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 .
Application Status
The amendment filed on 4/13/2026 in response to the Non-Final rejection of 12/12/2025 is acknowledged and has been entered. Claims 1-12 are currently pending and under consideration.
Response to Amendment
The declaration under 37 CFR 1.132 filed on 4/13/2026 by Dr. Öberg is insufficient to overcome the rejection of Claim(s) 1-12 under 35 U.S.C. 103 as being unpatentable over Albertella et al. in view of Al-Salama et al. as set forth in the last Office action for the following reasons:
The Declarant notes that body weight is widely used as a validated indicator of general toxicity in initial mouse models preclinical studies since body weight encompasses multiple organ systems and provides comprehensive information regarding the oval effect of the tested compounds. The Declarant further provides data presented in Figure 1 showing that the anti-tumor activity of the combination of MIV-818 and sorafenib was essentially identical to that for the combination of MIV-818 and Lenvatinib and Figure 2 showing the percent body weight change for single agent sorafenib or Lenvatinib treatment. Moreover, the Declarant provides data presented in Figure 3 showing the percent body weight changes for sorafenib and Lenvatinib combination treatment, wherein the declarant contends that it was unexpected and surprising that the combination of Lenvatinib with MIV-818 shows a decreased toxicity compared to the combination of sorafenib with MIV-818. For example, the Declarant asserts that based on the data of Figures 1 and 2, the expectation was that the combination of sorafenib and MIV-818 would be identical to that of Lenvatinib and MIV-818.
The Declarants assertions and data presented have been carefully considered, but are not found persuasive.
In response, the examiner recognizes that “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986)”, see MPEP 716.02. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992), see MPEP 716.02(b). In the instant case, the examiner acknowledges that the data presented in Figure 1 showing that the anti-tumor activity of the combination of MIV-818 and sorafenib was essentially identical to that for the combination of MIV-818 and Lenvatinib. In view of the teachings of Al-Salama et al. (cited above and in the previous office action), these results appear to be reasonably expected since Lenvatinib is known to be non-inferior, but not superior, to sorafenib. In addition, Al Salama et al. teach that Lenvatinib is associated with significant improvements compared to sorafenib in terms of all secondary endpoints (higher objective response rate (ORR), and longer progression-free survival (PFS) (abstract). Accordingly, despite the Declarant asserting what would have been expected based on Figure 1 and 2, in view of the teachings of Al Salama et al. it would appear one would have expected there to be differences in secondary endpoints between Lenvatinib and sorafenib treatments with significant improvements associated with Lenvatinib.
The declaration under 37 CFR 1.132 filed on 4/13/2026 by Dr. Öberg is insufficient to overcome the rejection of Claims 1 and 8 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 9 of U.S. Patent No. 12,303,521 to Albertella et al. in view of Al-Salama et al. as set forth in the last Office action for the following reasons:
The Declarant notes that the mechanisms of action of PD1-PDL1 and for Lenvatinib target completely different biochemical pathways in the cell. In addition, the Declarant asserts that the structures of anti-PD-L1 antibodies and Lenvatinib are extremely different. Thus, the Declarant contends that based on an understanding of the mechanisms of action and the knowledge of the data described in US12303521, there is no reasonable expectation of success for this particular combination. Lastly, the Declarant opinions that the synergistic enhancement of tumor growth inhibition when using the combination of MIV-818 and Lenvatinib is not obvious in view of the cited prior art and there would be no reasonable expectation of success in substituting Lenvatinib for an PD-L1 antibody.
The Declarants assertions have been carefully considered, but are not found persuasive.
