DETAILED ACTION
The examiner for your application at the USPTO has changed. Examiner Abigail VanHorn can be reached at 571-270-3502.
Election/Restrictions
Applicant’s election without traverse of Group I, STEAP4 in the reply filed on November 25 2025 is acknowledged. Claims 1-9, 12-13 and 16-23 are pending in the application. Claims 2-3, 7-9, 12-13 and 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on November 25 2025. Accordingly, claims 1, 4-6, 16 and 18-23 are being examined on the merits herein.
The examiner notes that while claim 7 does not have the status of withdrawn, the response filed November 25 2025 (see page 8, 3rd paragraph,) clearly indicates that claim 7 does not read on the elected species of STEAP4. For this reason, claim 7 is also withdrawn.
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 .
Priority
This application is a 371 of PCT/US2021/052927 (09/30/2021) which claims benefit of 63/085,917 (09/30/2020) as reflected in the filing receipt issued on November 15 2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 6 2023, May 12 2025 and November 25 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because: 37 C.F.R. 1.84 states “Character of lines, numbers, and letters. All drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined.”
While the letters in Figure 1 are legible. The shading is not. The difference between exceptional, strong, moderate and weak cannot be ascertained.
In Figure 2, 5C, 9, 10 and 11-25 none of the information on the right hand size is legible. Furthermore, the shading is not discernible.
In Figure 3A, 3B, 3C, 4A, 4B, 4C, 5A, 5B, 6A, 6B, 7A, 7B, 8B, the shading is not discernible
In Figure 8A, none of information running across the top of the columns is legible. Furthermore, the shading prevents identification of the mis-call extreme response and mis-call no response as indicated in the legend.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 1 is objected to because of the following informalities: the abbreviation ULK is present in the claim. When an abbreviation is included in a claim it should be spelt out the first time it occurs. Appropriate correction is required.
Claim 23 is objected to because of the following informalities: the abbreviation MEK is present in the claim. When an abbreviation is included in a claim it should be spelt out the first time it occurs. Appropriate correction is required.
Claim 23 is objected to because of the following informalities: docetaxel is incorrectly spelt as docetaxol and pembrolizumab is incorrectly spelt as pembroluzimab Appropriate correction is required.
Claim Rejections - 35 USC § 112-Indefiniteness
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, 4-6, 16 and 18-23 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.
Claims 1, 6, 7 and 16 as currently written are vague and indefinite. The claims all reference Table 1 and/or Table 2. "Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table 'is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.' Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)" (MPEP 2173.05(s)). Claims cannot refer back to tables in the specification. The contents in the table are required in the claims itself. Since there is no limit to the length of the claim, if the subject matter can be listed in the specification, then that list can be copied and pasted into a claim. Since Table 1 and Table 2 are directed to biomarker genes, this subject matter is clearly capable of being present in the claim.
Claim 5 recites the limitation “the cancer tissue” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Claim 5 depends from claim 1. Claim 1 merely refers to tissue or disorder.
Claim 21 recites the limitation "the cancer" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 21 depends from claim 1. Claim 21 merely refers to a disorder and never specifically refers to cancer.
Claim 22 recites the limitation "the cancer" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 22 depends from claim 1. Claim 21 merely refers to a disorder and never specifically refers to cancer.
Claim 23 recites the limitation "the cancer" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 23 depends from claim 1. Claim 21 merely refers to a disorder and never specifically refers to cancer.
Claims 4 and 18-20 are included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
Claim Rejections - 35 USC § 112-Written Description
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.
Claims 1, 4-6, 16 and 19-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The specification discloses chemicals, such as inhibitors of Formula A which meet the written description and enablement provisions of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. However, claim 1 encompasses administering a therapeutically effective amount of any ULK inhibitor including those which do not possess a pyrimidine and therefore only correspond in some undefined way to specifically instantly disclosed chemicals.
As taught by Zou et al. (Acta Pharmaceutica Sinica, 2022) merely having a pyrimidine is not sufficient to establish the compound would be a ULK inhibitor. For example, compound FL-411 contains a pyrimidine but it is a ULK activator not an inhibitor (Table 5). However, this compound does not fall within the scope of Formula A because at least instantly claimed formula A requires R6 to be a H, halogen or haloalkyl where this position in FL-411 is a C(O).
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Thus, recitation ULK inhibitor fails meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, due to lacking chemical structural information for what they are and chemical structures are highly variant and encompass a myriad of possibilities. The specification provides insufficient written description to support the genus encompassed by the claim. Note: MPEP 2163.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, (Fed. Cir. 1991), makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Univ. of Rochester v. G.D. Searle, 69 USPQ2d 1886, 1892 (CAFC 2004), further supports this by stating that:
The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. A description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) described even in terms of its functioning of lessening inflammation of tissues fails to distinguish any steroid from others having the same activity or function. A description of what a material does, rather than of what it is, usually does not suffice…. The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described. (Emphasis added).
