Notice of Pre-AIA or AIA Status89
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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/05/2025 has been entered.
The Amendment filed 12/05/2025 amended claim 38.
Claims 38 and 41-56 are pending.
Priority
This application claims the following priority:
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Election/Restrictions
Applicant elected, without traverse, the species GPNA as the inhibitor that modulates glutamine metabolism or suppresses metabolic enzymes with regard to glutamine, and the species, an inhibitor that blocks or inhibits PD-1 as the immune check-point inhibitor, in the reply filed on 09/30/2024.
Claims 38, and 41-56 are examined on the merits herein.
REJECTIONS WITHDRAWN
The status for each rejection and/or objection in the previous Office Action is set out below.
35 USC § 112(a)—New Matter
Applicant’s amendment to claim 38 is sufficient to overcome this rejection.
35 USC § 112(a)—Written Description
Applicant’s deletion of claim 40 is sufficient to overcome this rejection.
REJECTIONS--MAINTAINED, MODIFIED, & NEW
Applicant’s amendment to claim 38 has resulted in the below modified rejections.
Heffernan continues to be relied upon as a primary reference, and Molineaux and Hassanein as secondary references.
Claim Rejections - 35 USC § 112(a)-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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
(New) Claims 38 and 41-56 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 of treating a subject having NSCLC with a deregulated NRF2/KEAP1 pathway by administering a GPD2 inhibitor, does not reasonably provide enablement for a method of treating a subject having any cancer associated with a deregulated NRF2/KEAP1 pathway by administering any one or more glutamine transport inhibitors in combination with any one or more immune check-point inhibitors. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The criteria for enablement set out in the In re Wands, MPEP 2164.01(a), considers the following factors:
Breadth of the Claims
Independent claim 38 is directed toward a method of treating a subject having any cancer associated with a deregulated NRF2/KEAP1 pathway by administering any one or more glutamine transport inhibitors in combination with any one or more immune check-point inhibitors.
As such, the breadth of the claims is great.
Level of Skill in Art
The level of skill in the art is a scientist with a PhD or a clinician.
State of the Prior Art
US PG-PUB 2016/0058759 to Heffernan (published 2016, PTO-892 of 11/22/2024) teaches a method of treating cancer comprising determining that the NRF2/KEAP1 pathway is deregulated, and administering a glutaminase inhibitor to the subject (pg. 35, claims 1-7, 9-10).
Heffernan teaches the glutaminase inhibitors as chosen from Table 1 (pg. 35, claim 15; [0159]):
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Chen (Targeting Glutamine Induces Apoptosis: A Cancer Therapy Approach, Int. J. Mol. Sci., published 2015, PTO-892) teaches that glutamine metabolism has been proven to be dysregulated in many cancer cells, and is essential for proliferation of most cancer cells. In order to be well used by cells, glutamine must be transported to cells by specific transporters and converted to glutamate by glutaminase (abstract).
Chen teaches that increased glutamine transporters account for glutamine addiction in most cancer cells, and that glutamine transport inhibition is a way to restrict glutamine metabolism (pg. 22838 “3.2.”).
Chen teaches the following compounds as targeting glutamine metabolism in cancer research:
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(pg. 22839).
Chen also teaches inhibition of glutaminase as another means of targeting glutamine (pg. 22839, “3.3.”).
Hassanein (Targeting SLC1A5-mediated glutamine dependence in non-small cell lung cancer, IJC, published 07/14/2015, PTO-892 of 11/22/2024) teaches that administering GPNA, a glutamine transport inhibitor, to NSCLC cells greatly decreases cell growth (title, abstract). Hassanein teaches that “Although pharmacological strategies to inhibit glutamine metabolism using amino acid analogs such as acivicin and DON have been investigated, the lack of selectivity of these agents has shifted the efforts to developing agents directed at specific nodes of glutamine metabolism instead. Given the emerging role of glutamine metabolism in cancer and the differential expression of SLCIA5 in NSCLC, it was found that elevated SLC1A5 expression is a key pro-survival mechanism that promotes NSCLC progression by increasing tumor cells to transport and utilize glutamine” (pg. 1588, Col. 1, 1st two full paragraphs).
