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
The present application claims priority to the applications, EP 22150358.4 and PCT/EP2022/088098, with effective filing dates of 5 Jan 2022 and 30 Dec 2022.
Claim Status
This Office Action is in response to Applicant’s Response to Restriction Requirement filed, 15 July 2026.
Applicant’s election of Group I (claims 1-4 and 7-14) and Nec-1s, ML120B, and ABT-199 as the species in the reply filed on 15 July 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 5 and 15-23 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to a non-elected group (Group II: claim 5; Group III: claim 15; Group IV: 16-22; Group V: 23), there being no allowable generic or linking claim.
Claim 11 is withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to a non-elected species, there being no allowable generic or linking claim. Claim 11 recites the IKK inhibitor is LY2409881, which does not read on the elected species.
Claims 1-4, 7-10, and 12-14 are under consideration in the instant office action.
Information Disclosure Statement
The Information Disclosure Statement filed 28 June 2024 and the references cited therein have been considered, unless indicated otherwise.
Additionally, the Examiner notes that there is a listing of references in the specification. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Interpretation
For clarity, the Examiner interprets a proliferative disorder recited in claim 1 to be cancer.
Claim Rejections - 35 USC § 112
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.
1. Claim 4 is 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 4 specifies an antigen binding fragment and an antigen binding protein. While the specification broadly describes methods of treating hematological cancer with the combination of a RIPK inhibitor, an IKK inhibitor, and a BCL-2 inhibitor wherein any of the RIPK, IKK, and BCL-2 inhibitors are an antigen binding fragment or an antigen binding protein, the specification refers to several of the antigen binding fragment and antigen binding protein agents by their antigen ([48]; [50]; [106]).
Regarding reference to an antigen binding fragment and an antigen binding protein agent by their antigen, the disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017). See MPEP § 2163(II)(3)(a).
2. Claim 1-4, 7-10, and 12-14 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 autoimmune disorders, diseases in myeloid cells (such as bone marrow myeloid progenitor cell), and hematological cancers, does not reasonably provide enablement for a) preventing any and all cancer and b) treating any and all cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The criteria for enablement set out in the In re Wands, MPEP § 2164.01(a), considers the following factors:
Breadth of the claims
The instant claims are directed to a method of treating or preventing a proliferative disorder in a subject via administering a RIPK1 inhibitor, an IKK inhibitor, and a BCL-2 inhibitor. Thus, encompassing all cancers and prevention thereof.
As such, the breadth of the claims is great.
Level of Skill in the Art
The level of skill in the art is a clinician or an artisan with a PhD.
State of the Prior Art
Pasparakis (WO 2019/110832, published 13 June 2019; see IDS filed 28 June 2024) teaches treating diseases associated with a dysregulated immune response, such as autoimmune disorder, inflammatory diseases, or pathological immune responses as adverse effects of medical treatments via the combined use of a RIPK1 inhibitor and IKK inhibitor in a subject (abstract). Pasparakis teaches several autoimmune diseases, such as systemic lupus erythematosus, and that the cells associated with the diseases to be treated with the claimed invention are a myeloid cell, such as bone marrow myeloid progenitor cell, monocyte or macrophage (page 14, paragraph 5, page 15, paragraphs 1-2).
Huang (J. Experiment. Clinic. Cancer Res.¸2018, 37(310), 1-15) teaches methods to overcome resistance to regulated cell death in human cancers, particularly that of hematological cancers (abstract). Huang teaches that leukemia represents a class of hematologic malignancies that is characterized by dysregulation of cell death pathways and treatment-related resistance (abstract). Huang teaches that the majority of chemotherapeutic and targeted drugs that kill leukemia cells operated via triggering apoptosis and thus there is a need for novel therapeutic strategies to reactivate nonapoptotic cell death programs in refractory leukemia (abstract). Huang teaches that necroptosis is a regulated form of necrosis modulated by intracellular signaling pathways and is a potential solution to overcoming apoptosis resistance in leukemia (abstract). However, Huang also teaches that current views suggest that the choice of cell death (apoptosis versus necroptosis) is determined by a variety of factors, including stimuli, cell type, genetic background, and the intracellular environment (page 2, column 2, paragraph 2).