With the exception of the above specifically disclosed chemical structures, the skilled artisan cannot envision the detailed chemical structure of the encompassed ULK inhibitors regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The chemical structure itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Circ. 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016, (Fed. Cir. 1991). In Fiddes v. Baird, 30 USPQ2d 1481, 1483, (Bd. Pat. App. & Int. 1993), claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 (Fed. Cir. 1997) held that:
...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Furthermore, to the extent that a functional description can meet the requirement for an adequate written description, it can do so only in accordance with PTO guidelines stating that the requirement can be met by disclosing “sufficiently detailed, relevant identifying characteristics,” including “functional characteristics when coupled with a known or disclosed correlation between function and structure.” Univ. of Rochester v. G.D. Searle, 68 USPQ2d 1424, 1432 (DC WNY 2003).
Therefore, only the above chemically structurally defined chemicals, specifically those of Formula A, but not the full breadth of the claim(s) meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC § 112 is severable from its enablement provision. (See page 1115.)
Claim Rejections - 35 USC § 112-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.
Claims 1, 4-6, 16 and 18-23 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 treating ULK disorders which are associated with elevated ULK, does not reasonably provide enablement for treatment of any disorder which is mediated by ULK. 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. This is a scope of enablement rejection.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Formal, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The breadth of the claims and Nature of the Invention
The claim is very broad insofar as it recites treating a disorder mediated by ULK in a subject in need thereof. The broadest reasonable interpretation encompasses treating any disorder which is inclusive of disorders exhibiting reduced ULK expression as well as those disorder exhibiting increased ULK expression. However, the instant claims require administering a therapeutically effective amount of a ULK inhibitor to the subject.
As evidenced by Randhawa et al. (Gene, 2015), ULK ((Unc)51-like kinase includes ULK1 to 4 and STK36 (introduction). Therefore, the broadest reasonable interpretation of claim is that disorders include any disorder mediated by any of ULK1 to 4 and STK36.
The Relative Skill Level, the State of the Prior Art and The Level of
Predictability in the Art
The relative skill of those in the art is high, that of an MD or PHD. A medicinal chemist with experience in not only drug disease but therapeutic treatment protocols.
Zou et al. (Acta Pharm Sin B, 2022) is directed to autophagy and beyond, unraveling the complexity of UNC-51-like kinase 1(ULK1) from biological functions to therapeutic applications.
ULK1 is necessary for the occurrence and development of diseases, associated with autophagy or non-autophagy pathways. ULK1 has been proved to regulate cancer, neurodegenerative disorders, infection, cardiopathy and other disease. Small molecule compounds targeting ULK has been revealed as good therapeutic efficacy for multiple human diseases. ULK1 inhibitor SB1-0206965 inhibits ULK1-mediated phosphorylation to regulate autophagy and cell survival. ULK1 targeted activated LYN-1604 was designed (in 2017) and shown to exhibit good therapeutic potential for breast cancer by activation of ULK1 (page 3744, left column).
Autophagy shows a double-edged sword role in different types, stages and genetic contexts of cancers. In the early phases of tumorigenesis, activation of autophagy might prevent cancer development. On the contrary, in advanced cancer both autophagy enhancement and autophagy inhibition have been proposed as therapeutic strategies. The potential role of autophagy in cancer is of extreme complexity and always content dependent which deserves further discussion. Upregulation of ULK1 can contribute to the reduction of bone metastasis.(page 3756, section 4.1.1). Over-expression of ULK is negatively correlated with various cancers including colon cancer, pancreatic ductal adenocarcinoma, liver cancer, prostate cancer, chronic myelomonocytic leukemia and glioblastoma (page 3757). As shown in Figure 6, the autophagic and non-autophagic functions of ULK1 are involved in a variety of different diseases. In short, ULK1-mediated autophagy plays different roles in different tumor types and different conditions, acting as the criminal or savior. Based on the complex role of ULK1 in cancer, it is necessary to further clarify the exact role of ULK1 in different situations (page 3759, right column).
In neurodegenerative diseases, activation of autophagy can effectively reduce AD (Alzheimer’s disease) pathology. In Parkinson’s disease (PD) impaired steps in autophagy may contribute. Thus activation of autophagy may have potential therapeutic effects in PD patients. The ULK1 activator BL-918 indeed has shown considerable therapeutic potential in cell and animal models of PD (page 3760, 4.2.1). ULK1 was found to regulate the process of neuronal development and its loss of function would contribute to neurodegeneration. Therefore, ULK1 plays a protective role in most neurodegenerative diseases. Mechanistically, ULK1-mediated activation of autophagy can effectively reduce most pathologies associated with neurodegenerative diseases (page 3760, 4.2.2).
Some small-molecule compounds have been reported to affect disease progression and achieve therapeutic effects by modulating ULK1 (page 3762). Some inhibitors were specific some were not. One inhibitor, SBI-025965, is the most used ULK1 inhibitor. It can suppress ULK-1mediated phosphorylation events inhibiting autophagy and down-regulate ULK1 and selective inhibit ULK1-induced apoptosis in renal cell carcinoma cells. Another inhibitor SBP-7455 inhibits ULK1/2 activity and reduces TNBC cell proliferation. While a variety of ULK1 inhibitors have been discovered none have entered clinical trials (section 5.1). Figure 7 shows various structures of inhibitors and activators. Table 4/5 shows small molecule compounds that directly regulate ULK1. The inhibitors are indicated for hepatocellular carcinoma, lung cancer, TNBC (triple negative breast cancer) and NSCLC as well in various cell lines including those for lung cancer, gastric cancer, glioblastoma, colorectal cancer and myeloma. While activation is for treating bladder cancer, TNBC, colon cancer, lung cancer, AD, ischemic stroke hypertension, breast cancer, human prostate cancer, etc.
