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 .
Status of Claims
The amendment filed on 06/09/2026 cancelled claims 1-12 and added claims 13-21. Claims 13-21 are pending and will be examined on the merits.
Response to Amendment
The amendment filed 06/09/2026 in response to the office action mailed 03/11/2026 is acknowledged. The rejections set forth under 35 USC §112 and 102 are withdrawn for the following reasons:
Applicant cancelled all previously examined claims and submitted new claims 13-21. All rejections to previous claims are therefore withdrawn. Arguments will be addressed to the extent they are still relevant to the new claims below.
Claim Objections
Claim 14 is objected to because of the following informalities: Line 1 of claim 14 recites "the ubenimex is administer prior to...". This is grammatically incorrect. Examiner suggests amending the claim to recite "the ubenimex is administered prior to...". Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 16 and 17 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 16 and 17 recite the outcome of the method of treatment described in claim 13, and do not in any meaningful way further limit the method of claim 13. Merely reciting the outcome of a method of treatment, not adding any additional steps or specific limitations to the administration method, does not add patentable weight to a claim. Moreover, the outcome of treatment described in claims 16 and 17 will necessarily happen if the treatment is administered as claimed, as demonstrated in the instant specification. Therefore, claims 16 and 17 do not further limit instant claim 13. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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(s) 13-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/112364 A1, Goodman et al., published 06/21/2018, in view of Toshiyama et al. (2019), Oncogene, 38(2), 244-260 and Talmadge (2019), Immunostimulants in cancer therapy. In Nijkamp and Parnham's Principles of Immunopharmacology (pp. 491-531).
The instant claims are drawn to a method of treating a malignant tumor comprising administering ubenimex and at least one immune checkpoint inhibitor (ICI) selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody, wherein the ubenimex is administered daily and the immune checkpoint inhibitor is administered once every 1 to 3 weeks. Dependent claims further define that the ubenimex is administered first, the pharmacokinetics of the ubenimex, the result of the administration, and the type of cancer the tumor is from. A second set of claims is drawn to a similar method, but expands the administration window of the ICI to 4 days to three weeks.
Goodman et al. teach a method of treating melanoma tumors, one of the cancers described in instant claim 18, comprising administering to the subject a bacterial composition comprising a bacillus Calmette-Guerin (BCG) bacterium and an ICI (specifically, an anti-PD1 or anti-PD1-L antibody) in claim 1, 3 and 6. Claim 14 of Goodman et al. teaches administering the ICI after the BCG, as in instant claim 14 and 21. In paragraph [0033], Goodman et al. teach that the method can also be used to treat lung cancer, prostate cancer, ovarian cancer, and/or melanoma, as recited in claim 18. Goodman et al. teach administration of the ICI every 1-3 weeks or every 4 days to 3 weeks. Additionally, in Example 1, paragraph [0131], Goodman et al. teach an increase in TILs after treatment, as recited in instant claim 17.
Goodman et al. do not teach administration of ubenimex, although they do add that ubenimex can be added to the treatment method in paragraph [0077] and recite that dosing of any compound in the treatment can be administered as medically indicated in paragraph [0118].
Toshiyama et al. teach a method of administering ubenimex to treat hepatocellular carcinoma and other solid tumors by increasing the concentration of ubenimex in the tumor tissue by using a polymer conjugated to the drug (abstract, whole document). Toshiyama et al. teach that a serum concentration of 2.21 μg/mL after oral administration of ubenimex. Toshiyama et al. also teach that the mechanism of the immunomodulating action of ubenimex is attributed to the stimulation of T-lymphocyte proliferation, likely mediated through the activation of macrophages (page 252, left column) and that daily administration of ubenimex has been used to treat gastric, lung, bladder cancer, head and neck, ovarian, and esophageal cancers. Toshiyama et al. suggest that similar agents to ubenimex can be used in immunotherapies to treat cancer as well, and disclose that similar agents have been used, in combination with anti-PD-1 therapy, to successfully treat melanoma, due to increased tumor infiltration of CD8+ Tcells and induction granulocyte-macrophage colony-stimulating factor (GM-CSF). Toshiyama et al. teach that ubenimex administration, which induces CD8+ cell activity and both T cell and macrophage recruitment, is likely to increase the intratumoral infiltration of CD8+ T cells and potentiate the efficacy of anti-PD-1 therapy in a similar manner.
Talmadge reviews immunostimulants in the context of cancer immunotherapy and presents both bestatin (another name for ubenimex, as disclosed by the instant specification in paragraph [0014]) and BCG as biological response modifiers of the immune system that can be applied to cancer therapies in section 25.8 (see page 505 and page 512, left column). Talmadge reiterates the immunostimulating role of bestatin as a aminopeptidase inhibitor. Talmadge teaches that the immunostimulatory method of BCG is not known, but is thought to augment local immune response, including increasing macrophage recruitment with increased M-CSF production. Talmadge also describes ICI therapy, in section 25.9, and the combination of ICIs with the other agents presented in the review, in Box 25.7: Combination Chemo-Immunotherapy (Biochemotherapy) on page 520, emphasizing that ICIs are able to restore immune function in immunosuppressed tumors by blocking the signaling axis in T cells that inhibits immune responses. Importantly, Talmadge notes that immunotherapies, such as ICI treatment, and chemotherapies, like BCG or bestatin treatment, have different mechanisms of action and different resistance profiles, and thus can be advantageous to combine. Talmadge states “significant insight into the pharmacology and toxicology of the therapeutic agents is needed in order to successfully combine chemotherapy and immunotherapy”, meaning that a synergistic effect can only be expected if the mechanisms of actions of the individual therapies would complement each other.
