DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-19 are pending.
Priority
This application claims benefit to U.S. Provisional No. 63/394,327, filed on 08/02/2022.
Claim Rejections - 35 USC § 112
112(a)
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 1-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of comprising administering a combination of AZD6738 or M1774 with decitabine, does not reasonably provide enablement for a method of with the same method, nor for using any ATR inhibitor and any hypomethylating agent. 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 application 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 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
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 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). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 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:
1. The nature of the invention, state and predictability of the art, and relative skill of those in the art
The invention relates to a method of treating a cancer in a subject, comprising administering a composition comprising an ATR inhibitor and a hypomethylating agent.
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain). As illustrative of the state of the art of treating any cancer, the examiner cites Gura et al ("Systems for Identifying New Drugs are Often Faulty"); Johnson et al. ("Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials"); and Kunnumakkara et al (“Cancer drug development: The missing links”).
Gura, cited for evidentiary purposes, teaches that researches face the problem of sifting through potential anticancer agents to find ones promising enough to make human clinical trials worthwhile and further teach that since formal screening began in 1955, many thousands of drugs have shown activity in either cell or animal models, but only 39 have actually been shown useful for chemotherapy (see page 1041, first and second paragraph). Also, with regard to unpredictability, Johnson, also cited for evidentiary purposes, teach that the in vivo activity of 39 different agents in a particular histology in a tumor model did not correlate to activity in the same human cancer (see Results on page 1426). In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. Further, the mode of action of anticancer agents is often unknown or very unpredictable and administration of such agents is often accompanied by undesirable side effects.
Furthermore, with regard to unpredictability, Kunnumakkara, cited for evidentiary purposes, teaches cancer is a group of more than 200 neoplastic diseases caused by diverse deregulated cell signaling cascades (page 633, left, 1st paragraph); consumption of tobacco and alcohol, obesity, insufficient physical activity, exposure to ultraviolet radiation, and various dietary factors which include insufficient fruit, non-starchy vegetables, and fiber; red/processed meat are predicted to be strongly associated with the risk of diverse cancer types; cancer occurs as a result of the dysregulation of as many as 500 different genes which may happen over a very long duration of time (20–30 years) till the symptoms become apparent (page 633, right, last bridge paragraph). Kunnumakkara further teaches there exists a missing connection between preclinical data and clinical findings; although, a significantly huge amount of money is spent in the pre-clinical settings for target validation and drug optimization, most of the therapies fail in the clinical trials till date; this can be due to the reason that the models used in the pre-clinical setting are not the adequate ones to effectively mimic human responses (page 664, right, 2nd paragraph); although highly convenient, cancer cell line models are associated with several limitations as well; for example, existence of genomic instability which may result in differences between the original tumor and the respective cell line, culture conditions that can alter the morphology, gene expression pattern, genomic profile, cellular pathways and culture environment from that of the original tumor, loss of natural tumor heterogeneity; the generic transformations that occur upon culturing of the cancer cells are not restored when regrown in vivo; and cancer cells in the in vitro condition grow in absence of stroma which include lymphatic vessels and blood, associated fibroblasts and immune cells, and lack a complex extracellular matrix; therefore, in vitro data often exhibits fundamental mismatch with those obtained from clinical findings and hence this can be regarded as one prime reason behind the failure of novel drug development (page 665, last bridge paragraph). Kunnumakkara teaches the foremost shortcomings of the use of animal models are their inability to recapitulate the link between the tumor and its microenvironment completely and the requisite of an immunocompromised host; basically, these animal models do not have the ability to reflect all the features of human cancer impeccably. Kunnumakkara teaches that despite the advances in understanding of cancer biology and deriving different novel therapeutic targets, the translation of these understanding into therapies is poor due to higher failure rate (90%). The high failure rate could be due to non-consideration of factors such as clinical translation, drug delivery, drug pharmacokinetics, pre-clinical models, and tumor physiology, which are critical factors.
As illustrative of the state of the art of using hypomethylating agents, the examiner cites Ma et al. (“Comparison Between Decitabine and Azacitidine for Patients With Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndrome: A Systematic Review and Network Meta-Analysis”). Ma teaches that azacitidine (AZA) and decitabine (DAC) have different efficacies and side effects, despite both being hypomethylating agents (abstract, “For the indirect method, DAC showed a higher complete remission (CR) rate than AZA in patients with both AML (RR = 2.28, 95% CI 1.12–4.65) and MDS (RR = 7.57, 95% CI 1.26–45.54). Additionally, DAC significantly increased the risk of 3/4 grade anemia (RR = 1.61, 95% CI: 1.03–2.51), febrile neutropenia (RR = 4.03, 95% CI: 1.41–11.52), and leukopenia (RR = 3.43, 95% CI 1.64–7.16) compared with AZA”).