In conclusion, ULK1 is a key regulator in the initiation of mammalian autophagy. Autophagy may be beneficial or detrimental depending on the type or stage of one disease.
Thus, the state of the art with regards to the scope of disorders mediated by ULK and their treatment by administering a ULK inhibitor is unpredictable as some reports within the same disease an inhibitor may treat while other reports an activator will treat. Since the role of ULK1 is complex absent data demonstrating efficacy, there is unpredictability that administration of a ULK inhibitor can treat any disorder mediated by ULK in a subject.
Randhawa et al. (Gene, 2015) teaches that the essential components of autophagy is lacking in ULK3, ULK4 and STK36. Therefore, ULK1 and ULK2 are the primary candidate mammalian Atg1 orthologues essential for induction of autophagy (page 40, right column).
The amount of direction or guidance provided and the presence or absence of working examples
The instant specification teaches that in some embodiments the inhibitors inhibit ULK1, while in other embodiments the inhibitors inhibit both ULK1 and ULK2 (paragraph 0003). The instant specification teaches that effectiveness of treatment of a disorder mediated by ULK using ULK inhibitors in either monotherapy or combination therapy can vary based on the status of a disease or disorder. The specification then indicates the method of treatment are wherein the tissue has a distinct expression of at least one biomarker gene (paragraph 0116). The specification states: Table 1 of the instant specification shows exemplary genes that are highly expressed in cancer tissue that are very responsive to the ULK inhibitor treatment. Alternatively, Table 1 shows exemplary genes that are expressed lower in cancer tissue that are not responsive or less responsive to the ULK inhibitor treatment (paragraph 0117). Looking to Table 1 there are Gene names and UniProt Numbers listed but nowhere in the table does it indicate which one are highly expressed and responsive to cancer tissue and very responsive to ULK inhibitors vs those that are expressed lower in cancer and less responsive to ULK inhibitors. Perhaps such information is provided in the drawings. However, the instant specification provides no further explanation on the drawings.
Looking to the examples of the instant specification, example 1 which seems to correspond to figure 1 discusses 35 patient derived xenograft models that were injected to the flanks of nude mice and treated with UK inhibitors. However, the type of tumor is never indicated. Heat maps were generated to identify genes with high expression in all of the extreme responders compared to non-responders (UP) and genes with low expression of all the extreme responders compared to non-responders (down). It is stated that 167 were identified as UP and 258 identified as down. Paragraph 0136 states that tumors that express low levels of Col4a2, Gne, Ttll7, Prkacb, and Ppt2 concurrent with high expression of Steap4, Ephx3, Amn, and Slc34a2 would be predicted to be highly responsive to ULK1 inhibitors.
However, none of the examples actually show that a responsiveness to ULK1 inhibitors equates to treating any disorder mediated by any ULK in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a ULK inhibitor. No reasonably specific guidance is provided concerning useful therapeutic protocols for treating any disorder falling within the scope of the claims by administering a ULK inhibitor, other than stating it can be done.
The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed agents could be predictably used treat the full scope of disorders encompassed by the claims as inferred by the claim and contemplated by the specification. Even dependent claims, such as claim 21, encompass cancers, such as breast cancer, which the state of the art teaches can be treated with ULK activators which is the exact opposite of the instantly claimed ULK inhibitors. Additionally, the recitation ULK includes more than just ULK1 and ULK2 but the specification appears to only contemplate the use of the inhibitors with either ULK1 and/or ULK2.
Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1, 4-6, 16 and 18-22 are rejected under 35 U.S.C. 103 as being unpatentable over Tang et al. (Oncology Reports, cited on PTO Form 1449 filed 5/12/25-C100) as evidenced by Dite et al. (Journal of Biological Chemistry, 2018) in view of Guise et al. (WO2019125184).
Applicant Claims
The instant application claims a method of treating a disorder mediated by ULK in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a ULK inhibitor, wherein a tissue affected by the disorder in the subject has a distinct expression of at least one of biomarker genes in Table 1 or Table 2. As elected the biomarker is STEAP4. The scope of disorder mediated by ULK is interpreted as being limited to those disorders mediated by ULK overexpression such as non-small cell lung cancer.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Tang et al. is directed to SBI020695, a novel inhibitor of Ulk1, suppresses non-small cell lung cancer cell growth by modulating both autophagy and apoptosis pathways. Autophagy is a process of phagocytosis of unnecessary or dysfunctional components, fusion with lysosomes and degradation of the contents of the lysosomes to maintain cellular homeostasis. Dysregulation of autophagy is often observed in lung cancer. Inhibition of autophagy sensitizes NSCLC (non-small cell lung cancer) cells to chemotherapy (page 3449, right column). Ulk1 is upregulated in NSCLC cell lines and negatively correlated with prognosis in patients with NSCLC. Knockdown of ULK1 inhibited cell growth and sensitized NSCLC cells to cisplatin. Inhibition of ULK1 by SBI0206965 reduced the proliferation of NSCLC cells and induces cell apoptosis by inhibiting autophagy (page 3450, left column; page 3451, right column and Fig. 1). Ulk1 is required for autophagy in severe hypoxia (page 3456, left column). Many NSCLC cells acquire resistance to the cytotoxicity induced by cisplatin which limits the therapeutic efficacy. Knockdown of Ulk1 significantly impaired the viability of NSCLC cells after cisplatin treatment and markedly increased cisplatin-induced apoptosis. These rules suggest that knockdown of ULK1 can sensitize NSCLC cells to cisplatin (page 3452, last paragraph).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Tang et al. teaches the use of a ULK inhibitor in treating non-small cell lung cancer, Tang et al. does not expressly teach the use of biomarkers.