All of the above would be known to one of ordinary skill in the art of cancer treatment with immunotherapies. Taken together, one of ordinary skill in the art, before the effective filing date of the claimed invention, would be motivated to modify the treatment regimen of Goodman et al. to replace the BCG vaccine with ubenimex. As recited in Talmadge, BCG and ubenimex have similar mechanisms of action, stimulating localized immune responses and recruiting immune cells, such as macrophages and T cells, to a tumor environment. ICI therapy, which then helps activate T cells, would further augment the immune response in the tumor environment. Therefore, it would be obvious to one of ordinary skill in the art to modify the treatment regimen of Goodman et al. to replace the BCG vaccine with ubenimex. One would be motivated to do so because, as recited in Toshiyama et al., ubenimex will stimulate T-lymphocyte proliferation and macrophage recruitment. One would have reasonable expectation of success, as both Toshiyama et al. and Talmadge suggest that combination therapies are advantageous to tumor treatment if the mechanisms of action are synergistic, as ubenimex and ICI are suggested to be in Toshiyama et al. Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that a claim would have been obvious if the substitution of one known element for another yields predictable results to one of ordinary skill in the art. It would therefore be obvious to substitute ubenimex for BCG to be used in the method of Goodman et al., known in the art, to yield predictable results according to Toshiyama et al. and Talmadge. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary. Therefore, in view of Toshiyama et al. and Talmadge, it would be obvious to modify the method of Goodman et al. into a method of treating melanoma (or any of the other named cancers above) comprising administering an ICI and ubenimex. As taught in Goodman et al., one would be motivated to administer the ICI every 1-3 weeks and to administer the additional agent of ubenimex prior to the administration of the ICI. As stated in Toshiyama et al., one would administer the ubenimex daily. Additionally, the method of Goodman et al. shows increased TILs, and both Toshiyama et al. and Talmadge disclose increased cytokine response as a result of ubenimex and ICI treatment. Although the actual method as claimed is not performed, it would be reasonable to expect both increased TILs and cytokine production as a result of the treatment based on the data provided by Goodman et al. and Toshiyama et al., and the state of the art as reviewed in Talmadge. Moreover, as recited above, the limitations of claims 16 and 17 would naturally flow from such a treatment regimen, as there are no additional limitations recited in claims 16 and 17 that would impact the method of treating in a manner different than that made obvious by the combination of Goodman et al. and Toshiyama et al.
Finally, while none of the three sources disclose that the administration of ubenimex results in an area under a blood concentration-time curve (AUC) of 3.00 to 50.00 pg-hr/mL, the pharmacokinetics of ubenimex are well understood in the art (see, for example, Abe et al., Cancer Immunol Immunother 1989; 28(1):29-33) and reaching this administration would be well understood, routine, and conventional. Moreover, Toshiyama et al. disclose that increased concentrations of ubenimex are advantageous for tumor infiltration. Taken together, it would be obvious to one of ordinary skill in the art to administer ubenimex over a period of time to result in the claimed AUC range. Additionally, KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007), discloses that if a method is “obvious to try”, it is not patentable over the prior art. MPEP § 2144.05(II) recites that routine optimization is “obvious to try”, and therefore supported by said rational. Dosing parameters, such as how much of a medication is administered to achieve a specific pharmacokinetic outcome, could be routinely optimized in light of other dosing protocols and a well-established base of pharmacokinetic knowledge of the claimed drug, ubenimex. Therefore, it would be obvious to routinely optimize the dosing of ubenimex. Thus, the combination of prior art references, evidenced by Abe et al., provides a prima facie case of obviousness, absent convincing evidence to the contrary.
Therefore, claims 13-21 are obvious over Goodman et al., Toshiyama et al., and Talmadge, in view of the art.
Response to Arguments
Applicant's arguments filed 06/09/2026 have been fully considered but they are not persuasive. Applicant argues the combination of references provided do not disclose the claimed combination therapy method for treating a malignant tumor in a subject. Applicant argues that Abe et al. do not disclose an ICI and Sigl and Alt only mention ubenimex once in the entire disclosure, within a long list of other active ingredients.
Applicant’s arguments with respect to claim(s) 13-21 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Additionally, Examiner notes that in the previous set of claims, filed 11/27/2023 and rejected in the office action mailed on 03/11/2026, did not disclose a method of treating a malignant tumor, but were drawn to antitumor agents and/or medicaments that comprised only ubenimex OR an ICI and only the intended use of the agents in combination with each other, as stated in the previous office action under paragraph 6. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
A new rejection under USC 103 has been drafted to address the new claims, which recite a method of treating a malignant tumor. See paragraph 10 above.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 Amelia Stephens whose telephone number is (571)272-1006. The examiner can normally be reached M-F 8-5 EST.
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, Anne Gussow can be reached at (571) 272-6047. 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.
/AMELIA STEPHENS/Examiner, Art Unit 1645
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
Prosecution Insights