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 .
Information Disclosure Statement
Two information disclosure statements (IDS) submitted: one on 04/14/2022 and one on 05/03/2022. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The use of the term TWEEN® 20 (page 34, for example), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
While the Examiner has made every attempt to check the Specification for trade mark compliance, Applicant is required to carefully check the entire Specification for any and all issues regarding trade mark use compliance.
The disclosure is objected to because it contains an embedded hyperlink (page 42, line 5, for example) and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1, 6, 10, 17-19, 22-23, 25, 30-31, 34, 44, and 46) drawn to a method of reducing the production of glutamate from glutamine by GLS and GLS2 comprising selecting a cancerous cell or tissue and contacting with a dual GLS/GLS2 inhibitor of Formula IA, IB, IC, ID, II, III, or IV; in the reply filed on 01/02/2026 is acknowledged.
Upon election of Group I, Applicant was further required to elect a single compound of Formula IA, IB, IC, ID, II, III, or IV with all variables defined. Applicant elected compound 968, shown below (obtained from Wang et al.; Cancer Cell 18, 207–219, 2010; Figure 1C – cited in the instant specification, para. [0134], and incorporated by reference). The elected compound reads on Formula IA.
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Claims 2-5, 17, 22-23, 29, and 47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species or invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/02/2026.
Status of the Claims
Claims 1-6, 10, 17-19, 22-23, 25, 29-31, 34, 44, and 46-47 are pending in this application. Claims 7-9, 11-16, 20-21, 24, 26-28, 32-33, 35-43, 45, and 48-55 have been cancelled by Applicant. Claims 1, 6, 10, 18-19, 25, 30-31, 34, 44, and 46 are under examination herein. Claims 2-5, 17, 22-23, 29, and 47 have been withdrawn from consideration.
Examiner Notes
While claims 22-23 are not under examination herein, for the purposes of compact prosecution Examiner would like to point out that claims are presented as being dependent upon cancelled claim 11.
Claim Objections
Claim 46 is objected because the claim reads: “wherein said contacting comprises inhibiting cell proliferation . . .” Claim should read: “wherein said contacting results in inhibiting cell proliferation . . .”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 6, 10, 18-19, 25, 30-31, 34, 44, and 46 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is rejected because it states: “selecting a cancerous cell or cancerous tissue”. It is unclear how this “selecting” step will be performed. On what basis is the specific cancerous cell or cancerous tissue being selected? Does the cancerous cell or cancerous tissue being selected have to show overexpression of GLS and GLS2 (since they are being contacted with a dual GLS/GLS2 inhibitor), or does any cancerous cell or cancerous tissue work? – if so, why is a specific cancerous cell or cancerous tissue being “selected”?
Claims 6, 10, 17-19, 25, 30-31, 34, 44, and 46 are rejected for depending upon the limitations of claim 1.
Claims 18-19 are rejected as being indefinite for depending upon cancelled claim 11. For the purposes of applying art, the claims will be interpreted as being dependent upon the limitations of claim 10.
Regarding claim 46, it is unclear how the contacting of a cancerous cell with the dual GLS/GLS2 inhibitor, as recited in claim 1, can inhibit proliferation, tumorigenesis, tumor growth, tumor initiation, and/or metastasis in a cancerous cell.
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, 6, 30-31, 34, 44, and 46 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yue-Zhi et al. (Oncotarget, 5, 2014, 6087-6101 – previously cited) (“Yue-Zhi”).
Regarding claim 1, Yue-Zhi teaches GLS2 inhibitor AV-1 (see page 6092, Figure 2-D, entry 1) which has a selectivity index of only 7.50 for GAB (glutaminase B – corresponding to GLS2; see page 6088, col. 1, first 2 lines) over KGA (kidney isoform – corresponding to GLS; see page 6087, col. 2, end of page) – thus, production of glutamate from both, GLS and GLS2 was reduced. Yue-Zhi discloses their study was performed on HepG2 and A549 (cancer cells) (Materials and Methods, starting page 6096, col. 2).
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Regarding claim 6, Yue-Zhi discloses their AV-1, which inhibits GAB and KGA (thus anticipating inhibition of GLS2 and KGA; and/ or GAB inhibition.
Regarding claims 30-31, Yue-Zhi discloses GAB (GLS2) levels were high in human hepatoma HepG2 and lung carcinoma A549 cells (page 6091, col. 2, last para., lines 1-3) (anticipating liver cancer and lung cancer).
