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
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2/5/2026 has been entered.
Claims 1-3, 5, and 7-9 are now pending and currently under prosecution.
Maintained Rejection
(Arguments and Amendments Addressed)
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.
Claim(s) 1-3, 5 and 7-9 remain rejected under 35 U.S.C. 103 as being unpatentable over Nakamura et al (2014) (US9303086 B2, Published 7/10/2014; of record), in view of, Personeni et al. (“Lenvatinib for the treatment of unresectable hepatocellular carcinoma: evidence to date.” Journal of hepatocellular carcinoma vol. 6 31-39. 31 Jan. 2019; of record).
Nakamura (2014) teaches an antibody against human DLK-1, which has in vivo antitumor activity, or an antibody fragment derived from the antibody, for the treatment of hepatocellular carcinoma. [Abstract] Nakamura teaches that the antibody is a chimeric antibody or a humanized antibody. [col 20 lines 25-65] Nakamura teaches that the antibody or antibody fragment is in the form of a conjugate with a compound having antitumor activity and/or cell killing activity. [col 25, section 3] Nakamura teaches a kit for treating hepatocellular carcinoma, which comprises the antibody against human DLK-1. [pg 29, section 6] Nakamura teaches and demonstrates the use of the antibody against xenograft treatment models using human hepatocellular carcinoma cells., HepG2. Nakamura demonstrates that there was extremely high anti-tumor activity in the treatment group compared to the control group. Nakamura also teaches that even after treatment there was extremely high-anti tumor activity. [fig 29, Example 11,13, 14, 16]
Nakamura teaches that the antibody is an antibody in which the amino acid sequences as noted
Amino acid sequence of H chain V region consists of the amino acid sequence shown in SEQ ID NO: 77, which matches 100% to the instantly claimed SEQ ID NO: 36, , amino acid sequence of L chain V region consists of the amino acid sequences shown in SEQ ID NO: 45, which matches 100% to the instantly claimed SEQ ID NO: 46.
SEQ ID NO: 36
Query Match 100.0%; Score 647; Length 121;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKGSGYTFTDYAMHWVRQAPGQGLEWIGVISTYYGNTNY 60
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Db 1 QVQLVQSGAEVKKPGASVKVSCKGSGYTFTDYAMHWVRQAPGQGLEWIGVISTYYGNTNY 60
Qy 61 NQKFKGKATMTVDKSTSTAYMELRSLRSDDTAVYYCARGGLREYYYAMDYWGQGTMVTVS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NQKFKGKATMTVDKSTSTAYMELRSLRSDDTAVYYCARGGLREYYYAMDYWGQGTMVTVS 120
Qy 121 S 121
|
Db 121 S 121
SEQ ID NO: 46
Query Match 100.0%; Score 587; Length 113;
Best Local Similarity 100.0%;
Matches 113; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIVMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWYQQKPGQPPKLLVYFASTR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIVMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWYQQKPGQPPKLLVYFASTR 60
Qy 61 ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYSTPPTFGQGTKLEIK 113
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYSTPPTFGQGTKLEIK 113
However, Nakamura does not explicitly teach a pharmaceutical combination of lenvatinib and an antibody against human DLK-1 for treating hepatocellular carcinoma and that the combination allows for tumor reduction.
Personeni teaches that lenvatinib is an oral multi kinase inhibitor and is a first-line treatment for hepatocellular carcinoma. Personeni teaches that lenvatinib demonstrated statistically significant superiority compared to other tyrosine kinase inhibitors. [pg 32, 2nd column] Personeni teaches that novel combination of lenvatinib and immunotherapy may be a promising step forward in the hepatocellular carcinoma landscape. [pg 38, Conclusion]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine lenvatinib and an antibody against human DLK-1 for the treatment of hepatocellular carcinoma and for tumor reduction. One would have been motivated to because: (1) Nakamura teaches treating hepatocellular carcinoma comprising administering an antibody against human DLK-1, (2) Personeni teaches treating hepatocellular carcinoma comprising administering lenvatinib, and (3) Personeni teaches that combinations of lenvatinib and immunotherapies may be a promising treatment strategy. One of ordinary skill in the art would have a reasonable expectation of success, because: (1) Nakamura demonstrates that an antibody against human DLK-1 demonstrates high anti-tumor activity, and (2) Personeni teaches that lenvatinib demonstrates significant antitumor activity.
Those of skill in the art recognize that the two agents, an antibody against human DLK-1 and lenvatinib, are both known to successfully, pharmaceutically treat hepatocellular carcinoma, and could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat hepatocellular carcinoma and allow for tumor reduction, and have additive effects through the combination of the two agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective at treating the same patient population, hepatocellular carcinoma, thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “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 which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the 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 which is to be used for the very same purpose of treating hepatocellular carcinoma and tumor reduction.
