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 .
Priority
This application, filed 27 December, 2021, is a national stage application of PCT/US2020/040075, filed 29 June, 2020, which claims the benefit of U.S. Provisional Application 62/867,991, filed 28 June, 2019.
Status of the Application
Receipt is acknowledged of Applicant's claimed invention, filed 14 October, 2025, in the matter of Application No. 17/623,060. Said documents have been entered on the record.
Claim 10 is amended. No new matter was introduced.
Thus, Claims 10, 12-16, and 18-20 represent all claims currently under consideration.
Response to Arguments & Amendments
The amendment to Claim 10 has overcome the previous objection filed 16 July, 2025.
Applicant's arguments filed 14 October, 2025 have been fully considered but they are not persuasive.
Applicant contends that the 2007 reference is invalid because as of the instant application’s effective date (2019), it was known in the art that the QGY-7703 cell line is a HeLa derivative rather than a true hepatocellular (HCC) line, and therefore no one of ordinary skill would have expected homoharringtonine (HHT) to be effective against liver cancer.
This argument is not persuasive because obviousness is determined based on the teachings of the prior art as they existed and the knowledge of one of ordinary skill in the art at the time the invention was made, not on later-discovered facts or reinterpretations of prior disclosures.
The QGY-7703 cell line was widely accepted and routinely used as an HCC model at the time the 2007 publication (Jin) was made, and the reference expressly teaches HHT as a potent antitumor agent by inducing apoptosis via several signaling pathways and specifically notes “HHT is a potential drug in the treatment of liver cancer” based on data in that model. One of ordinary skill in the art would have been motivated to evaluate the activity of HHT against multiple tumor types, to include liver cancer, since identifying new indicators for known antitumor compounds is a routine aspect of oncology drug research. A reference remains prior art for all that it reasonably teaches, even if its experimental model was later found to be inoperative or based on a mistaken premise. See MPEP §2121.01(II) The date at which a reference becomes available to the public, not the date when its correctness is confirmed or refuted, governs its prior-art status.
Furthermore, all references relied upon in the previous rejections (Jin published in 2007, Rong in 2014, and Jones in 2014) predate the 2017 disclosure provided by Applicant identifying QGY-7703 as a HeLa derivative. Each therefore reflects the accepted state of the art at its time of publication, and their teachings properly represent what a person of ordinary skill would have considered known and reasonably expected to succeed in treating liver cancer prior to the instant application’s effective filing date. The subsequent 2017 identification of the cell line as mischaracterized does not retroactively alter the content of the 2007 and 2014 disclosures, nor does it negate the reasonable expectation of success that existed when those references were published. Accordingly, the prior art remains valid and sufficient to support the 103 rejections of record, which are hereby maintained.
Claim Rejections - 35 USC § 103 (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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Jin et al. (Acta Pharmacol Sin, 2007 Jun; 28 (6): 859–868, previously cited), hereinafter Jin.
Jin discloses a gene expression studies involving homoharringtonine (HHT, also known as omacetaxine mepesuccinate), and teaches that HHT is an alkaloid with antileukemia activity against a variety of acute myeloid leukemic cells. The results suggest that the antitumor mechanism of HHT is related to its activity to induce apoptosis (2007, Introduction.) Jin concludes from the study results that “HHT is a potential drug in the treatment of liver cancer” (2007, Abstract & Conclusion.)
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to treat liver cancer by administering HHT/omacetaxine mepesuccinate, as Jin teaches that HHT has demonstrated activity against liver cancer and suggests its use as a therapeutic agent. A person of ordinary skill in the art would have been motivated to develop or use HHT for the treatment of liver cancer, with a reasonable expectation of success in light of Jin’s findings.
Claims 10 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Rong et al. (US 2014/0206669 A1, previously cited), hereinafter Rong, and further in view of Jin (Acta Pharmacol Sin, 2007 Jun; 28 (6): 859–868, previously cited).
Regarding Claims 10 and 18, Rong teaches a method for treating a subject suffering from tumor, such as from liver cancer or cholangiocellular carcinoma, comprising administering to the subject in need thereof an effective amount of an aminated or amidated homoharringtonine. (‘669, Pg. 3, Para 0013.) Rong teaches that aminated or amidated small molecules have been widely applied in pharmaceutical research (‘669, Pg. 2, Para 0007.) Rong discloses that the aminated homoharringtonine derivatives can induce the cell death of human solid tumor cells, to include Hep-2 (human hepatocellular carcinoma), and inhibit the growth of these tumor cells (‘669, Pg. 17, Example 4, Para 0175, 0181, and Table 2). Rong teaches both homoharringtonine (HTT) and aminated homoharringtonine derivatives inhibit the tumor cells (‘669, Pg. 17, Example 4, Para 0175 and Table 2.)
