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 .1
This application has been reassigned from Examiner, Jed A. Kucharczk to Examiner William Lee, in Art Unit 1623. In order to expedite accurate processing of the application papers, all future correspondence with the office should reflect this change.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-7, 9-14 and 20, drawn to methods of treatment in the reply filed on Feb 27 2026 is acknowledged.
Claims 21-25 and 27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected Group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on Feb 27 2026.
NOTE: Claims 8, 15-19 and 26 were cancelled by Applicant amendment on Nov. 6 2023 where the November 2026 claim set was relied upon Examiner Kucharczk to restrict the claims. In the current and examined Feb. 27, 2026 set of claims, Applicant has reintroduced the claims, where canceled claims 8, 15-19 and 26 appear with the claim identifier “(Original).” Canceled claims 8 and 15-19 and 26 remain canceled as they cannot be reintroduced for examination by re-listing them in the latest set of claims. When responding to this office action, Applicant must correct the claims to indicate these claims as canceled. The most recent claim set also reintroduces many improper multiple dependent claims.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on Nov 6 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 4, 7, 12-14, 20 and 26 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from another multiple dependent claim. See MPEP § 608.01(n). Accordingly, claims 4, 7-8, 12-16 and 18-20 not been further treated on the merits.
Claim 3, and 11 are objected to because of the following informalities:
Claims 3 and 11, line 1 recites “wherein solid tumor.” Claim 3 depends from both claim 1 and claim 2, where the first occurrence of “solid tumor” is claim 2. Claim 11 depends from both claim 9 and claim 10 where the first occurrence of “solid tumor” is claim 10. Claims 3 and 11 must be amended to recite “the” before “solid tumor” for proper antecedent basis. Note, claim 1 does not introduce the term “solid tumor” for, so claim 3 fails to further limit claim 1, where claim 3 recites “solid tumors” of claim 1 or 2. Examiner suggests amending claim 3 to depend only from claim 2.
Canceled claims 8, 15-19 and 26 are listed by the claim identifier “(Original).” They recite their original claim language and reappear, in the latest set of examined claims of Feb. 27, 2026. Claims 8, 15-19 and 26 were cancelled by amendment on Nov. 6, 2023 where the Nov 2026 claim set was relied upon Examiner Kucharczk to restrict the claims. Canceled claims 8 and 15-19 and 26 remain canceled as they cannot be reintroduced for consideration/examination by re-listing them in the latest set of claims. Applicant must correct the claims to note the correct status as canceled claims.
Claim Interpretation
Claims 5 and 6 recite the transition phrase “comprises” to define the claimed M1 aminopeptidase inhibitors to note they are a particular type of inhibitor, such as a puromycin-sensitive aminopeptidase (NPEPPS) inhibitor, or in particular tosedostat. The particular terms are interpreted to mean not only compounds individually, but also a class of compounds that belong to classes of M1 aminopeptidase inhibitors or puromycin-sensitive aminopeptidase (NPEPPS) inhibitors (tosedostat).
Support for this interpretation can be found in paragraphs 7-8 of the specification, where embodiments of the invention’s M1 aminopeptidase inhibitor are to referred to as “one or more,” thus defining the term M1 aminopeptidase inhibitor as being a class of compounds, rather than a single compound per se.
Claim Rejections - 35 USC § 112 (Scope of Enablement)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-3, 5-6, and 9-11 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for treating a tumor (solid or not) with tosedostat (as the M1 aminopeptidase inhibitor, specifically a puromycin-sensitive aminopeptidase (NPEPPS) inhibitor) with cisplatin to treat bladder cancer/tumors, does not reasonably provide enablement for the full scope of treating any tumor, solid, nonsolid, cancerous or otherwise, with the full scope of any M1 aminopeptidase inhibitor or any platinum chemotherapy drug.
Also note, an enabled scope of the invention is the use of M1 aminopeptidase inhibitor, Ubenimex (aka Bestatin) to treat gastric cancers/tumors as detailed in the novelty rejection below.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in the FULL scope with these claims.