These articles plainly demonstrate that the art of developing and testing anticancer drugs, particularly for use in humans, is extremely unpredictable, particularly in the case of a single compound or genus of compounds being used to treat any and all cancers. Even single drugs in the same genus of compounds have different efficacies and side effects, let alone in combination with other drugs.
2. The breadth of the claims
Claims 1, 9-10, 11, and 19 are very broad in that they recite a method of treating any cancer, comprising administering any ATR inhibitor with any hypomethylating agent. Although claims 9 and 19 further specify that the cancer is resistant to cytarabine, daunorubicin, or cisplatin, this property can be broadly found in a wide range of cancer types. Although claims 2-3 and 12-13 specify the ATR inhibitor and hypomethylating agent, they still claim the treatment of any cancer. Although claims 4-8 and 14-18 specify the cancer to be treated, they still claim the use of any ATR inhibitor and any hypomethylating agent.
Furthermore, the breadth of hypomethylating agents and ATR inhibitors encompassed by claims 1, 4-11, and 14-19 includes all hypomethylating agents and all ATR inhibitors known presently, as well as any compounds either presently unknown, or later classified under the umbrella of hypomethylating agents or ATR inhibitors. Can Applicant simply “reach through” and obtain patent protection for the administration of a combination of compounds not yet discovered, but are later invented and classified as ATR inhibitors and hypomethylating agents?
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification provides support for using decitabine and AZD6738 to treat TP53-mutated AML in a mouse xenotransplantation model (Example 1 in specification, p. 42, lines 5-9 and 22-24; also Figures 11A-C). The specification also provides support for using decitabine and M1774 (Example 2 in specification, Figures 18-19).
4. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, one of ordinary skill in the art would not accept that Examples 1 and 2 could be predictably used to treat TP53-mutated cancers by administering any ATR inhibitor with any hypomethylating agent, nor to treat all cancers with a combination of decitabine and AZD6738 or M1774, let alone to treat to treat all cancers by administering any ATR inhibitor with any hypomethylating agent. Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent protection' is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" (42 USPQ 2d 1001, Fed. Circuit 1997).
As noted above, the specification provides no experimental support for the use of ATR inhibitors and hypomethylating agents for the treatment of cancers other than TP53-mutated AML and MDS, nor does it provide support for the use of ATR inhibitors other than AZD6738 or M1774 and hypomethylating agents other than decitabine. A review of the state of the art fails to reveal that Examples 1 and 2 are useful as therapeutic for the treatment of any cancer within the scope of the instant claims. Determining if any particular claimed compound would treat any particular cancerous disease state would require synthesis of the compound, formulation into a suitable dosage form, and subjecting it to clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the limited guidance and direction provided by Applicant. As noted supra, even in vitro and in vivo assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy.
Accordingly, claims 1-19 do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
112(b)
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Huber (US 2016/0015702 A1).
Claim 23 of Huber teaches a method of treating cancer comprising co-administering to a subject in need thereof an aminoheteroaryl compound with chemotherapy. Claim 23 teaches that one such chemotherapy is an ATR inhibitor. Claim 25 teaches that one such chemotherapy is decitabine.
Although Huber does not explicitly teach the use of decitabine and an ATR inhibitor together, the courts have recognized that combining equivalents known for the same purpose supports a prima facie case of obviousness. See MPEP 2144.06: "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, 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) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Because Huber teaches decitabine and an ATR inhibitor individually as chemotherapy agents to treat cancer, it would have been obvious to one of ordinary skill in the art prior to the filing of the instant application to administer them in combination to treat TP53-mutated AML. One would have been motivated and had a reasonable expectation of success in doing so based on the teaching of Huber that each compound individually works as a chemotherapy agent to treat cancer.
Furthermore, although Huber does not teach decitabine as a hypomethylating agent, its use as such is evidenced by the inclusion of decitabine in instant claim 2 as a hypomethylating agent. Thus claim 1, directed to the use of a composition comprising an ATR inhibitor and a hypomethylating agent to treat cancer in a subject and claim 2, wherein the hypomethylating agent is decitabine, are rejected.