While Rong (2014) teaches the effects of both HHT and aminated derivates thereof, the reference focuses on their derivatives. However, the teachings of Jin (2007) are set forth in the above 35 U.S.C. 103 Rejections and are incorporated herein, which suggests the treatment of liver cancer with HHT/omacetaxine mepesuccinate.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to substitute the amidated HHT of Rong, with the omacetaxine mepesuccinate (HHT) of Jin. One would have been motivated to do, with a reasonable expectation of success, because Rong demonstrates that both HHT and aminated HHT are effective at inhibiting human liver cells, and both Jin and Rong teach treatments for tumors related to liver cancer.
Claims 10, 12-16, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Rong and Jin (cited above), and further in view of Jones et al. (WO 2014/031936 A2, cited in the IDS), hereinafter Jones.
The teachings of Rong and Jin are set forth in the above 35 U.S.C. 103 Rejections and
are incorporated herein. Rong and Jin teach a method for treating a subject suffering from tumor, such as from liver cancer, hepatocellular carcinoma, or cholangiocellular carcinoma, comprising administering to the subject in need thereof an effective amount of homoharringtonine (also known as HHT or omacetaxine mepesuccinate.)
Rong and Jin fail to teach a combination therapy which comprise omacetaxine mepesuccinate, a biologically active agent, and a chemotherapeutic (anti-cancer) agent. However, Jones teaches just such combination therapies.
Regarding Claims 10 and 18, Jones teaches methods for treating a HIF pathway-mediated disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition according to the present invention (‘936, Pg. 8, Para 014.) Inhibitors of protein translation may also be useful in combination with the present invention. Examples of inhibitors of protein translation include but are not limited to omacetaxine mepesuccinate (‘936, Pg. 68, Para 0208, 32.) The compounds, compositions, and methods disclosed herein are useful for the treatment of disease…including cancer…the cancer is a solid tumor (‘936, Pg. 71, Para 0215.) Cancers to be treated by the methods disclosed include…liver, hepatocellular carcinoma (‘936, Pg. 71-72, Para 0216.)
Regarding Claim 12-13 and 15-16, Jones teaches the compounds of formula I can be administered in combination with one or more agent selected from aromatase inhibitors… anti-cancer agent, inhibitors of angiogenesis, topoisomerase l and 2 inhibitors, alkylating agents… and a protein kinase inhibitor, e.g., a tyrosine kinase or serine/threonine kinase inhibitor (‘936, Pg. 59, Para 0205.)
Regarding Claim 14, Jones teaches anticancer agents suitable for use in the combination therapy with compounds as disclosed herein include, but are not limited to: …cabozantinib, sorafenib (‘936, Pg. 60 and 65, Para 0208, 26-a.)
Regarding Claims 19-20, Jones teaches pharmaceutical compositions comprising one or
more compounds disclosed herein together with a pharmaceutically acceptable carrier (‘936, Pg. 8, Para 014.)
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to treat solid liver cancer – including drug-resistant or advanced forms – by administering omacetaxine mepesuccinate in combination with a biologically active agent, and a chemotherapeutic (anti-cancer) agent.
Jin teaches that homoharringtonine (HHT, omacetaxine mepesuccinate), known for its use with acute myeloid leukemia, exhibits therapeutic relevance in treating liver cancer based on gene expression studies. Rong further teaches methods of treating liver cancer – to include aggressive and hard-to-treat forms such as hepatocellular carcinoma and cholangiocellular carcinoma – by administering HHT and its derivatives, thereby reinforcing its suitability as a treatment option.
Jones, while primarily focused on novel compounds found to inhibit the HIF pathway, expressly discloses combination therapies for treating a range of HIF pathway-mediated diseases, which include liver cancers such as hepatocellular carcinoma, and includes omacetaxine mepesuccinate, a biologically active agent, and a chemotherapeutic (anti-cancer) agent, among the potential therapeutic agents. Jones also highlights the rationale for combination therapy in managing complex or treatment-resistant diseases by targeting multiple biological pathways.
In view of the known challenges associated with treating liver cancer – to include aggressive and hard-to-treat forms such as hepatocellular carcinoma and cholangiocellular carcinoma – a person of ordinary skill in the art would have been motivated to explore combination therapies in order to enhance therapeutic efficacy, reduce resistance, or achieve synergistic effects with a reasonable expectation of success.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Donna M. Nestor whose telephone number is (703)756-5316. The examiner can normally be reached generally (w/flex): 5:30a-5p EST M-Th.
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/D.M.N./Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627