GPNA inhibits growth in SLCaA5-high expressing cells in a time and dose dependent manner, which indicates that GPNA preferentially inhibits SLC1A5-high expressing NSCLC lines (pg. 1590, Col. 1).
Thus, while the prior art teaches that it is known to treat cancers associated with a deregulated NRF2/KEAP1 pathway by administering inhibitors of glutamine metabolism, such as glutamine transporter inhibitors, the prior art is limited to the teaching of a small number of species of cancer and a small number of species of inhibitors of glutamine metabolism, wherein the species of inhibitors of glutamine transporters in the prior art are limited to GPNA, BCH, alpha-methyl-DL-tryptophan, tamoxifen, and raloxifene.
Predictability in the Art
Hassanein teaches that “Although pharmacological strategies to inhibit glutamine metabolism using amino acid analogs such as acivicin and DON have been investigated, the lack of selectivity of these agents has shifted the efforts to developing agents directed at specific modes of glutamine metabolism instead. Given the emerging role of glutamine metabolism in cancer and the differential expression of SLCIA5 in NSCLC, it was found that elevated SLC1A5 expression is a key pro-survival mechanism that promotes NSCLC progression by increasing tumor cells to transport and utilize glutamine” (pg. 1588, Col. 1, 1st two full paragraphs).
Chen teaches that more studies are required to figure out the molecular mechanism in the relationship between glutamine and apoptosis in cancers. Chen further teaches that in some cancers, glucose and glutamine are complementary to each other, and that inhibiting one nutrient may be useless in treating some cancer cells when another nutrient is available (pg. 22844).
Thus, the prior art teaches that the art of treating cancer by administering glutamine metabolism inhibitors in unpredictable due to the lack of selectivity of pharmacological agents and the ability of different cancers to utilize glucose instead of glutamine when glutamine metabolism is inhibited.
Working Examples
Example 1 ([0170]) shows that Keap1 is a tumor suppressor with genotype-specific metabolic vulnerabilities in KRAS driven lung cancer.
Example 2 ([217]) provides additional Keap1 data to demonstrate that loss of Keap1 accelerates lung tumorigenesis, that KEAP1/NRF2 status correlates with poor clinical outcome, and that Keap1 mutant cells require uptake of serine and glutamine.
Example 3 ([0225]) is a GPD2 study. This study shows that three out of four sgRNAs against the GPD2 were depleted in KPK (Krasp53Keap mutant) but not KP (Krasp53 mutant) cells, suggesting a synthetic lethal interaction of GPD2 with Keap1 mutation.
Example 4 ([0229]) is a Slc1a5 study that determines the role of Slc1a5 in Keap1 mutant lung tumorigenesis using GEMMS (genetically engineered mouse models), wherein the results confirm that Slc1a5 is essential for KEAP1 mutant tumors, wherein Slc1a5 is a neutral amino acid transporter responsible for importing serine and glutamine from the extracellular environment ([0237]).
Example 5 ([0241]) determines the role of Gpd2 in Keap1 mutant lung tumorigenesis. “Gpd2 is required for the growth of Keap1 mutant lung cancer cells in vitro, which indicates that Gpd2 plays a crucial role in the maintenance of KPK tumors in vivo.” These studies establish the function of Gpd2 in a Keap1 mutant human mouse model of NSCLC ([0248]). Example 5 states that “recent data demonstrated that the guanides/biguanides anti-diabetic drug metformin inhibits GPD2 enzymatic activity in vivo. Metformin has been previously used extensively in pre-clinical trials for various types of studies, including various cancer models, however, its activity in the context of KRAS; KEAP1 mutant NSCLC has not been previously determined.” And Example 5 further shows metformin repression of tumor growth in KPK GEMMs and PDX (patient derived xenograft) models with KRAS;KEAP1 mutations, confirming the efficacy of a GPD2 inhibitor. Example 5 concludes by stating “GPD2 is predicted to be essential for Keap1 mutant cells because they rely on GPD2 to maintain homeostatic levels of NAD/NADH in order to maintain glycolysis and TCA (Krebs/citric acid) cycle. Therefore, genetic loss or pharmacological inhibition of GPD2 will lead to decreased NAD/NADH levels and a decreases in Keap1 mutant but not WT cells” ([0250]-[0256]).