Leenaars (J. Transl. Med., 2019, 17(223), 1-22) teaches that current drug development is handicapped by high attrition rates and that many molecules that were promising during preclinical development fail during subsequent clinical testing (page 1, column 1, paragraph 1). Leenaars further teaches that animals and humans are complex systems and therefore always unpredictable (page 2, column 1, paragraph 1), which further underscores the unpredictability of the art and translation of promising candidate from in vitro models to in vivo models and beyond into humans.
Additionally, Comprehensive Hematology Oncology (“What Causes Blood Cancer, and Can It Be Prevented?” Comprehensive Hematology Oncology, 2026, <comphemonc.com/2025/07/09/what-causes-blood-cancer-and-can-it-be-prevented/>, accessed 28 Aug 2026) teaches that the etiology of blood cancer is not yet well known and prevention is a complicated phenomenon (page 1, paragraph 1). Comprehensive Hematology Oncology teaches that there are three broad categories of blood cancer: leukemia, lymphoma, and myeloma (page 2, paragraph 2). Comprehensive Hematology Oncology teaches that there are several causative risk factors and genetic changes for blood cancer: genetic mutations, environmental and occupational exposures, infections, immune system disorders, family history and genetics, and lifestyle factors (page 2, paragraph 3, page 2, items 1-2; page 3, items 2-6). However, Comprehensive Hematology Oncology teaches that blood cancer cannot be prevented as there is no foolproof method to avoid blood cancer (page 4, paragraph 1). Comprehensive Hematology Oncology teaches that there are precautions to minimize the risk of developing blood cancer, particularly if the individual is already genetically or environmentally predisposed and specifically teaches managing chronic infections to reduce the risk of immune system failure (one of the most common causes of blood cancer) and regular medical checkups to detect blood cancer signs early (page 4, paragraph 1; page 4, items 1-6).
Predictability in the Art
Pasparakis teaches treating diseases associated with a dysregulated immune response, such as autoimmune disorder, inflammatory diseases, or pathological immune responses as adverse effects of medical treatments via the combined use of a RIPK1 inhibitor and IKK inhibitor in a subject (abstract). Pasparakis teaches several autoimmune diseases, such as systemic lupus erythematosus, and that the cells associated with the diseases to be treated with the claimed invention are a myeloid cell, such as bone marrow myeloid progenitor cell, monocyte or macrophage (page 14, paragraph 5, page 15, paragraphs 1-2).
Huang teaches methods to overcome resistance to regulated cell death in human cancers, particularly that of hematological cancers (abstract). Huang teaches that necroptosis is a regulated form of necrosis modulated by intracellular signaling pathways and is a potential solution to overcoming apoptosis resistance in leukemia (abstract). However, Huang teaches that current views suggest that the choice of cell death (apoptosis versus necroptosis) is determined by a variety of factors, including stimuli, cell type, genetic background, and the intracellular environment (page 2, column 2, paragraph 2). Huang also teaches that evidence has shown that some components of the cell death pathway that mediate necroptosis are often scarce or even lacking and that a better understanding of the underlying molecular mechanisms of necroptosis is required before necroptosis can be used in clinical therapeutic interventions (page 10, column 2, paragraph 1), underscoring the unpredictability of the art.
Diaz-Uriarte (PLOS Computational Biology, 2019, 15(8): e1007246, 1-29) teaches that improving the ability to predict paths of tumor progression is helpful for diagnostic, prognostic, and treatment purposes (page 2, paragraph 2). Diaz-Uriarte describes that direct information about paths of tumor progression is scarce, but cancer progression models can be used to predict
the tumor progression path and use cross-sectional data as input (abstract). Diaz-Uriarte teaches that the best performing cancer progression model was unreliable when applied to twenty-two cancer data sets and that feature selection can have a detrimental selection on the performance of the model, thus highlighting the unpredictability of the art (abstract; page 22, paragraph 2).
Leenaars teaches that current drug development is handicapped by high attrition rates and that many molecules that were promising during preclinical development fail during subsequent clinical testing (page 1, column 1, paragraph 1). Leenaars further teaches that animals and humans are complex systems and therefore always unpredictable (page 2, column 1, paragraph 1), which further underscores the unpredictability of the art and translation of promising chemical candidate from in vitro models to in vivo models and beyond into humans.