Guise et al. is directed to the use of biomarker in cancer therapy. Taught is the use of a hypoxia-activated prodrug (HAP) for use in the treatment of cancer in an individual comprising a) determining the level of STEAP4 expression in tumor cells of in the individual; b) predicting the individual as being likely to be responsive to treatment by a HAP if the tumor cells exhibit an elevated level of STEAP4 expression and administering a therapeutically effective amount of a HAP to the individual if the tumor cells exhibit an elevated level of STEAP4 expression (claim 2). The cancer is non-small cell lung cancer (claim 13; example 11). The HAP agent can be administered with an additional agent such as a MEK inhibitor (claim 22). HAP compounds include pyrimidines (claim 46). STEAP4 has been shown to be highly induced by hypoxia, i.e. low oxygen at the tissue level. Hypoxia with tumors is associated with poor prognosis of cancer patients with treatment failure such as resistance to radiotherapy and traditional chemotherapy (page 1).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Tang et al. and Guise and et al. administer a therapeutically effective amount of SBI020695, a novel inhibitor of Ulk1, to a subject affected with non-small cell lung cancer. One skilled in the art would have been motivated to administer SBI020695 as it inhibits the autophagy associated with NSCLC. Regarding the claimed “tissue affected by the disorder in the subject has a distinct expression of at least one biomarker gene, STEAP4”, this limitation merely requires that the tissue affected by the disorder is identified as having a distinct expression of the biomarker not that it is required for treatment. Guise et al. teaches that tumor cells exhibit an elevated level of STEAP4 expression and the cancer is non-small cell lung cancer. This suggest the tissue affected by the disorder taught in Tang et al. would possess elevated STEAP4.
Regarding claims 4-5 and 21, Tang et al. teaches NSCLC which is a lung cancer.
Regarding claim 6 and 16, Guise et al. teaches tumor cells exhibit an elevated level of STEAP4 expression.
Regarding the claimed ULK1 inhibitor and claim 18, as evidenced by Dite et al., SBI-0205965 has the following structure:
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. This reads on instantly claimed Formula A, wherein R10 is NR1R2 wherein R1 is H and R2 is optionally substituted aryl; R4 is optionally substituted aryloxy; R5 is halo; and R6 is H.
Regarding claim 19, Tang et al. teaches administration of just SBI-0206965 (i.e. a monotherapy).
Regarding claim 20 and 22, Tang et al. teaches many NSCLC cells acquire resistance to the cytotoxicity induced by cisplatin (i.e. refractory to a prior treatment) which limits the therapeutic efficacy. Knockdown of Ulk1 significantly impaired the viability of NSCLC cells after cisplatin treatment and markedly increased cisplatin-induced apoptosis. These results suggest that knockdown of ULK1 can sensitize NSCLC cells to cisplatin. This suggest administration of a ULK inhibitor to a subject with an additional therapeutic agent (i.e. cisplatin) as well as the cancer being refractory to a prior treatment.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Tang et al. as evidenced by Dite et al. in view of Guise et al. as applied to claims 1, 4-6, 16 and 18-22 above and in further view of Li et al. (Chin J Cancer, 2017).
Applicant Claims
The instant application claims the cancer is refractory to a prior treatment. The instant application claims he cancer is refractory to carboplatin, a carboplatin analog, an MEK inhibitor, trametinib, cobimetinib, binimetinib, selumetinib, erlotinib, gefitinib, osimertinib, crizotinib, pemetrexed, docetaxel, or pembrolizumab.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Tang et al. and Guise et al. are set forth above. Tang et al. teaches many NSCLC cells acquire resistance to the cytotoxicity induced by cisplatin (i.e. refractory to a prior treatment) which limits the therapeutic efficacy. Knockdown of Ulk1 significantly impaired the viability of NSCLC cells after cisplatin treatment and markedly increased cisplatin-induced apoptosis. These results suggest that knockdown of ULK1 can sensitize NSCLC cells to cisplatin. This suggest the cancer being refractory to a prior treatment. Guise et al. teaches combination with other agents which include carboplatin, cisplatin an MEK inhibitor, trametinib, cobimetinib, binimetinib, erlotinib, osimertinib, crizotinib, and docetaxel. (page 134).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Tang et al. suggest the cancer being refractory to a prior treatment, Tang et al. does not expressly teach one of the instantly claimed drugs. However, this deficiency is cured by Li et al.
