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 .
DETAILED ACTION
This Office Action is in response to Applicant’s Arguments and Amendment filed, 05/26/2026, wherein the Amendment amended claims 38 and cancelled claim 41.
Claims 38 and 42-56 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 42-56 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REJECTIONS WITHDRAWN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)—Scope of Enablement
Applicant’s amendment to independent claim 38 that limits the method to enhancing tumor response and check-point inhibitor efficacy in a subject having caner, that limits the cancer to one associated with a deregulated NRF2/KEAP1 pathway, and that limits the immune check-point inhibitor to one that blocks or inhibits CTLA-4, PD-1, and/or PD-L1 is sufficient to overcome this rejection
REJECTIONS MAINTAINED
The below rejections have been slightly modified in view of the amendment to independent claim 38 and the cancellation of claim 41.
The same prior art references continue to be relied upon.
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.
(Slightly Modified) Claims 38, 42-44, 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 preamble in claim 38, though the combined method of Heffernan, Chen, Hassanein, and Molineaux does not teach “enhancing tumor response and check-point inhibitor efficacy,” it would necessarily have this effect since it administers the same active agents, glutamine transport inhibitor and check-point inhibitor that blocks or inhibits CTLA-4, PD-1 and/or PD-L1, to the same patient population (cancer subject with a cancer associated with a deregulated NRF2/KEAP1 pathway) in amounts effective to treat the cancer associated with a deregulated NRF2/KEAP1 pathway. See MPEP 2111.02 and 2112.02.
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 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, 42-44, 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, 42-44, 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
On pgs. 9-10, Remarks, Applicant argues that Heffernan specifically and solely describes glutaminase inhibitors which is not the same as blocking overall glutamine utilization by cells or glutamine transport inhibitors, wherein glutamine transport inhibitor cuts of access to the nutrient itself whereas glutaminase inhibitors target only one enzymatic step downstream.
This argument has been fully considered, but is not found persuasive.
As discussed in the above rejection. Heffernan, as a whole, is directed toward inhibiting glutamine metabolism to thereby inhibit its support and survival of cancer cells. Heffernan specifically teaches NRF2/KEAP1 pathway tumors as having an addiction to glutamine. Thus, the whole purpose of Heffernan is to limit, prevent, or inhibit glutamine metabolism and cancer cells’ access to glutamine in order to treat cancer. While Heffernan teaches limiting, preventing, or inhibiting glutamine by administering a glutaminase inhibitor, which inhibits cells from converting glutamine into glutamate, the purpose of Heffernan and the instant claims is the same, i.e., to limit, prevent, or inhibit glutamine’s access by cancer cells.
Moreover, the instant specification teaches both glutaminase inhibitors in combination with check-point inhibitors or glutamine transport inhibitors in combination with check-point inhibits as aspects of its invention that treat cancers associated with NRF2/KEAP1 ( [0035]-[0036], [0163]-[0164], [0191], [0215]-[0216], [0247], [0264], [00273], [0295], [0297]). As such, the instant specification provides evidence that both glutamine transport inhibitors and glutaminase inhibitors are used to limit, prevent, or inhibit glutamine access by cancer cells.
On pg. 10, Remarks, Applicant argues that Molineaux is directed toward glutaminase inhibitors and does not disclose data or specific results regarding anything other than the glutaminase inhibitor CB-839.
This argument has been fully considered, but is not found persuasive. Applicant is respectfully reminded that patents are relevant as prior art for all they contain and “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994),” see MPEP 2123.
While Molineaux is directed toward glutaminase inhibitors, Molineaux teaches its glutaminase inhibitors as inhibiting the metabolism of glutamine for the treatment of cancer, which is also taught by Heffernan. Since there are two alternative obviousness statements wherein one is directed toward adding a glutamine transporter inhibitor to the methods of Heffernan, an ordinary skilled artisan would have reasonably expected that such a combination would provide the additive or synergistic effects taught by Molineaux. Applicant is respectfully reminded that obviousness does not require absolute predictability, but a reasonable expectation of success, MPEP 2143.02.
On pg. 10, Remarks, Applicant argues that Chen is a general review, that Chen does not address NRF2/KEAP1, that Chen acknowledges glutamine restriction may be ineffective if cancer cells can switch to glucose, and that Chen provides no data on glutamine transport inhibitor efficacy.
These arguments have been fully considered, but are not found persuasive. It is respectfully pointed out that Chen is relied upon in combination with Heffernan and Hassanein, wherein Chen teaches that it is known in the cancer art that glutamine transport inhibitors target glutamine metabolism inhibition to treat cancer. Though Chen may not provide data, in Table 1 on pg. 22839, Chen teaches “Compounds targeting glutamine metabolism in cancer research” and specifies five glutamine transporters and provides references regarding the glutamine transporters, with further details.
On pgs. 10-11, Remarks, Applicant argues that Hassanein only serves to describe SC1A5, when overexpressed in certain NSCLC cells, as being a target of the inhibitor GPNA and that there is no teaching or discussion in Hassanein regarding check point inhibitors or NRF2/KEAP1.
This argument has been fully considered, but is not found persuasive. It is respectfully pointed out that Hassanein is not relied upon to teach check-point inhibitors or NRF2/KEAP1. Hassanein is relied upon to teach 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).
On pg. 11, Remarks, Applicant argues that the teaching regarding one directed therapy and a unique target is not relevant as to obviousness of another directed therapy and distinct target and that it is well known and accepted that targeted specific therapy is particularly relevant, if not essential, in much if not most of current clinical cancer therapy approaches and cancer treatment protocols.
These arguments have been fully considered, but are not found persuasive. It is first respectfully pointed out in reference to the assertions regarding “targeted specific therapy,” that the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965), MPEP 716.01(c).
Moreover, it is respectfully pointed out, as detailed above, that Heffernan and the instant claims are both directed toward a method of treating cancers associated with a deregulated NRF2/KEAP1 pathway by inhibiting glutamine metabolism, wherein the prior art teaches that it is known in the art to inhibit glutamine metabolism to treat cancer with glutaminase inhibitor and glutamine transporter inhibitors. Moreover, the instant specification teaches both glutaminase inhibitors in combination with check-point inhibitors or glutamine transport inhibitors in combination with check-point inhibits as aspects of its invention that treat cancers associated with NRF2/KEAP1 ( [0035]-[0036], [0163]-[0164], [0191], [0215]-[0216], [0247], [0264], [00273], [0295], [0297]). As such, the instant specification provides evidence that both glutamine transport inhibitors and glutaminase inhibitors are used to limit, prevent, or inhibit glutamine access by cancer cells.
Further, one of the obviousness statements is directed toward adding a glutamine transporter inhibitor to the methods of Heffernan; applicant is respectfully reminded that obviousness does not require absolute predictability, but a reasonable expectation of success, MPEP 2143.02.
On pg. 12, Remarks, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
The additional arguments are fully addressed above.
For these reasons, Applicant’s arguments are not persuasive to overcome the instant rejections.
Conclusion
No claims are 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 LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Jim) Alstrum-Acevedo can be reached on 571-272-5548. 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.
/LAUREN WELLS/Examiner, Art Unit 1622
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