Additionally, Comprehensive Hematology Oncology teaches that the etiology of blood cancer is not yet well known and prevention is a complicated phenomenon (page 1, paragraph 1). Comprehensive Hematology Oncology teaches that there are several causative risk factors and genetic changes for blood cancer: genetic mutations, environmental and occupational exposures, infections, immune system disorders, family history and genetics, and lifestyle factors (page 2, paragraph 3, page 2, items 1-2; page 3, items 2-6). However, Comprehensive Hematology Oncology teaches that blood cancer cannot be prevented as there is no foolproof method to avoid blood cancer (page 4, paragraph 1), thus emphasizing the unpredictability in preventing blood cancer.
Thus, Pasparakis and Huang teach treating autoimmune disorders, diseases in myeloid cells (such as bone marrow myeloid progenitor cell), and hematological cancers is predictable, but Diaz-Uriarte, Leenaars, and Comprehensive Hematology Oncology teach that treating all cancer is unpredictable, much less preventing cancer (and specifically preventing hematological cancer).
Working Examples
The instant specification teaches treating lymphoma in mouse models (Examples 1-3, pages 46-49). The instant specification does not teach applying the claimed method to any cancer cell lines for in vitro testing, much less in vivo or in patient testing.
Thus, it is not possible to determine all the types of cancer that the claimed method can treat, much less prevent.
Quantity of Experimentation
The amount of experimentation required to determine which compound, which cancer, in
what amounts, what order, would be astronomical. A skilled artisan would be required to start with
proof-of-concept and proceed through all levels of lead identification and optimization, which is
invention and not development; this is undue amount of experimentation.
As such, while the specification is enabling for treating autoimmune disorders, diseases in myeloid cells (such as bone marrow myeloid progenitor cell), and hematological cancers, it does not reasonably provide enablement for a) preventing any and all cancer or b) treating any cancer.
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.
3. Claims 3-4, 8-10, and 12-14 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 3-4, 8-10, and 12-14 recite a broad limitation followed by a narrow range or limitation. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 3 recites the broad recitation the IKK/NFKB signaling inhibitor (b) is an IKK inhibitor, and the claim also recites preferably an IKK2/IKKP inhibitor, which is the narrower statement of the range/limitation.
Claim 4 recites the broad recitation of an antisense or inhibitory DNA or RNA, a ribozyme, an RNA or DNA aptamer, RNAi, siRNA, shRNA, and the like, and the claim also recites including variants of derivatives thereof, which is the narrower statement of the range/limitation.
Claim 8 recites the broad recitation of a group of RIPK1 inhibitors and the claim also recites preferably necrostatin-1 stable, which is the narrower statement of the range/limitation.
Claim 9 recites the broad recitation of the IKK/NFKB signaling inhibitor is an IKK inhibitor, and the claim also recites 1) preferably an IKK2/IKK3 inhibitor; 2) more preferably wherein the IKK2/IKK3 inhibitor is selected from a group of IKK2/IKK3 inhibitors; and 3) preferably is LY2409881, which are narrower statements of the range/limitation.
Claim 10 recites the broad recitation of a group of BCL-2 inhibitors and the claim also recites preferably venetoclax, which is the narrower statement of the range/limitation.
Claim 12 recites the broad recitation of a solid cancer or hematologic cancer and the claim also recites for example including leukemias, lymphomas, and myelomas, which is the narrower statement of the range/limitation.
Claim 13 recites the broad recitation of a list of cancers and the claim also recites preferably B cell non-Hodgkin’s lymphoma (B-NHL) and/or B-cell mature acute lymphoblastic leukemia (B-cell ALL), which is the narrower statement of the range/limitation.
Claim 14 recites the broad recitation of the subject is a mammal and the claim also recites 1) preferably a human and 2) more preferably a human patient suffering from a proliferative disorder, which are narrower statements of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Additionally, claims 4 and 12-14 recite the phrase “for example.” Regarding claims 4 and 12-14, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim 4 recites “for example” in lines 3 and 5. Claim 12 recites “for example” in line 2. Claim 13 recites “for example” in line 4. Claim 14 recites “for example” in line 2.