Li et al. is directed to autophagy and multidrug resistance in cancer. It is taught that multidrug resistance (MDR) occurs frequently after long-term chemotherapy, resulting in refractory cancer and tumor recurrence. Autophagy universally arises during the treatment of sensitive and MDR cancer (abstract). Substantial evidence demonstrates that MDR develops after autophagy. The enhanced autophagy levels detected in patients with poor prognosis indicate that the presence of autophagy may catalyze development of MDR. Inhibition of autophagy can re-sensitize resistance cancer cells and enhance the effect of chemotherapeutic agents (page 4, left column). Table 1 teaches docetaxel and cisplatin.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Tang et al., Guise et al. and Li et al. and administer a ULK inhibitor to a subject whose cancer is refractory. One skilled in the art would administer the inhibitor in order to inhibit autophagy and re-sensitize resistant cancer cells as suggested by both Tang et al. and Li et al. Since multidrug resistance occurs frequently after long-term chemotherapy and carboplatin, an MEK inhibitor, trametinib, cobimetinib, binimetinib, erlotinib, osimertinib, crizotinib, and docetaxel are all known drugs used for cancer treatment as taught by Guise et al., one skilled in the art would have been motivated to administer the ULK inhibitor to a cancer who has become resistant to known chemotherapeutics. Since Tang et al. and Li et al. both teach that inhibition of autophagy can sensitize cells to chemotherapeutics there is a reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 4-6, 16 and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,266,549 in view of Tang et al. as evidenced by Dite et al. and Guise et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims a method of treating a disorder mediated by ULK in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a ULK inhibitor, wherein a tissue affected by the disorder in the subject has a distinct expression of at least one of biomarker genes in Table 1 or Table 2.
Patent ‘549 claims a compound which includes
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which as evidenced by Dite et al. is SBI-0205965.
While Patent ‘549 claims a compound which falls within the scope of the instantly claimed ULK inhibitors, Patent ‘549 does not expressly claim a method. However, this deficiency is cured by Tang et al. and Guise et al.
Tang et al. is directed to SBI020695, a novel inhibitor of Ulk1, suppresses non-small cell lung cancer cell growth by modulating both autophagy and apoptosis pathways. Autophagy is a process of phagocytosis of unnecessary or dysfunctional components, fusion with lysosomes and degradation of the contents of the lysosomes to maintain cellular homeostasis. Dysregulation of autophagy is often observed in lung cancer. Inhibition of autophagy sensitizes NSCLC (non-small cell lung cancer) cells to chemotherapy (page 3449, right column). Ulk1 is upregulated in NSCLC cell lines and negatively correlated with prognosis in patients with NSCLC. Knockdown of ULK1 inhibited cell growth and sensitized NSCLC cells to cisplatin. Inhibition of ULK1 by SBI0206965 reduced the proliferation of NSCLC cells and induces cell apoptosis by inhibiting autophagy (page 3450, left column; page 3451, right column and Fig. 1). Ulk1 is required for autophagy in severe hypoxia (page 3456, left column). Many NSCLC cells acquire resistance to the cytotoxicity induced by cisplatin which limits the therapeutic efficacy. Knockdown of Ulk1 significantly impaired the viability of NSCLC cells after cisplatin treatment and markedly increased cisplatin-induced apoptosis. These rules suggest that knockdown of ULK1 can sensitize NSCLC cells to cisplatin (page 3452, last paragraph).
Guise et al. is directed to the use of biomarker in cancer therapy. Taught is the use of a hypoxia-activated prodrug (HAP) for use in the treatment of cancer in an individual comprising a) determining the level of STEAP4 expression in tumor cells of in the individual; b) predicting the individual as being likely to be responsive to treatment by a HAP if the tumor cells exhibit an elevated level of STEAP4 expression and administering a therapeutically effective amount of a HAP to the individual if the tumor cells exhibit an elevated level of STEAP4 expression (claim 2). The cancer is non-small cell lung cancer (claim 13; example 11). The HAP agent can be administered with an additional agent such as a MEK inhibitor (claim 22). HAP compounds include pyrimidines (claim 46). STEAP4 has been shown to be highly induced by hypoxia, i.e. low oxygen at the tissue level. Hypoxia with tumors is associated with poor prognosis of cancer patients with treatment failure such as resistance to radiotherapy and traditional chemotherapy (page 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘549, Tang et al. and Guise and et al. administer a therapeutically effective amount of SBI020695, a novel inhibitor of Ulk1, to a subject affected with non-small cell lung cancer. One skilled in the art would have been motivated to administer SBI020695 as it inhibits the autophagy associated with NSCLC. Regarding the claimed “tissue affected by the disorder in the subject has a distinct expression of at least one biomarker gene, STEAP4”, Guise et al. teaches that tumor cells exhibit an elevated level of STEAP4 expression and the cancer is non-small cell lung cancer. This suggest the tissue affected by the disorder taught in Tang et al. would possess elevated STEAP4.
Regarding claims 4-5 and 21, Tang et al. teaches NSCLC which is a lung cancer.
Regarding claim 6 and 16, Guise et al. teaches tumor cells exhibit an elevated level of STEAP4 expression.
Regarding the claimed ULK1 inhibitor and claim 18, as evidenced by Dite et al., SBI-0205965 has the following structure:
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. This reads on instantly claimed Formula A, wherein R10 is NR1R2 wherein R1 is H and R2 is optionally substituted aryl; R4 is optionally substituted aryloxy; R5 is halo; and R6 is H. Thus the claimed compound of Patent ‘549 falls within the scope of instantly claimed Formula A.