Response to Relevant Arguments
Applicant argues the following:
Lack of a Prima Facie Case of Obviousness: Applicant argues that Personeni discusses “immunotherapies” in the specific context of immune checkpoint inhibitors, and that there is no disclosure or suggestion or teaching in Personeni that would lead a person to select DLK-1. Applicant argues that Personeni documents multiple failed first-line combination studies.
Unexpected Results: Applicant submitted a Declaration under 37 C.F.R 1.132 to demonstrate synergistic effect of the claimed antibody, in combination with Lenvatinib.
The Relevant Question is post-treatment behavior, not merely additive effects during dosing: Applicant argues that claim 1 expressly recites a pharmaceutical combination that suppresses cancer cell proliferation or causes tumor reduction or disappearance after completing the administration of the pharmaceutical combination.
The experimental record demonstrates post-treatment effects not predicable from the prior art: Applicant argues that in Figure 6, the studies evaluated lenvatinib monotherapy, anti-DLK-1 antibody monotherapy and the combination in human hepatocellular carcinoma xenograft models. Applicant argues that the results led to tumor regression after completion of treatment in the combination group.
Results were not expected: Applicant argues that nothing in the prior art suggested that combining lenvatinib with an anti-DLK-1 antibody would yield durable tumor control after treatment cessation.
Lack of motivation to combine: Applicant argues that the cited art does not provide motivation to combine.
Applicant’s arguments have been considered but are not persuasive. The claims are drawn to the combination for lenvatinib an antibody against human-DLK-1 for the treatment of hepatocellular carcinoma. The Examiner relied on the combination of references to render the combination obvious to try. To reiterate the teachings of the 35 U.S.C. 103 rejection above:
Nakamura teaches the instantly claimed human DLK-1 antibody for the treatment of hepatocellular carcinoma. Nakamura teaches that the antibody resulted in high anti-tumor activity in the treatment group compared to the control group, with sustained anti-tumor effects post treatment
Personeni teaches the use of lenvatinib for the treatment of hepatocellular carcinoma. Personeni teaches that lenvatinib is the first line treatment in this cancer type. Personeni teaches that this agent can be combined with immunotherapy.
Both of these agents are known to successfully and pharmaceutically treatment hepatocellular carcinoma and could have been combined by known methods. The results in the specification demonstrate that lenvatinib and the anti-DLK-1 antibody, administered separately, were able to reduce tumor size significantly. [see at least Figure 1A] The results of the combination resulted in greater significant reductions. Each of the agents are effective at treatment of hepatocellular carcinoma, and that combining the two agents was additive. Regarding after administration, the tumor volume in the lenvatinib and the antibody groups significantly reduced compared to the control, and had additive effects in the combination. [see 0087 in the specification]
With regards to unexpected results, the MPEP states the following:
716.02(c) Weighing Evidence of Expected and Unexpected Results [R-08.2012]
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II. EXPECTED BENEFICIAL RESULTS ARE EVIDENCE OF OBVIOUSNESS
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"Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967) (resultant decrease of dental enamel solubility accomplished by adding an acidic buffering agent to a fluoride containing dentifrice was expected based on the teaching of the prior art); Ex parte Blanc, 13 USPQ2d 1383 (Bd. Pat. App. & Inter. 1989) (Claims at issue were directed to a process of sterilizing a polyolefinic composition which contains an antioxidant with high-energy radiation. Although evidence was presented in appellant’s specification showing that particular antioxidants are effective, the Board concluded that these beneficial results would have been expected because one of the references taught a claimed antioxidant is very efficient and provides better results compared with other prior art antioxidants.).
Thus, the arguments presented by the Applicant demonstrate that the combination of lenvatinib and the anti-human DLK-1 antibody demonstrated only additive or combined effects, compared to when each agent is administered alone. In the examples cited the Applicant, the Applicant’s demonstrate that tumor volume decreases with each agent as monotherapy, compared to the control group. When the combination of lenvatinib and the anti-human DLK-1 is administered, the effect of this shows the additive effects (tumor volume) of each agent, rather than synergistic effects: Example 1 of the instant specification (pgs 24-25) demonstrate that after 25 days, the tumor volume of the control was 557.5 +/- 240.5 mm3, 268.1 +/- 175.7 mm3 in the lenvatinib group, 144.6 +/- 111.2 mm3 in the HuBA-1-3-D antibody group, and 66.2 +/- 59.1 mm3 in the lenvatinib + HuBA-1-3D antibody group. The results demonstrate that lenvatinib alone reduced tumor volume about 50%, the antibody alone reduced tumor volume by around 75% (up to 90% reduction), and the combination resulted in reductions greater than 90%. Thus, demonstrating that each agent demonstrates significant effects alone, and when combined the effectiveness of each agent is additive rather than synergistic. As noted prior, if the combination of lenvatinib and the anti-human DLK-1 antibody demonstrated synergistic effects rather than additive effects, this would have rendered the claims as non-obvious.