Thus, none of the instant examples are directed toward a method of treating a subject having cancer associated with a deregulated NRF2/KEAP1 pathway with a glutamine transporter inhibitor. The only exemplified cancer therapeutic is metformin, wherein Example 5 states that “KP, KPK GEMMs and PDX models described above are used to perform pre-clinical studies with metformin.” However, metformin is not a glutamine transporter inhibitor.
Direction and Guidance
In view of the state of the prior art, the unpredictability of the art of treating cancers associated with deregulated NRF2/KEAP1 pathways with glutamine metabolism inhibitors, and the lack of working examples, the instant specification does not provide sufficient direction and guidance to use the invention as instantly claimed.
Quantity of Experimentation
The amount of experimentation required to determine which cancers associated with a deregulated NRF2/KEAP1 pathway are treated when which glutamine transporter inhibitors combined with which check-point inhibitors, would be astronomical, amounting to invention and not development; it is an undue amount of experimentation.
Thus, while being enabling for a method of treating a subject having NSCLC with a deregulated NRF2/KEAP1 pathway by administering a GPD2 inhibitor, the instant specification does not reasonably provide enablement for a method of treating a subject having any cancer associated with a deregulated NRF2/KEAP1 pathway by administering any one or more glutamine transport inhibitors in combination with any one or more immune check-point inhibitors.
Claim Rejections - 35 USC § 103
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 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.
(Modified) Claims 38, 41-44, 46-50, 53-56 are rejected under 35 U.S.C. 103 as being unpatentable over US PG-PUB 2016/0058759 to Heffernan (published 2016, PTO-892 of 11/22/2024) in view of Chen (Targeting Glutamine Induces Apoptosis: A Cancer Therapy Approach, Int. J. Mol. Sci., published 2015, PTO-892) Hassanein (Targeting SLC1A5-mediated glutamine dependence in non-small cell lung cancer, IJC, published 07/14/2015, PTO-892 of 11/22/2024), US PG-PUB 2017/0095473 to Molineaux (published 2017, PTO-892 of 11/22/2024).
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Heffernan teaches a method of treating cancer comprising determining that the NRF2/KEAP1 pathway is deregulated, and administering a glutaminase inhibitor to the subject (pg. 35, claims 1-7, 9-10).
Heffernan teaches the glutaminase inhibitors as chosen from Table 1 (pg. 35, claim 15; [0159]).
Heffernan teaches glutamine as playing an essential role in providing cancer cells with biosynthetic intermediates to support proliferation and survival ([0002]). In addition to supporting cell growth, glutamine metabolism plays a critical role in maintaining cellular redox homeostasis as glutamate can be converted into glutathione, the major intracellular antioxidant; many cancer cells have evolved a dependence on glutamine metabolism for growth and survival ([0003]).
Heffernan teaches that deregulation of the NRF2/KEAP1 pathway, NRF2 signaling, or mutations in KEAP1 or NRF2 confer a dependence of tumors on reduced glutathione, the major endogenous antioxidant comprised of glycine, cysteine, and glutamine-derived glutamate ([0016]). Tumors that harbor somatic mutations that deregulate the NRF2/KEAP1 pathway evolve a dependence on glutathione and an addiction on glutamine ([0497]).
Heffernan specifically teaches NSCLC cell lines as having a dependence on glutamine metabolism for survival ([0475]).
Regarding claim 38, while Heffernan teaches a method of treating NSCLC, comprising determining that the NRF2/KEAP1 pathway is deregulated, and administering (pgs. 32-34, Examples 1-4) to a subject, a glutaminase inhibitor to suppress glutamine, it differs from that of claim 38 in that it does not teach administering a glutamine transport inhibitor.
Chen teaches that glutamine metabolism has been proven to be dysregulated in many cancer cells, and is essential for proliferation of most cancer cells. Chen teaches that in order to be well used by cells, glutamine must be transported to cells by specific transporters and converted to glutamate by glutaminase (abstract).