Regarding claim 19, Tang et al. teaches administration of just SBI-0206965 (i.e. a monotherapy).
Regarding claim 20 and 22, Tang et al. teaches many NSCLC cells acquire resistance to the cytotoxicity induced by cisplatin (i.e. refractory to a prior treatment) which limits the therapeutic efficacy. Knockdown of Ulk1 significantly impaired the viability of NSCLC cells after cisplatin treatment and markedly increased cisplatin-induced apoptosis. These results suggest that knockdown of ULK1 can sensitize NSCLC cells to cisplatin. This suggest administration of a ULK inhibitor to a subject with an additional therapeutic agent (i.e. cisplatin) as well as the cancer being refractory to a prior treatment.
Claims 1, 4-6, 16 and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over 1-20 of U.S. Patent No. 10,689,397 in view of Tang et al. as evidenced by Dite et al. and Guise et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘397 claims a compound of formula A which has the same base structure as instantly claimed.
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(claim 1). Claimed is R10 is NR1N2; R1 is H and R2 can be
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and R6 is H (claim 2; 5). R4 is optionally substituted heteroaryloxy (claim 9).
While Patent ‘397 claims compounds which falls within the scope of the instantly claimed ULK inhibitors, Patent ‘397 does not expressly claim a method. However, this deficiency is cured by Tang et al. and Guise et al.
The teachings of Tang et al. and Guise et al. are set forth above
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘397, Tang et al. and Guise and et al. administer a therapeutically effective amount of SBI020695, a novel inhibitor of Ulk1, to a subject affected with non-small cell lung cancer. SBI020695 results from the claims of Patent ‘397. One skilled in the art would have been motivated to administer SBI020695 as it inhibits the autophagy associated with NSCLC. Regarding the claimed “tissue affected by the disorder in the subject has a distinct expression of at least one biomarker gene, STEAP4”, Guise et al. teaches that tumor cells exhibit an elevated level of STEAP4 expression and the cancer is non-small cell lung cancer. This suggest the tissue affected by the disorder taught in Tang et al. would possess elevated STEAP4.
Regarding claims 4-5 and 21, Tang et al. teaches NSCLC which is a lung cancer.
Regarding claim 6 and 16, Guise et al. teaches tumor cells exhibit an elevated level of STEAP4 expression.
Regarding the claimed ULK1 inhibitor and claim 18, as evidenced by Dite et al., SBI-0205965 has the following structure:
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. This reads on instantly claimed Formula A and formula A of Patent ‘397, wherein R10 is NR1R2 wherein R1 is H and R2 is optionally substituted aryl; R4 is optionally substituted aryloxy; R5 is halo; and R6 is H. Thus the claimed compound of Patent ‘397 falls within the scope of instantly claimed Formula A.
Regarding claim 19, Tang et al. teaches administration of just SBI-0206965 (i.e. a monotherapy).
Regarding claim 20 and 22, Tang et al. teaches many NSCLC cells acquire resistance to the cytotoxicity induced by cisplatin (i.e. refractory to a prior treatment) which limits the therapeutic efficacy. Knockdown of Ulk1 significantly impaired the viability of NSCLC cells after cisplatin treatment and markedly increased cisplatin-induced apoptosis. These results suggest that knockdown of ULK1 can sensitize NSCLC cells to cisplatin. This suggest administration of a ULK inhibitor to a subject with an additional therapeutic agent (i.e. cisplatin) as well as the cancer being refractory to a prior treatment.
Claims 1, 4-6, 16 and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over 1-20 of U.S. Patent No. 10,774,092 in view of Tang et al. as evidenced by Dite et al. and Guise et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘092 claims a compound of formula A which has the same base structure as instantly claimed.
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(claim 1). Claimed is R10 is NR1N2; R1 is H and R2 can be
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and R6 is H (claim 2; 5). A specific compound claimed is:
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which is SBI020695.
While Patent ‘092 claims compounds which falls within the scope of the instantly claimed ULK inhibitors, Patent ‘092 does not expressly claim a method. However, this deficiency is cured by Tang et al. and Guise et al.
The teachings of Tang et al. and Guise et al. are set forth above
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘092, Tang et al. and Guise and et al. administer a therapeutically effective amount of SBI020695, a novel inhibitor of Ulk1, to a subject affected with non-small cell lung cancer. One skilled in the art would have been motivated to administer SBI020695 as it inhibits the autophagy associated with NSCLC. Regarding the claimed “tissue affected by the disorder in the subject has a distinct expression of at least one biomarker gene, STEAP4”, Guise et al. teaches that tumor cells exhibit an elevated level of STEAP4 expression and the cancer is non-small cell lung cancer. This suggest the tissue affected by the disorder taught in Tang et al. would possess elevated STEAP4.
Regarding claims 4-5 and 21, Tang et al. teaches NSCLC which is a lung cancer.
Regarding claim 6 and 16, Guise et al. teaches tumor cells exhibit an elevated level of STEAP4 expression.
Regarding the claimed ULK1 inhibitor and claim 18, as evidenced by Dite et al., SBI-0205965 has the following structure:
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. This reads on instantly claimed Formula A and formula A of Patent ‘397, wherein R10 is NR1R2 wherein R1 is H and R2 is optionally substituted aryl; R4 is optionally substituted aryloxy; R5 is halo; and R6 is H. Thus the claimed compound of Patent ‘397 falls within the scope of instantly claimed Formula A.