Additionally, as noted previously, the instantly claimed anti-human DLK-1 antibody and lenvatinib are both known to treat the same patient population, hepatocellular carcinoma and are suggested to be used in combination, and the use of lenvatinib with other anti-tumor agents are already known to have additive effects as demonstrated by the prior art and summarized below.
Although the prior art did not exemplify administering the combination of an anti-human DLK1 antibody and lenvatinib, both agents are known to treat the same patient population and the effects of combining each agent is expected to have beneficial effects. Personeni further teaches that combinations of lenvatinib and immunotherapies may be a promising treatment strategy. Prior art demonstrates that when lenvatinib is combined with other agents it shows enhanced antitumor activity. Kato et al (Kato et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One. 2019;14(2):e0212513. Published 2019 Feb 27; of record) teaches a combination of lenvatinib plus anti-PD-1 antibody in hepatocellular carcinoma cell lines [pg 2, last paragraph] and that the combination of lenvatinib plus anti-PD-1 antibody increased the percentage of T cells, including CD8+ T cells, [pg 7, last paragraph] compared to monotherapy, which suggest that lenvatinib upregulates CD8+ T-cells and their cytotoxic activity. [pg 8] Kato concludes that lenvatinib shows more potent antitumor immune responses when combined with PD-1 blockade, due to enhanced activation of IFN signaling pathway. [pg 14, Conclusion]
Maintained Rejection
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 1-3, 5 and 7-9 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, 9-12, 14, 15, and 17-20 of copending Application No. 18/030,203 (reference application), in view of Personeni et al. (“Lenvatinib for the treatment of unresectable hepatocellular carcinoma: evidence to date.” Journal of hepatocellular carcinoma vol. 6 31-39. 31 Jan. 2019).
The co-pending Application recites a pharmaceutical combination for the treatment of cancer (hepatocellular carcinoma), comprising: (1) a substance which inhibits or suppresses the tyrosine kinase activity of fibroblast growth factor receptor 4 (FGF4), or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, and (2) an antibody against human DLK-1, which has in vivo anti-tumor activity, or an antibody fragment derived from the antibody. The co-pending Application also recites the following: (1) that the antibody is chimeric or humanized, (2) that the antibody is form of a conjugate with a compound having antitumor activity and/or cell killing activity, (3) the pharmaceutical combination allows suppression of cancer cell proliferation or allows tumor reduction or disappearance even after completing the administration of the pharmaceutical combination or pharmaceutical composition, and (4) the instantly claimed sequences of the antibody.
However, the co-pending application does not recite that the substance that inhibits the tyrosine activity of FGF4 is lenvatinib.
Personeni teaches that lenvatinib is an oral multi kinase inhibitor and is a first-line treatment for hepatocellular carcinoma. Personeni teaches that lenvatinib inhibits fibroblast growth factor 1-4 (FGFR1-4). Personeni teaches that lenvatinib demonstrated statistically significant superiority compared to other tyrosine kinase inhibitors. [pg 32, 2nd column] Personeni teaches that novel combination of lenvatinib and immunotherapy may be a promising step forward in the hepatocellular carcinoma landscape. [pg 38, Conclusion]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use lenvatinib as the substance that inhibits the tyrosine kinase inhibitor of FGF4 in the pharmaceutical combination of the co-pending application. One would have been motivated to because: (1) the co-pending application recites the pharmaceutical combination comprising a substance which inhibits or suppresses tyrosine kinase activity of FGF4 and an antibody against human DLK-1 for the treatment of hepatocellular carcinoma, (2) Personeni teaches that lenvatinib is a tyrosine kinase inhibitor, and inhibits FGFR4, and (3) Personeni teaches the use of lenvatinib for the treatment of hepatocellular carcinoma. One of ordinary skill in the art would have a reasonable expectation of success, because Personeni teaches that lenvatinib demonstrates significant antitumor activity. Given the known need to treat hepatocellular carcinoma, and given the known mechanism of action lenvatinib to inhibit FGF4, and given the known use of lenvatinib for the treatment of hepatocellular carcinoma, one of skilled in the art could have pursued using lenvatinib as the substance that suppresses FGF4 in the pharmaceutical combination of the co-pending application, with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
The rejection is not held in abeyance, and therefore is maintained.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 SARAH A ALSOMAIRY whose telephone number is (571)272-0027. The examiner can normally be reached Monday-Friday 7:30 AM to 5:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at (571) 272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600