Independent claims 1 and 9 are similarly directed to a method for treating a tumor (solid tumor per claim 9), comprising administering to a subject in need thereof an (effective amount per claim 9) M1 aminopeptidase inhibitor; wherein the subject is undergoing or will undergo an anti-cancer therapy comprising one or more platinum-based chemotherapeutic agent and (sensitizing the tumor to platinum-based chemotherapeutic agents in the subject per claim 1); wherein puromycin-sensitive aminopeptidase (NPEPPS) gene expression or protein level is measured in a tumor biopsy sample from the subject at least one of before, during, and after the treatment.
Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set eight forth factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
The predictability or unpredictability of the art: The instant claimed invention is highly unpredictable since a person having ordinary skilled in the art (PHOSITA) recognizes the difficulties associated in treating any single cancer let alone the full scope of treating any tumor (cancerous or not) as presently claimed.
Initially, the claims at their broadest and reasonable encompass treatment of both cancerous and non-cancerous (benign) tumors. It is known in the art that platinum-based chemotherapy (cisplatin), where platinum binds to tumor cell DNA via intra- and inter-crosslinking, changes the structure and damages the DNA to prevent the cancer cell cycle and induce apoptosis in rapidly proliferating tumor cells. See page 2116 column 1 bridging to page 2117 column 2 of Zhang et al.2 In contrast, benign tumor cells do not undergo the rapid division, rapid growth and metastatic spread of cancer cells required by platinum chemotherapy to work. Therefore, the art recognizes the unpredictability of treating benign tumors with platinum based chemotherapy.
Further, Jones et al. 3 evidences the benefits and the potential of treating bladder cancer with the claimed combination of tosedostat (M1 aminopeptidase/(NPEPPS) inhibitor and cisplatin. Note lead author Robert Jones is listed as co-inventor on the examined application, and the Jones article was cited on the IDS as NPL Ref. D6.
However, Jones et al. cautions that NEPPPS could have effects on treatment response outside of platinum drugs. See page 1715, column 2.4
Further, while the specification and Jones provide evidence of NPPEPS as a driver of cisplatin resistance, and therefore use of a NPEPPS inhibitor such as tosedostat with cisplatin to overcome said resistance in bladder cancer, the art recognizes that ”the molecular mechanisms by which CDDP [cisplatin] resistance develops are not clear but are believed to be multi-factorial.” See abstract of Lugones et al.5 The mechanism of action of cisplatin can be summarized as Pre-Target Resistance (reduction of cisplatin entry into the cell, etc.); On-Target Resistance (cellular activation of DNA repair mechanisms, etc.); Post-Target Resistance (inactivation of TP53 gene producing a loss of apoptotic activity, etc.); and Off-Target Resistance (alterations in signaling pathways that are not directly related to cisplatin but interfere with cisplatin-induced proapoptotic events). See pages 2-5 of Lugones et al. Section 3 and Figure 2. Resistance to Cisplatin Treatment. See also Section 4 of Lugones starting on page 5, noting cisplatin resistance is multifactorial and cannot be explained by deregulation of single molecular mechanism, but also epigenetic factors (heritable changes in gene expression not attributable to variations in DNA sequence, i.e. non-coding RNA), associated with Pre-, on- and Post-Target Resistance. See also Table 1 of Lugones. While certain aspects of M1 aminopeptidase/NPEPPS inhibition has been demonstrated with these compounds with cisplatin, the unpredictability of cisplatin resistance known in the art precludes a finding of enablement of the full scope treating all cancers/tumors as claimed.
Therefore, the unpredictability of the art is a Wands factor against of enablement of the full scope of the invention.
The breadth of the claims: The instant claims are deemed to be broad as they purport to treat any tumor (cancerous and non-cancerous) with any platinum drug and any M1 aminopeptidase (NPEPPS) inhibitor. The breadth of claims is a Wands factor against enablement of the full scope of the invention.
The amount of direction or guidance presented, and the presence or absence of working examples: It has been established that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” In re Fisher, 427 F.2d 833, 839 166 USPQ 18, 24 (CCPA 1970).