Chen teaches that increased glutamine transporters account for glutamine addiction in most cancer cells, so glutamine transport inhibition is a way to restrict glutamine metabolism (pg. 22838 “3.2.”).
Chen teaches the following compounds as targeting glutamine metabolism in cancer research:
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(pg. 22839).
Chen also teaches inhibition of glutaminase as another means of targeting glutamine (pg. 22839, “3.3.”).
In summary, Chen teaches that “Glutamine is a versatile amino acid and is used to support cell growth and proliferation. It has been proved that glutamine is irreplaceable especially for most tumor cells. Restriction of glutamine metabolism through depriving glutamine, blocking glutamine transporters, or inhibiting GLS activity have been proven to be effective in inhibiting tumor cell growth by inducing apoptosis and/or autophagy. . .they are also effective in increasing cancer cells’ sensitivity to other common chemotherapy when they work together” (pg. 22843, “Conclusions”).
Hassanein teaches that administering GPNA to NSCLC cells greatly decreases cell growth (title, abstract).
Hassanein teaches that “Although pharmacological strategies to inhibit glutamine metabolism using amino acid analogs such as acivicin and DON have been investigated, the lack of selectivity of these agents has shifted the efforts to developing agents directed at specific nodes of glutamine metabolism instead. Given the emerging role of glutamine metabolism in cancer and the differential expression of SLCIA5 in NSCLC, it was found that elevated SLC1A5 expression is a key pro-survival mechanism that promotes NSCLC progression by increasing tumor cells to transport and utilize glutamine” (pg. 1588, Col. 1, 1st two full paragraphs).
GPNA inhibits growth in SLCaA5-high expressing cells in a time and dose dependent manner, which indicates that GPNA preferentially inhibits SLC1A5-high expressing NSCLC lines (pg. 1590, Col. 1).
In summary, Hassanein teaches a) that SLC1A1, a glutamine transporter, is overexpressed protein in NSCLC (abstract); b) that in the presence of increasing concentrations of GPNA, a dose-dependent growth inhibition of SLC1A5 high expressing cells is observed (pg. 1590, Figs. 1a-1c); c) GPNA treatment causes a marked increase in cell death (pgs. 1590-1591); c) GPNA treatment significantly reduces xenograft tumor growth when compared to controls and these results provide the first in vivo proof-of-concept for targeting SLC1A5 as a therapeutic candidate for NSCLC (pg. 1594, 1596).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to add GPNA to the methods of Heffernan, to arrive at a method of treating NSCLC comprising determining that the NRF2/KEAP1 pathway is deregulated, and administering, to a subject, a glutamine transport inhibitor (GPNA). One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-Heffernan, Chen, and Hassanein are all directed toward methods of treating cancer by administering inhibitors of glutamine metabolism, and Hassanein and Heffernan are specifically directed toward methods of treating NSCLC by administering an inhibitor of glutamine metabolism,
-Chen teaches that in order to be well used by cells, glutamine must be transported to cells by specific transporters and converted to glutamate by glutaminase, and teaches that both glutaminase inhibitors and glutamine transport inhibitors are known in the art to target glutamine metabolism to treat cancer (Table 1, Chen),
-Hassanein teaches that glutamine plays an essential role in providing cancer cells with biosynthetic intermediates required to support proliferation and survival, and that many cancer cells have evolved a dependence on glutamine metabolism for growth and survival,
-Hassanein teaches GPNA as inhibiting/suppressing glutamine metabolism by inhibiting SLC1A5 in NSCLC, wherein SLC1A5 is the primary transporter of glutamine, a modulator of cell growth and oxidative stress in NSCLC (abstract), and
-"It is prima facie obvious to combine two compositions (inhibitors of glutamate metabolism) each of which is taught by the prior art to be useful for the same purpose (treating cancer, such as NSCLC), in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980), MPEP 2144.06
As such an ordinary skilled artisan would have been motivated to make such an addition to predictably arrive at a method that more potently inhibits glutamine metabolism, i.e., inhibiting the conversion of glutamine to glutamate and inhibiting the transport of glutamine into a NSCLC cell, and thus more effectively restricts the tumor cells’ access to glutamine, thereby treating NSCLC by decreasing tumor growth and tumor cell survival.