Regarding claim 19, Tang et al. teaches administration of just SBI-0206965 (i.e. a monotherapy).
Regarding claim 20 and 22, Tang et al. teaches many NSCLC cells acquire resistance to the cytotoxicity induced by cisplatin (i.e. refractory to a prior treatment) which limits the therapeutic efficacy. Knockdown of Ulk1 significantly impaired the viability of NSCLC cells after cisplatin treatment and markedly increased cisplatin-induced apoptosis. These results suggest that knockdown of ULK1 can sensitize NSCLC cells to cisplatin. This suggest administration of a ULK inhibitor to a subject with an additional therapeutic agent (i.e. cisplatin) as well as the cancer being refractory to a prior treatment.
Claim 23 is rejected on the ground of nonstatutory double patenting as being unpatentable over 1-20 of U.S. Patent No. 10,774,092 or 10, 266,549 or 10689397 in view of Tang et al. as evidenced by Dite et al. and Guise et al. as applied to claims 1, 4-6, 16 and 18-22 above and in further view of Li et al. (Chin J Cancer, 2017). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims the cancer is refractory to a prior treatment. The instant application claims he cancer is refractory to carboplatin, a carboplatin analog, an MEK inhibitor, trametinib, cobimetinib, binimetinib, selumetinib, erlotinib, gefitinib, osimertinib, crizotinib, pemetrexed, docetaxel, or pembrolizumab.
The teachings of Patent ‘092, ‘549, ‘397, Tang et al. and Guise et al. are set forth above.
Tang et al. teaches many NSCLC cells acquire resistance to the cytotoxicity induced by cisplatin (i.e. refractory to a prior treatment) which limits the therapeutic efficacy. Knockdown of Ulk1 significantly impaired the viability of NSCLC cells after cisplatin treatment and markedly increased cisplatin-induced apoptosis. These results suggest that knockdown of ULK1 can sensitize NSCLC cells to cisplatin. This suggest the cancer being refractory to a prior treatment. Guise et al. teaches combination with other agents which include carboplatin, cisplatin an MEK inhibitor, trametinib, cobimetinib, binimetinib, erlotinib, osimertinib, crizotinib, and docetaxel. (page 134).
The cancer being refractory to one of the instantly claimed drugs is not claimed. However, this deficiency is cured by Li et al.
Li et al. is directed to autophagy and multidrug resistance in cancer. It is taught that multidrug resistance (MDR) occurs frequently after long-term chemotherapy, resulting in refractory cancer and tumor recurrence. Autophagy universally arises during the treatment of sensitive and MDR cancer (abstract). Substantial evidence demonstrates that MDR develops after autophagy. The enhanced autophagy levels detected in patients with poor prognosis indicate that the presence of autophagy may catalyze development of MDR. Inhibition of autophagy can re-sensitize resistance cancer cells and enhance the effect of chemotherapeutic agents (page 4, left column). Table 1 teaches docetaxel and cisplatin.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘549 OR ‘397 OR ‘092 and Tang et al., Guise et al. and Li et al. and administer a ULK inhibitor to a subject whose cancer is refractory. One skilled in the art would administer the inhibitor in order to inhibit autophagy and re-sensitize resistant cancer cells as suggested by both Tang et al. and Li et al. Since multidrug resistance occurs frequently after long-term chemotherapy and carboplatin, an MEK inhibitor, trametinib, cobimetinib, binimetinib, erlotinib, osimertinib, crizotinib, and docetaxel are all known drugs used for cancer treatment, one skilled in the art would have been motivated to administer the ULK inhibitor to a cancer who has become resistant to known chemotherapeutics. Since Tang et al. and Li et al. both teach that inhibition of autophagy can sensitize cells to chemotherapeutics there is a reasonable expectation of success.
Claims 1, 4-6, 16 and 18-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 7-9, 14-15, 18-20, 23-24, 50-54 and 57-58 of copending Application No. 17799641(USPGPUB No. 20230130766) in view of Guise et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Copending ‘641 claims a method for treating cancer in a subject in need thereof the method comprising administering to the subject a therapeutically effective amount of a ULK inhibiting having a structure of formula A. Formula A is the same as instantly claimed. The administration can be a monotherapy (claim 3). An additional therapeutic is claimed (claim 5). Additional therapeutic agents include carboplatin, MEK inhibitor, trametinib, etc. (claims 7-9). The cancer can be lung cancer including non-small cell lung cancer (claims 14-15).The cancer is refractory to a prior treatment.
The difference between copending ‘641 and the instant claims is that copending ‘641 does not claim a biomarker. However, this deficiency is cured by Guise et al.
The teachings of Guise et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘641 and Guise and et al. administer a therapeutically effective amount of the ULK inhibitors of copending ‘641 to a patient with lung cancer. One skilled in the art would have been motivated to administer the inhibitors in this manner as this is expressly claimed by copending ‘639. Regarding the claimed “tissue affected by the disorder in the subject has a distinct expression of at least one biomarker gene, STEAP4”, Guise et al. teaches that tumor cells exhibit an elevated level of STEAP4 expression and the cancer is non-small cell lung cancer. This suggest the tissue affected by the disorder taught in copending ‘641 would possess elevated STEAP4.
