known to act in a similar manner, inducing lysosomal membrane permeabilization (LMP) in cancer cells, leading to induced cell death. See Domagala:
“LMP can be also achieved by increasing sphingosine composition within the lysosomal bilayer. Inhibition of sphingosine kinase increases the ratio sphingosine/sphingosine-phosphate and thus augments the tendency toward LMP. Accordingly, cathepsin B-mediated cleavage of sphingosine-kinase 1 and inhibition of sphingosine-kinase 2 by the selective inhibitor, opaganib (ABC294640), induced cell death associated with alterations in lysosomal compartment. Opaganib, which is orally available, shows potent antitumor activity in various cancer models and is now tested in stage II clinical trials in patients with multiple myeloma and liver cancer.”
[Domagala, pg. 7]
Domagala teaches that sphingosine-kinase 2 inhibitors, including Opaganib, had similar anticancer activity to spingosine-kinase 1 inhibitors, and acted via a similar mechanism, by inducing lysosomal membrane permeabilization in cancer cells.
One of ordinary skill in the art would therefore find the treatment of lung cancer with the combination of opaganib and an anti-CTLA4 antibody prima facie obvious.
Claims 57 and 58 requires that the anti-CTLA4 antibody is a monoclonal antibody and a human monoclonal antibody, respectively. Levade teaches that the antibodies are human monoclonal antibodies (Levade, pg. 1, Background; Levade, pg. 26), and claims 57 and 58 are prima facie obvious.
Claims 59 and 60 require that opaganib and the anti-CTLA4 antibody are co-administered and separately administered, respectively. Levade teaches both simultaneous and sequential administration of the sphingosine-kinase inhibitor and immune checkpoint inhibitor (Levade, pg. 29) and claims 59 and 60 are prima facie obvious.
Conclusion
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.
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/A.J.S./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629