Alternatively, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the glutaminase inhibitor of Heffernan with GPNA, to arrive at a method of treating cancer comprising determining that the NRF2/KEAP1 pathway is deregulated, and administering, to a subject, a glutamate transport inhibitor, such as GPNA, to suppress glutamine. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
- Heffernan, Chen, and Hassanein are all directed toward methods of treating cancer by administering inhibitors of glutamine metabolism, and Hassanein and Heffernan are specifically directed toward methods of treating NSCLC by administering an inhibitor of glutamine metabolism,
-Chen teaches that in order to be well used by cells, glutamine must be transported to cells by specific transporters and converted to glutamate by glutaminase, and teaches that both glutaminase inhibitors and glutamine transport inhibitors are known in the art to target glutamine metabolism to treat cancer (Table 1, Chen),
-Hassanein teaches that glutamine plays an essential role in providing cancer cells with biosynthetic intermediates required to support proliferation and survival, and that many cancer cells have evolved a dependence on glutamine metabolism for growth and survival,
-Hassanein teaches GPNA as inhibiting/suppressing glutamine metabolism by inhibiting SLC1A5 in NSCLC, wherein SLC1A5 is the primary transporter of glutamine, a modulator of cell growth and oxidative stress in NSCLC (abstract), and
-substituting equivalents (inhibitors of glutamine metabolism) known for the same purpose (treating NSCLC) is prima facie obvious, see MPEP 2144.06.
As such an ordinary skilled artisan would have been motivated to make such an substitution to predictably arrive at a method that inhibits glutamine metabolism by inhibiting glutamate transport, thus treating NSCLC by restricting the tumor cells’ access to glutamine, thereby decreasing tumor growth and tumor cell survival.
Further regarding claim 38, while the combination of Heffernan, Hassanein, and Chen teaches a method of treating NSCLC comprising determining that the NRF2/KEAP1 pathway is deregulated, and administering a glutamate transport inhibitor to the subject, it differs from that of claim 38 in that it does not explicitly teach administration in combination with one or more immune check-point inhibitors.
Heffernan additionally teaches that its treatment may be used together with anticancer agents such as the immune checkpoint regulators ipilimumab and nivolumab. As evidenced by [0030] of the specification, nivolumab is a PD-1 inhibitor.
Molineaux teaches methods of treating cancer by administering a combination of a glutaminase inhibitor, which inhibits the metabolism of glutamine into glutamate ([0132]), and an immune-oncology therapeutic agent, such as CTLA-4 and/or PD-1/PD-L1 (abstract).
Molineaux teaches this combination as providing additive and synergistic effects (pg. 20, claims 1-4, 7-8; Figures 1-6; Examples 1-2, [0237]-[0238]).
Specifically, the data from Molineaux shows that a glutaminase inhibitor in combination with an anti-PD-L1 antibody greatly decreases tumor volume in comparison to the glutaminase inhibitor alone or an anti-PD-L1 antibody alone (Figure 1; Examples 1-2, [0237]-[0238]).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to add an immune checkpoint inhibitor to the combination of Heffernan, Chen, and Hassanein, to arrive at instant claim 38. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-both Molineaux and the combination of Heffernan, Chen, and Hassanein, are directed toward a method of treating cancer by administering inhibitors of glutamine metabolism,
-Heffernan specifically teaches that immune check point inhibitors can be used in its methods, and
-Molineaux teaches that adding immune check point inhibitors to compounds that inhibit glutamine metabolism, results in an additive or synergistic effect, in methods of treating cancer.
As such, an ordinary skilled artisan would have been motivated to make such an addition to predictably achieve a more therapeutically effective additive or synergistic treatment for cancer.
Further regarding claim 38, the following is noted:
-Heffernan teaches that deregulation of the NRF2/KEAP1 pathway is determined by obtaining a biological sample ([0007], Examples 3 & 6, [0481]-[0485], [0496]).