Regarding claim 10, the wherein limitation of this claim is considered to simply express the intended result of a process step positively recited, which is not given patentable weight (See MPEP 2111.04: [T]he court noted (quoting Minton v. Nat'lAss'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQgd 1614, 1690 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.'" Hoffer v. Microsoft Corp., 405 F.3d 1396, 1399, 74 USPQgd 1481, 1483 (Fed. Cir. 2005).). In the instant case, the wherein clause is directed to the intended result (i.e. increasing DNA replication stress in cancer cells or enhancing killing of cancer cells) of the process step positively recited (i.e. administering a compound comprising an ATR inhibitor and a hypomethylating agent). Because claim 1 is rejected in view of Huber, claim 10 is rejected as well.
Regarding claims 11-12, Huber teaches a method for treating cancer comprising administering decitabine and an ATR inhibitor. Administering decitabine and an ATR inhibitor to a subject suffering from cancer reads on inducing DNA replication stress or cell death in a cancer cell, comprising contacting the cell with the decitabine and ATR inhibitor. Thus, claim 11, directed towards a method comprising contacting a cancer cell with an ATR inhibitor and a hypomethylating agent, and claim 12, wherein the hypomethylating agent is decitabine, are rejected.
Claims 1-3 and 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over Huber (US 2016/0015702 A1) in view of Wilson (“ATR Inhibitor AZD6738 (Ceralasertib) Exerts Antitumor Activity as a Monotherapy and in Combination with Chemotherapy and the PARP Inhibitor Olaparib”, published 03/15/2022).
As discussed supra, Huber teaches a method of treating cancer comprising co-administering to a subject in need thereof an aminoheteroaryl compound with chemotherapy. Huber teaches that this chemotherapy can be decitabine or an ATR inhibitor. Huber does not teach the use of AZD6738 as an ATR inhibitor.
Wilson teaches that AZD6738 is an ATR inhibitor (abstract).
As discussed supra, it would have been obvious prior to the filing of the instant application to use decitabine in conjunction with an ATR inhibitor in view of the teachings of Huber. The reasons and rationales are applied as before and are not reiterated here, thereby rejecting claims 1-2 and 10-12.
Furthermore, it would have been obvious to one of ordinary skill in the art prior to the filing of the instant application to modify the method of cancer treatment comprising administering decitabine and an ATR inhibitor as taught by Huber with the use of AZD6738 as an ATR inhibitor as taught by Wilson. One would have been motivated and had a reasonable expectation of success in doing so giving the teaching by Huber that decitabine and an ATR inhibitor can be used together to treat cancer along with the teaching by Wilson that AZD6738 is an ATR inhibitor. Thus, claim 3, directed to a method of treating a cancer in a subject comprising administering an ATR inhibitor and a hypomethylating agent, wherein the ATR inhibitor is selected from a group including AZD6738; and claim 13, directed to a method of inducing cell death in a cancer cell, comprising contacting the cell with an ATR inhibitor and a hypomethylating agent, are rejected.
Claims 1-2, 4, 6, 10-12, 14, and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Stuart (US 2023/0172936 A1, with an effectively filed date of 05/11/2020).
Claim 27 of Stuart, which depends on any of its claims 1-26, teaches a method of treating a cancer in a subject in need thereof, comprising administering a pharmaceutical composition comprising a certain carboxamide compound and a second therapeutic agent. Claim 29 teaches that this second therapeutic agent can be decitabine. Claim 33 teaches that the second therapeutic agent can be an ATR inhibitor. Claim 7 of Stuart teaches that the cancer is acute myeloid leukemia or myelodysplastic syndrome. Claim 9 of Stuart teaches that the AML is de novo AML or therapy-related AML. Claim 26 teaches that the cancer is TP53-mutated AML.
Although Stuart does not explicitly teach the use of decitabine and an ATR inhibitor together, the courts have recognized that combining equivalents known for the same purpose supports a prima facie case of obviousness. See MPEP 2144.06: "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, 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) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Because Stuart teaches decitabine and an ATR inhibitor individually as agents to treat TP53-mutated AML, it would have been obvious to one of ordinary skill in the art prior to the filing of the instant application to administer them in combination to treat TP53-mutated AML. One would have been motivated and had a reasonable expectation of success in doing so based on the teaching of Stuart that each agent individually works to treat TP53-mutated AML.
Furthermore, although Stuart does not teach decitabine as a hypomethylating agent, its use as such is evidenced by the inclusion of decitabine in instant claim 2 as a hypomethylating agent. Thus claim 1, directed to the use of a composition comprising an ATR inhibitor and a hypomethylating agent to treat cancer in a subject; claim 2, wherein the hypomethylating agent is decitabine; claim 4, wherein the cancer comprises a TP53-mutated cancer; and claim 6, wherein the cancer is AML or MDS, are all rejected.