There is no working example to support the full scope of the claimed invention. The specification only provides limited data for experiments specifically focused on bladder cancer cells in vitro, in particular with either cisplatin and/or gemcitabine and tosedostat. See paragraphs 17-32 detailing Figs. 1A-1C, Figs. 2A-2E, Figs. 3A-3H, 4A-4F (CRISPR identification of muscle invasive bladder cells, synthetic lethality for NPEPPS protein expression; genetic pharmacological inhibition of NPEPPS in resistant cells, NPEPPS interaction with VRAC channels and cisplatin drug response). Fig. 6 to Figs. 12A-12K to Figs.16A-16D from paragraphs 22 to 32, describe various in vitro only experiments regarding NPEPPS response and expression with regard to various cell lines and possible potentiation of cisplatin.
Figs. 5A-5L are supportive of the limited, enabled scope of the invention, noting the pharmacological inhibition of NPEPPS re-sensitizing in vivo and ex vivo models of bladder cancer. See paragraph 21. Figs. 5A-5L are detailed further in the specification’s Example 5 (paragraph 110 starting at page 41). Example 5 notes Figs. 10A-10B demonstrate patient bladder cancer cell organoids, when treated with increasing cisplatin and 20µM of tosedostat significantly decreased bladder cancer organoid growth. Id. at paragraph 110, page 43.
With the exception of the Example 5 supporting the limited scope of cisplatin and tosedostat as the NPEPPS inhibitor to treat bladder cancer tumors, the lack of working examples cannot support the full scope of the claimed invention.
Therefore, in view of the Wands factors as discussed above, Applicant fails to provide information sufficient to practice the full scope of the claimed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3 are rejected under 35 U.S.C. 102(a)(1) as anticipated by Guo et al. Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells- by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis, Aging 2020 Volume 12, No. 1 pp. 80-105. Guo is NPL No. D7 on the IDS dated 11/2023,.
Regarding claims 1-3 and claimed combination of M1 aminopeptidase inhibitor, platinum drug to treat platinum (cisplatin) resistant metastatic solid tumors (stomach cancer) , Guo teaches Ubenimex (aka Bestatin) a known M1 aminopeptidase inhibitor6, was investigated in combination with the platinum cancer drug, cisplatin (CDDP)-based chemotherapy to treat gastric [stomach] cancer (GC). See abstract. Guo teaches gastric cancer’s resistance to cisplatin chemotherapy is caused by the transmembrane enzyme CD13. Id. Guo teaches with cisplatin treated gastric cancer patients, tumor metastasis and local recurrence become increasingly common due such chemoresistance. See page 80, column 1. Guo teaches that Bestatin (therein called Ubenimex) is a CD13 inhibitor that reverses cisplatin resistance and renders cisplatin resistant gastric cancer cells sensitive to cisplatin. Id. With regard to claims 1-3, Guo teaches the claimed subjects in need suffering from GC, cisplatin-resistant subjects are mouse subject treated with a combination of cisplatin and Ubenimex (aka Bestatin). See page 94, column 1.
Conclusion and Correspondence
In conclusion, no claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can be reached M-F.
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, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 CONTINUING DATA
This application is a 371 of PCT/IB2022/056778 07/22/2022
PCT/IB2022/056778 has PRO 63/224,691 07/22/2021
2 Zhang et al. Platinum-based drugs for cancer therapy and anti-tumor strategies, Theranostics. 2022 Feb 7;12(5):2115–2132..
3 Jones et al. NPEPPS Is a Druggable Driver of Platinum Resistance Cancer Res; 84(10) May 15, 2024 pp. 1969-1718.
4 Jones states: NPEPPS is upregulated in the Gem-resistant cell lines (Fig. 2), and whereas we show that genetic NPEPPS loss is specific to cisplatin response (Fig. 3; Supplementary Fig. S4), NPEPPS upregulation could be part of broader cellular stress responses. NPEPPS is upregulated in the Gem-resistant cell lines (Fig. 2), and whereas we show that genetic NPEPPS loss is specific to cisplatin response (Fig. 3; Supplementary Fig. S4), NPEPPS upregulation could be part of broader cellular stress responses. Id.
5 Lugones et al. Cisplatin Resistance: Genetic and Epigenetic Factors Involved, Biomolecules. 2022 Sep 24;12(10):1365. doi: 10.3390/biom12101365
6 See specification paragraph 47
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