-Since the subject, in the combined method of Heffernan, Chen, Hassanein, and Molineaux, is determined to have to have an NRF2/KEAP1 pathway deregulation, and is then administered the treatment, the limitation of “selecting a subject having cancer associated with a deregulated NRF2/KEAP1 pathway, wherein said selecting comprises detecting deregulation of the NRF2/KEAP1 pathway in a biological sample from the subject,” is met.
Regarding the “wherein” clause in claims 38 and 56, MPEP 2111.04 states, a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
In claims 38 and 56, the wherein clauses expresses the desired result of the positive step of administering a glutamine transport inhibitor, in combination with one or more immune check point inhibitors, in a cancer patient that has a deregulated NRF2/KEAP1 pathway. Since the combination of Heffernan, Chen, Hassanein, and Molineaux teaches these method steps, these limitations are met. See also MPEP 2112.02.
Further regarding the wherein clause in claim 38, it is noted that Molineaux teaches that adding immune check point inhibitors to glutaminase inhibitors for the treatment of cancer, results in an additive or synergistic effect. And it is further noted, regarding claim 56, that Heffernan teaches its methods as inhibiting cell growth ([0020]).
As such, these limitations are met.
Regarding instant claim 41, Heffernan teaches the immune check point inhibitor as ipilimumab and nivolumab. As evidenced by [0030] of the instant specification, at least nivolumab is a PD-1 inhibitor.
Regarding instant claims 42-44, Heffernan teaches NSCLC as the cancer (pgs. 35-36, claims 10-12).
Regarding instant claims 46-48, Heffernan teaches the additional administration of an anti-cancer agent such as a platinum-based agent, a taxane-based agent, an immunotherapy and a targeted therapy (pg. 36, claims 17-19). Cisplatin is taught as a platinum-based agent (Heffernan, [0448])). Thus, an ordinary skilled artisan would be motivated to add cisplatin to the combined methods of Heffernan, Chen, Hassanein, and Molineaux, to predictably arrive at a more potent, more multifaceted, and/or more therapeutically effective method of treating cancer.
Regarding instant claim 49, Heffernan teaches its methods as further comprising radiation therapy (pg. 36, claims 21-22).
Regarding claims 50 and 53, Heffernan teaches that the term altered NRF2/KEAP1 pathway is used interchangeably with and refers to a subject in which a deregulated NRF2/KEAP1 pathway is present, hyperactive NRF2 signaling is present, a loss of function mutation in KEAP1 is present, a gain of function mutation in NRF2 is present, or increased intracellular concentration of glutathione is present ([0069]; pg. 32, claim 1).
Regarding instant claim 54, Heffernan teaches its formulations as being administered orally, parenterally, and by other modes ([0407]).
Regarding instant claim 55, Heffernan teaches the subject as human (pg. 36, claim 16).
Claim 45 is rejected under 35 U.S.C. 103 as being unpatentable over US PG-PUB 2016/0058759 to Heffernan (published 2016, PTO-892 of 11/22/2024) in view of Chen (Targeting Glutamine Induces Apoptosis: A Cancer Therapy Approach, Int. J. Mol. Sci., published 2015, PTO-892) Hassanein (Targeting SLC1A5-mediated glutamine dependence in non-small cell lung cancer, IJC, published 07/14/2015, PTO-892 of 11/22/2024), US PG-PUB 2017/0095473 to Molineaux (published 2017, PTO-892 of 11/22/2024), as applied to claims 38, 41-44, 46-50, 53-56 above, and further in view of Karachaliou (“KRAS Mutations in Lung Cancer,” Clinical Lung Cancer, Vol 14, 05/2013, PTO-892 of 11/22/2024).
Heffernan, Chen, Hassanein, and Molineaux are applied as discussed in the above rejection and incorporated herein.
While the combination of Heffernan, Chen, Hassanein, and Molineaux teaches a method of treating NSCLC comprising determining that the NRF2/KEAP1 pathway is deregulated in a subject, and administering a glutamine transport inhibitor and PD-1 inhibitor, to the subject, it differs from that of claim 45, in that it does not teach the cancer as mediated by a KRAS gene mutations.
As discussed above, Heffernan teaches NSCLC as the cancer (pgs. 35-36, claims 10-12).