Regarding claim 10, the wherein limitation of this claim is considered to simply express the intended result of a process step positively recited, which is not given patentable weight. (See MPEP 2111.04: [T]he court noted (quoting Minton v. Nat'lAss'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQgd 1614, 1690 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.'" Hoffer v. Microsoft Corp., 405 F.3d 1396, 1399, 74 USPQgd 1481, 1483 (Fed. Cir. 2005).). In the instant case, the wherein clause is directed to the intended result (i.e. increasing DNA replication stress in cancer cells or enhancing killing of cancer cells) of the process step positively recited (i.e. administering a compound comprising an ATR inhibitor and a hypomethylating agent). Because claim 1 is rejected in view of Stuart, claim 10 is rejected as well.
Regarding claims 11-12, 14, and 16-17, Stuart teaches a method for treating cancer comprising administering decitabine and an ATR inhibitor, as discussed prior. Administering decitabine and an ATR inhibitor to a subject suffering from cancer reads on inducing DNA replication stress or cell death in a cancer cell, comprising contacting the cell with the decitabine and ATR inhibitor. The same goes for treating TP53-mutated cancer, AML, MDS, and therapy-related AML in a subject vs. in a cell. Thus, claim 11, directed towards a method comprising contacting a cancer cell with an ATR inhibitor and a hypomethylating agent; claim 12, wherein the hypomethylating agent is decitabine; claim 14, wherein the cancer cell is TP53-mutated; claim 16, wherein the cancer cell is an AML or MDS cell; and claim 17, wherein the cancer cell is de novo AML or therapy-related AML, are all rejected.
Claims 1-4, 6, 10-14, and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Stuart (US 2023/0172936 A1) in view of Wilson (“ATR Inhibitor AZD6738 (Ceralasertib) Exerts Antitumor Activity as a Monotherapy and in Combination with Chemotherapy and the PARP Inhibitor Olaparib”).
As discussed supra, Stuart teaches the use of decitabine as well as the use of an ATR inhibitor to treat cancer in a subject. Stuart also specifies that this cancer may be AML, MDS, or therapy-related or de novo AML. Stuart does not teach the use of AZD6738.
Wilson teaches that AZD6738 is an ATR inhibitor (abstract). Wilson also teaches that “AZD6738 showed combinatorial efficacy with agents associated with replication fork stalling and collapse” and that “these preclinical data provide rationale for clinical evaluation of AZD6738 as a monotherapy or combinatorial agent” (abstract).
As discussed previously, it would have been obvious prior to the filing of the instant application to use decitabine in conjunction with an ATR inhibitor in view of the teachings of Stuart. The reasons and rationales are applied as before and are not reiterated here, thereby rejecting claims 1-2, 4, 6, 10-12, 14, and 16-17.
Furthermore, it would have been obvious to one of ordinary skill in the art prior to the filing of the instant application to modify the method of cancer treatment comprising administering decitabine and an ATR inhibitor as taught by Stuart with the use of AZD6738 as an ATR inhibitor as taught by Wilson. One would have been motivated and had a reasonable expectation of success in doing so giving the teaching by Stuart that decitabine and an ATR inhibitor can be used together to treat a TP53-mutated cancer along with the teaching by Wilson that AZD6738 is an ATR inhibitor, as well as the teaching by Wilson that AZD6738 combinatorial efficacy with other agents provide rational for clinical evaluation of AZD6738 as a combinatorial agent. Thus, claim 3, directed to a method of treating a cancer in a subject comprising administering an ATR inhibitor and a hypomethylating agent, wherein the ATR inhibitor is selected from a group including AZD6738; and claim 13, directed to a method of inducing cell death in a cancer cell, comprising contacting the cell with an ATR inhibitor and a hypomethylating agent, are rejected.
Claims 1-2, 4, 6, 10-12, 14, and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Stuart (US 2023/0172936 A1) in view of Leone (“De Novo and Therapy-Related Myelodysplastic Syndromes: Analogies and Differences”, published 05/01/2022).
As discussed supra, Stuart teaches the use of decitabine as well as the use of an ATR inhibitor to treat cancer in a subject. Stuart also specifies that this cancer may be AML, MDS, or therapy-related or de novo AML. Stuart does not teach the treatment of therapy-related MDS.
Leone teaches that “the prognosis and the consequent therapy [of therapy-related MDS] can be established following the same criteria as for p-MDS [primitive MDS], and the therapy is generally decided using the same criteria”.