Claims 1, 4-6, 16 and 18-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5, 10-11, 14, 22, 25, 33, 38, 40, 43-44, 50, 191, 192-193, 195-196, 199-200 and 205 of copending Application No. 17799639 (USPGPUB No. 20230135635) in view of Guise et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘639 claims a compound of formula IA:
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R1A can be H or halogen (corresponding to instantly claimed R6); R2A can be H, halo (corresponding to instantly claimed R5); XA can be NR3AR4A or OR4A wherein R3A can be H, substituted or unsubstituted alkyl, R4A can be aryl (reading on instantly claimed R4) (claim 1). Claimed is a method of treating a ULK1 mediated disease in a subject in need thereof comprising administering to the subject the compound of claim 1. The ULK1 mediated disease is characterized by abnormal autophagy. Lung cancer is claimed. Additional therapeutics are claimed. Carboplatin and MEK inhibitor is claimed.
While copending ‘639 claims compounds which falls within the scope of the instantly claimed ULK inhibitors and that the inhibitors can be used in a method of treating a ULK mediated disease, copending ‘639 does not expressly claim a biomarker. However, this deficiency is cured by Guise et al.
The teachings of Guise et al. are set forth above
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘639 and Guise and et al. administer a therapeutically effective amount of the ULK inhibitors of copending ng ‘639 to a patient with lung cancer. One skilled in the art would have been motivated to administer the inhibitors in this manner as this is expressly claimed by copending ‘639. Regarding the claimed “tissue affected by the disorder in the subject has a distinct expression of at least one biomarker gene, STEAP4”, Guise et al. teaches that tumor cells exhibit an elevated level of STEAP4 expression and the cancer is non-small cell lung cancer. This suggest the tissue affected by the disorder taught in copending ‘639 would possess elevated STEAP4.
Regarding claims 4-5 and 21, copending ‘639 claims the same cancer.
Regarding claim 6 and 16, Guise et al. teaches tumor cells exhibit an elevated level of STEAP4 expression.
Regarding claim 19, copending ‘639 claims administration of just the ULK inhibitor.
Regarding claim 20, copending ‘639 claims additional therapeutic agents.
Claims 1, 4-6, 16 and 18-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 54-57, 59-60, 65-66 of copending Application No. 17799634 (USPGPUB No. 20230099804) in view of Guise et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims are set forth above.
Copending ‘634 claims a compound such as
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. This compound falls within the instantly claimed scope when R6 is H, R5 is substituted alkyl or halo, R4 and R10 together form a cyclic structure.
Claimed is a method of treating a ULK mediated disease in a subject in need thereof, the method comprising administering to the subject the compound. The ULK mediated disease is characterized by abnormal autophagy. The disease is lung cancer. The compound is administered with an additional therapeutic agent. Additional therapeutic agents include carboplatin, MEK inhibitor, etc.
While copending ‘634 claims compounds which falls within the scope of the instantly claimed ULK inhibitors and that the inhibitors can be used in a method of treating a ULK mediated disease, copending ‘634 does not expressly claim a biomarker. However, this deficiency is cured by Guise et al.
The teachings of Guise et al. are set forth above
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘634 and Guise and et al. administer a therapeutically effective amount of the ULK inhibitors of copending ‘634 to a patient with lung cancer. One skilled in the art would have been motivated to administer the inhibitors in this manner as this is expressly claimed by copending ‘639. Regarding the claimed “tissue affected by the disorder in the subject has a distinct expression of at least one biomarker gene, STEAP4”, Guise et al. teaches that tumor cells exhibit an elevated level of STEAP4 expression and the cancer is non-small cell lung cancer. This suggest the tissue affected by the disorder taught in copending ‘639 would possess elevated STEAP4.
Regarding claims 4-5 and 21, copending ‘634 claims the same cancer.
Regarding claim 6 and 16, Guise et al. teaches tumor cells exhibit an elevated level of STEAP4 expression.
Regarding claim 19, copending ‘634 claims administration of just the ULK inhibitor.
Regarding claim 20, copending ‘634 claims additional therapeutic agents.
Claims 22-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 17799634 OR 17799639 in view of Guise et al. as applied to claims 1, 4-6, 16 and 18-21 above and in further view of Li et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
The teachings of copending ‘’634 and ‘639 are set forth above.
The cancer being refractory to one of the instantly claimed drugs is not claimed. However, this deficiency is cured by Li et al.
The teachings of Li et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘634 OR ‘639, Guise et al. and Li et al. and administer a ULK inhibitor to a subject whose cancer is refractory. One skilled in the art would administer the inhibitor in order to inhibit autophagy and re-sensitize resistant cancer cells as suggested by Li et al. Since multidrug resistance occurs frequently after long-term chemotherapy and carboplatin and an MEK inhibitor are known drugs used for cancer treatment as claimed by copending ‘634 and ‘639, one skilled in the art would have been motivated to administer the ULK inhibitor to a cancer who has become resistant to known chemotherapeutics. Since Li et al. both that inhibition of autophagy can sensitize cells to chemotherapeutics there is a reasonable expectation of success.
Conclusion
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636