Karachaliou teaches KRAS mutations in lung cancer (title). KRAS mutations were identified in NSCLC tumors more than 20 years ago (abstract). Almost 15-25% of patients with NSCLC have KRAS mutations (pg. 205, Col. 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select a subject with a KRAS gene mutation, as the subject in the combined methods of Heffernan, Chen, Hassanein, and Molineaux, to arrive at claim 45. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-the combined method of Heffernan, Chen, Hassanein, and Molineaux teaches a method of treating NSCLC, and
-Karachaliou teach that 15-25% of patients with NSCLC have KRAS mutations.
As such, an ordinary skilled artisan would reasonably expect the combined method of Heffernan, Chen, Hassanein, and Molineaux to treat a NSCLC that is caused by KRAS mutations.
Claims 51-52 are rejected under 35 U.S.C. 103 as being unpatentable over US PG-PUB 2016/0058759 to Heffernan (published 2016, PTO-892 of 11/22/2024) in view of Chen (Targeting Glutamine Induces Apoptosis: A Cancer Therapy Approach, Int. J. Mol. Sci., published 2015, PTO-892) Hassanein (Targeting SLC1A5-mediated glutamine dependence in non-small cell lung cancer, IJC, published 07/14/2015, PTO-892 of 11/22/2024), US PG-PUB 2017/0095473 to Molineaux (published 2017, PTO-892 of 11/22/2024), as applied to claims 38, 41-44, 46-50, 53-56 above, and further in view of Singh (“Dysfunctional KEAP1-NRF2 Interaction in Non-Small-Cell Lung Cancer,” PLOS Medicine, published 2016, PTO-892 of 11/22/2024).
Heffernan, Chen, Hassanein, and Molineaux are applied as discussed in the above rejection and incorporated herein.
While the combination of Heffernan, Chen, Hassanein, and Molineaux teaches a method of treating NSCLC comprising determining that the NRF2/KEAP1 pathway is deregulated in a subject, and administering a glutamine transport inhibitor and PD-1 inhibitor, to the subject, it differs from that of claims 51-52, in that it does not teach detecting the deregulated NRF2/KEAP1 pathway by assessing NQO1 levels.
Singh teaches dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer (tile). In Figure 3, Singh teaches immunohistochemical analysis of NQO1 as indicative of dysfunctional KEAP1-NRF2 Interaction in NSCLC tumors (pg. 1870). See also pg. 1870, Col. 2, that teaches “We also studied levels of known NRF2 targets in tumor samples by measuring NQO1 and GST enzyme activities and total GSH levels in 13 pairs of primary NSCLC tumors and adjacent normal tissue. . .Both NQO1 and total GST activities and GSH levels were significantly higher in tumor tissues than in their corresponding normal bronchi.” And pg. 1873, Col. 2, that teaches “In corroboration with the above finding that suggest loss of functional KEAP1 in lung cancers, immunohistochemical staining of NRF2 in lung adenocarcinoma tissues showed increased staining in tumor tissue compared to paired normal tissue. As anticipated NQO1 and GST enzyme activities and GSH levels were significantly elevated in the tumors compared with those in the matched normal tissue.”
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to add measuring NQO1 levels by immunohistochemical staining, to the combined methods of Heffernan, Chen, Hassanein, and Molineaux, to arrive at instant claims 51-52. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-both Singh and the combination of Heffernan, Chen, Hassanein, and Molineaux are directed toward a patient population with NSCLC and a deregulated NRF2/KEAP1 pathway, and
-Singh teaches measuring NQO1 levels to determine dysfunctional KEAP1-NRF2.
Thus, an ordinary skilled artisan would have been motivated to make such an addition, to predictably arrive at a means of measuring NRF2/KEAP1 pathway dysfunction.
Regarding instant claim 51, it is noted that “assessing NQO1 levels” is interpreted as encompassing measuring NQO1 levels since NQO1 levels cannot be assessed unless they are measured.
Response to Arguments
The rejections have been modified to address the amendments to independent claim 38. As such, the arguments are no longer pertinent to the modified rejection.
Conclusion
No claims are allowed.
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/LAUREN WELLS/Examiner, Art Unit 1622