In the instant case, the examiner acknowledges and does not dispute the Declarants contention that the mechanisms of action and chemical structure of an anti-PDL1 antibody and Lenvatinib are extremely different. However, the examiner recognizes that both anti-PDL1 antibodies and Lenvatinib have been taught in the prior art to be effective at treating liver cancer, wherein Lenvatinib represents a long-awaited alternative to sorafenib (standard of care). As such, it would be prima facia obvious to substitute an anti-PDL1 antibody as claimed in the conflicting patent with Lenvatinib. Moreover, "It 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) see MPEP 2144.06. Regarding Declarants brief mention of synergy, the examiner recognizes that while the specification mentions synergy within the context of “the discovery that certain treatment combinations of Lenvatinib and MIV-818 are particularly effective at inhibiting, and preventing the proliferation of, liver cancer cells” (page 4, lines 21-23), the claims do not appear to be commensurate in scope with the alleged synergistic results since the claims do not appear to encompass these “certain treatment combinations”.
Rejections Maintained:
Note: Applicants arguments set forth in the response mirror those of the Declaration which have been addressed above and incorporated herein.
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.
Claim(s) 1-12 remain rejected under 35 U.S.C. 103 as being unpatentable over Albertella et al. (US2019/0091246A1, 2019-03-28) in view of Al-Salama et al. (Drugs (2019); 79:665-674).
Albertella et al. teach a method of treating liver cancer or liver metastasis, comprising administering to a subject in need thereof a targeted therapeutic agent, wherein the targeted therapeutic agent is sorafenib in combination with a phosphoramidate prodrug of troxacitabine having the formula
PNG
media_image1.png
175
340
media_image1.png
Greyscale
(claim 1 of Albertella et al). Specifically, the PGPub teaches Sorafenib and a phosphoramidate prodrug of troxacitabine having the formula
PNG
media_image2.png
145
290
media_image2.png
Greyscale
were assayed in a combinatorial cell culture assay and had a log volume of 40 at 95% confidence calculated by MacSynergy II, which corresponds to strong-antiproliferative synergy (paragraph 0331-0333, Example 4). With regards to the liver cancer and/or liver metastasis, the PGPUB teaches that the liver cancer is HCC or intra-hepatic cholangiocarcinoma and the liver metastasis is derived from colorectal cancer, breast cancer, esophageal cancer, lung cancer, melanoma, pancreatic cancer or stomach cancer (claims 12-14 of Albertella et al). With regards to the treatment, Albertella et al. teach that sorafenib and the prodrug are each administered on the same day either co-delivered in a common, orally administered dosage form or administered as separate orally administered dosage units, wherein the dosage units of each drug are administered at least 6 hours apart on any given day (claims 6-9 of Albertella et al.). Moreover, Albertella et al. teach that sorafenib and the prodrug are alternatively administered in monotherapy treatment cycles of 1-28 days, wherein the treatment commences with a sorafenib cycle and includes 4 or 3 consecutive weeks with 1 week, 2 weeks or 3 consecutive weeks off (claim 10-11 of Albertella et al and paragraph 0225). Additionally, Albertella et al. teach that sorafenib and the prodrug are each administered daily as QD, BID or TID on the same day (claim 15 of Albertella et al.).
Albertella et al. does not specifically teach Lenvatinib in combination with the phosphoramidate prodrug of troxacitabine having the formula
PNG
media_image2.png
145
290
media_image2.png
Greyscale
for treating liver cancer or liver metastasis.
Al-Salama et al. teach Lenvatinib is an oral small molecule inhibitor of multiple receptor tyrosine kinases, and is approved for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) in the USA, EU, Japan and China (Abstract). Moreover, Al-Salama et al. teach that given its non-inferior efficacy to sorafenib and manageable tolerability profile, Lenvatinib represents a long-awaited alternative option to sorafenib for the first-line systemic treatment of patients with unresectable HCC (abstract).
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 substitute sorafenib as taught by Albertella et al. with Lenvatinib in view of the teachings of Al-Salama et al.. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Al-Salama et al. teaches that Lenvatinib efficacy is non-inferior to sorafenib, and represents a long-awaited alternative to sorafenib.
Moreover, "It 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) see MPEP 2144.06.
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 1-12 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 10,960,017 to Albertella et al. (2021-03-30) in view of Al-Salama et al. (Drugs (2019); 79:665-674).