As discussed previously, it would have been obvious prior to the filing of the instant application to use decitabine in conjunction with an ATR inhibitor to treat cancer in a subject or kill cancer cells in view of the teachings of Stuart. In additional view of Wilson, it would have also been obvious to use AZD6738 as an ATR inhibitor. The reasons and rationales are applied as before and are not reiterated here, thereby rejecting claims 1-2, 4, 6, 10-14, and 16-17.
Furthermore, it would have been obvious to one of ordinary skill in the art prior to the filing of the instant application to modify the method of treating MDS comprising administering decitabine and an ATR inhibitor in view of Stuart to treat therapy-related MDS as taught by Leone. One would have been motivated and had a reasonable expectation of success to do so given the teaching by Stuart that decitabine and an ATR inhibitor can be used in combination to treat MDS and the teaching by Leone that treatments for MDS and therapy-related MDS are generally decided using the same criteria. Thus claim 18, directed to contacting an MDS cell with a combination of a hypomethylating agent and an ATR inhibitor, wherein the MDS is selected from a group including therapy-related MDS, is rejected.
Claims 1-3, 9-13, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Viet (“Decitabine Rescues Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma”) in view of Leonard (“ATR inhibition sensitizes HPV− and HPV+ head and neck squamous cell carcinoma to cisplatin”).
Viet teaches that decitabine and cisplatin synergistically treat head and neck squamous cell carcinoma (HSNCC) (p. 4, “In our HNSCC mouse model, combination treatment with decitabine and cisplatin produced a more robust anti-tumor effect than either drug alone”). Viet also teaches that decitabine treats cisplatin-resistant head and neck squamous cell carcinoma by sensitizing cancer cells to cisplatin (abstract, “…decitabine treatment of cisplatin-resistant HNSCC cells reversed methylation and gene expression toward a cisplatin-sensitive profile. The study provides direct evidence that decitabine restores cisplatin sensitivity in in vitro and in vivo models of HNSCC.”) and reverses cisplatin resistance (also p. 4, “Decitabine pre-treatment in vitro reversed cisplatin-resistance in SCC-25/CP cells”). Viet does not teach the use of AZD6738.
Leonard teaches that a combination of AZD6738 and cisplatin synergistically treats head and neck squamous cell carcinoma both in vitro and in vivo (p. 38, NSG mice were implanted with tumor tissue derived from an HPV− PDX (PDX6851) or an HPV+ PDX (PDX7157), followed by randomization and treatment with vehicle, cisplatin, AZD6738, or the combination (Fig. 5C and D). As was seen with the cell line-derived xenografts, treatment with cisplatin plus AZD6738 resulted in greater tumor growth inhibition than treatment with either agent alone”).
Although neither Viet nor Leonard teaches the use of decitabine and AZD6738 together to treat HNSCC, the courts have recognized that combining equivalents known for the same purpose supports a prima facie case of obviousness. See MPEP 2144.06: "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, 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) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Because Viet teaches decitabine in combination with cisplatin to treat HNSCC and Leonard teaches AZD6738 in combination with cisplatin to treat HNSCC, it would have been obvious to one of ordinary skill in the art prior to the filing of the instant application to administer them in combination with cisplatin to treat cisplatin-resistant HNSCC. One would have been motivated and had a reasonable expectation of success in doing so based on the teaching of Viet that decitabine reverses cisplatin resistance in HNSCC cells and based on the teaching of Viet and Leonard that each agent individually sensitizes HNSCC to cisplatin both in vivo and in vitro. Thus, claim 1, directed to treating a cancer in a subject by administering an ATR inhibitor with a hypomethylating agent; claim 2, wherein the hypomethylating agent is decitabine; claim 3, where the ATR inhibitor is selected from a group including AZD6738; claim 9, wherein the cancer is resistant to cisplatin; and claim 10, wherein the combination enhances killing of cancer cells, are all rejected. In addition, claim 11, directed to inducing cell death in a cancer cell by administering an ATR inhibitor with a hypomethylating agent; claim 12, wherein the hypomethylating agent is decitabine; claim 13, where the ATR inhibitor is selected from a group including AZD6738; and claim 19, wherein the cancer cell is resistant to cisplatin, are all rejected as well.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Ahmed (“Mutant TRP53-R172H Has Gain-of-Function or Dominant-Negative Effects in Response to Different Hematopoietic Stressors in Mice”) teaches the effects of 5-fluorouracil on mice with mutant TP53-R172H.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OLIVER D. HEES whose telephone number is (571)272-9840. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
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/OLIVER D HEES/ Examiner, Art Unit 1628
/AMY L CLARK/ Supervisory Patent Examiner, Art Unit 1628