Regarding claim 34, Yue-Zhi teaches GAB and KGA protein expression levels were found to be higher in human hepatoma HepG2; LGA protein expression was low in each cell line but expressed slightly more in HepG2. Yue-Zhi specifically teaches that their dual inhibitor AV-1 inhibited colony formation of HepG2 cells (page 6091, col. 2, last para., 5 lines from bottom) – thus, Yue-Zhi anticipates contacting a cancerous cell wherein the cancer has moderate to high GLS2 expression and low GLS expression (See Table 2, pages 27-28 of the instant spec.).
Regarding claim 44, Yue-Zhi discloses that AV-1 comparably inhibited the wild type and the two KGA mutants (GLS), which were resistant to BPTES inhibition (a GLS-specific inhibitor) (page 6091, col. 2, para. 2).
Regarding claim 46, Yue-Zhi discloses that GLS2 inhibition with AV-1 inhibited cancer colony formation (tumor growth) (page 6091, col. 2, last para., 5 lines from bottom).
Claims 1, 6, 10, 18-19, 25, 30-31, 34, and 46 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Katt et al. (Future Med. Chem. (2017) 9(2), 223–243) (“Katt”).
Regarding claims 1 and 6, Katt discloses the elected compound, 968, as a dual GLS/GLS2 inhibitor in cancerous cells (see Executive Summary; page 238; and Figure 8, bottom row) – “968 class of inhibitors is less well investigated, but evidence suggests that they inhibit GLS and LGA with similar potency.” (wherein LGA corresponds to GLS2); and discloses 938 has shown efficacy with cell cultures and animal models (page 237, para. bridging col. 1-2) – thus, Katt anticipates the instant claim to a method of reducing glutamine production by GLS and GLS2 by contacting a cancerous cell with a dual GLS/GLS2 inhibitor. Applicant is advised that products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
Regarding claims 10 and 18-19, Katt discloses compound 968, which anticipated the instant compounds of Formula IA; wherein R4a is not H (claim 18) and wherein at least two of R2a-6a are not H (claim 19). Specifically, instant R4a is -N(Me)2 and instant R3a is Br.
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Regarding claim 25, Katt discloses compound 968 with the “active moiety”
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.
Regarding claims 30-31 and 46, Katt discloses that LGA inhibition (GLS2) inhibited growth of both A549 lung cancer cells and HepG2 hepatoma cells (lung and liver cancers, which exhibit active GLS2; and anticipating inhibition of tumor growth (claim 46)) (page 235, col. 1, lines 8-10).
Regarding claim 34, Katt discloses GLS2 is relatively highly expressed in cancers of the liver (page 233, top text). Katt also discloses that LGA inhibition (GLS2) inhibited growth of HepG2 hepatoma cells (liver cancers) – thus Katt anticipates contacting HepG2 hepatoma cells with 968, wherein the cancer has high GLS2 expression and low GLS expression – in accordance with the parameters of the instant specification (See Table 2, pages 27-28 of the instant spec.).
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 44 is rejected under 35 U.S.C. 103 as being unpatentable over Katt et al. (Future Med. Chem. (2017) 9(2), 223–243) (“Katt”); as applied to claims 1, 6, 10, 18-19, 25, 30-31, 34, and 46.
The teachings of Katt are disclosed in the 102-section above and incorporated herein.
Regarding claim 44, Katt discloses a major question is the importance of LGA in tumors, and whether its expression could lead to resistance to GLS-specific inhibitors. Katt discloses that inhibition of GLS alone is insufficient to halt progression of some tumors (page 238, col. 2). Katt also teaches that many cancer cells exhibit an altered metabolic phenotype, in which glutamine consumption is upregulated relative to healthy cells, often depending upon mitochondrial glutaminase activity, which converts glutamine to glutamate via GLS and GLS2 (or LGA) (abstract); and discloses 968 as a dual GLS/GLS2 (LGA) inhibitor, which has shown efficacy in cell and animal models.
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to contact a cancerous cell or tissue with Katt’s dual GLS/ GLS2 inhibitor to a cancer cell or cancerous tissue showing resistance to GLS-specific inhibitors. One of ordinary skill would have been motivated to do so because Katt suggests LGA expression might lead to resistance to GLS-specific inhibitors; and teaches that glutamine consumption is upregulated in cancerous cells relative to healthy ones, depending on glutaminase activity (GLS and GLS2) for glutamine production (which feeds cancerous cells). One of ordinary skill would have had a reasonable expectation of success because a cancerous cell or cancerous tissue that is resistant to GLS-inhibitors would be expected to respond to Katt’s 968 dual inhibitor to inhibit glutamine formation via GLS2 activity.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627