US Patent No 10,960,017 claims a method of treating liver cancer or liver metastasis, comprising administering to a subject in need thereof a targeted therapeutic agent, wherein the targeted therapeutic agent is an isotope of sorafenib in combination with a phosphoramidate prodrug of troxacitabine having the formula
PNG
media_image1.png
175
340
media_image1.png
Greyscale
(claim 1 of the US Patent). Specifically, the US Patent No 10,960,017 claims Sorafenib and a phosphoramidate prodrug of troxacitabine having the formula
PNG
media_image2.png
145
290
media_image2.png
Greyscale
(claim 4). With regards to the liver cancer and/or liver metastasis, the US Patent No 10,960,017 claims that the liver cancer is HCC or intra-hepatic cholangiocarcinoma and the liver metastasis is derived from colorectal cancer, breast cancer, esophageal cancer, lung cancer, melanoma, pancreatic cancer or stomach cancer (claims 11-13). With regards to the treatment, US Patent No 10,960,017 claims that sorafenib and the prodrug are each administered on the same day either co-delivered in a common, orally administered dosage form or administered as separate orally administered dosage units, wherein the dosage units of each drug are administered at least 6 hours apart on any given day (claims 5-8). Moreover, US Patent No 10,960,017 claims that sorafenib and the prodrug are alternatively administered in monotherapy treatment cycles of 1-28 days, and interspersed with treatment-free periods of 1-28 days(claim 9-10, 15). Additionally, US Patent No 10,960,017 claims that sorafenib and the prodrug are each administered daily as QD, BID or TID on the same day (claim 14).
US Patent No 10,960,017 does not specifically claim Lenvatinib in combination with the phosphoramidate prodrug of troxacitabine having the formula
PNG
media_image2.png
145
290
media_image2.png
Greyscale
for treating liver cancer or liver metastasis.
Al-Salama et al. teach Lenvatinib is an oral small molecule inhibitor of multiple receptor tyrosine kinases, and is approved for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) in the USA, EU, Japan and China (Abstract). Moreover, Al-Salama et al. teach that given its non-inferior efficacy to sorafenib and manageable tolerability profile, Lenvatinib represents a long-awaited alternative option to sorafenib for the first-line systemic treatment of patients with unresectable HCC (abstract).
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 substitute sorafenib as claimed by the US Patent with Lenvatinib in view of the teachings of Al-Salama et al.. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Al-Salama et al. teaches that Lenvatinib efficacy is non-inferior to sorafenib, and represents a long-awaited alternative to sorafenib.
Moreover, "It 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) see MPEP 2144.06.
Claims 1 and 8 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 9 of U.S. Patent No. 12,303,521 to Albertella et al. (2025-05-20) in view of Al-Salama et al. (Drugs (2019); 79:665-674).
US Patent No 12,303,521 claims a method of treating liver cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula
PNG
media_image2.png
145
290
media_image2.png
Greyscale
in combination with monoclonal antibody which blocks binding of PD-L1 (claim 1). With regards to the liver cancer, US Patent No 12,303,521 claims that the liver cancer is HCC (claim 9).
US Patent No 12,303,521 does not specifically claim Lenvatinib in combination with the phosphoramidate prodrug of troxacitabine having the formula
PNG
media_image2.png
145
290
media_image2.png
Greyscale
for treating liver cancer or liver metastasis.
Al-Salama et al. teach Lenvatinib is an oral small molecule inhibitor of multiple receptor tyrosine kinases, and is approved for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) in the USA, EU, Japan and China (Abstract). Moreover, Al-Salama et al. teach that given its non-inferior efficacy to sorafenib and manageable tolerability profile, Lenvatinib represents a long-awaited alternative option to sorafenib for the first-line systemic treatment of patients with unresectable HCC (abstract).
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 substitute the antibody as claimed by the US Patent with Lenvatinib in view of the teachings of Al-Salama et al.. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Al-Salama et al. teaches that Lenvatinib efficacy is non-inferior to sorafenib, and represents a long-awaited alternative to sorafenib.
Moreover, "It 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) see MPEP 2144.06.
Conclusion
Therefore, No claim is 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 BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BRANDON J FETTEROLF/Primary Examiner, Art Unit 1626
Prosecution Insights