Additionally, claims 4, 10, and 13-14 recite the phrase “such as.” Regarding claim 4, 10, and 13-14, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). claim 4 recites “such as” in lines 4 and 7 (twice). Claim 10 recites “such as” in line 6. Claim 13 recites “such as” in line 4. Claim 14 recites “such as” in line 1.
Additionally, claim 4 recites the phrase “or the like.” Regarding claim 4, the phrase "or the like" renders the claim(s) indefinite because the claim(s) include(s) elements not actually disclosed (those encompassed by "or the like"), thereby rendering the scope of the claim(s) unascertainable. See MPEP § 2173.05(d). Claim 4 recites “and the like” in line 6.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
4. Claim(s) 1* is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lee (Nutr. Res. Pract., 2021, 15(1), 12-25; of record, see PTO-892 mailed 10 June 2026) as evidenced by Xu (Front. Neurosci., 2018, 12(690), 1-10; of record, see PTO-892 mailed 10 June 2026) and Liu (Clin. Transl. Oncol.¸2013, 15, 741-746; of record, see PTO-892 mailed 10 June 2026).
*While Applicant elected the compounds, necrostatin-1, ML120B, and venetoclax, Lee applies to the broader genus, and the rejection over the broader genus is made in favor of compact prosecution. However, the Examiner notes that the full genus was not searched.
Lee teaches the pre-treatment of necrostatin-1 (a RIPK1 inhibitor) and then treating cancer cells with resveratrol (an IKK/NFκβ inhibitor and BCL-2 inhibitor) (page 13, paragraph 2; page 16, paragraph 1; page 18, paragraph 2) as evidenced by Xu and Liu. Xu teaches that resveratrol is an IKK/NFκβ inhibitor (page 2, column 1, paragraph 2). Liu teaches that resveratrol is an inhibitor of BCL-2 (page 744, column 2, paragraph 2). Accordingly, Lee teaches a method of treating cancer via administering a RIP1 inhibitor, an IKK inhibitor, and a BCL-2 inhibitor.
Regarding claim 1, Lee teaches the pre-treatment of necrostatin-1 (a RIPK1 inhibitor) and then treating cancer cells with resveratrol (an IKK/NFκβ inhibitor and BCL-2 inhibitor) (page 13, paragraph 2; page 16, paragraph 1; page 18, paragraph 2) as evidenced by Xu (page 2, column 1, paragraph 2) and Liu (page 744, column 2, paragraph 2).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
5. Claim(s) 1-4, 7-10, and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Pasparakis (WO 2019/110832, published 13 June 2019; see IDS filed 28 June 2024) in view of Huang (J. Experiment. Clinic. Cancer Res.¸2018, 37(310), 1-15) as evidenced by Med Chem Express (“MLN120B,” Med Chem Express, 2026, < www.medchemexpress.com/MLN120B.html?utm_source=google&utm_medium=CPC&utm_campaign=Small%20Molecules2&utm_term=HY-15473&utm_content=MLN120B&gad_source=1&gad_campaignid=24085468214&gclid=EAIaIQobChMI0b72qNTDlgMVkHBHAR2RKx1LEAAYASAAEgIgyvD_BwE>, accessed 28 Aug 2026).
Pasparakis teaches treating diseases associated with a dysregulated immune response, such as autoimmune disorder, inflammatory diseases, or pathological immune responses as adverse effects of medical treatments via the combined use of a RIPK1 inhibitor and IKK inhibitor in a subject (abstract). Pasparakis teaches several autoimmune diseases, such as systemic lupus erythematosus, and that the cells associated with the diseases to be treated with the claimed invention are a myeloid cell, such as bone marrow myeloid progenitor cell, monocyte or macrophage (page 14, paragraph 5, page 15, paragraphs 1-2). Pasparakis teaches that IKK are key regulatory signaling molecules that coordinate the activation of NF-κB (page 1, paragraph 3). Pasparakis teaches that the IKK complex and its catalytic subunits IKKα/IKK1 and IKKβ/IKK2 are essential for activation of NF-κB (page 1, paragraph 4). Pasparakis teaches that IKK inhibitors have great potential but that IKKβ knockout or inhibition resulted in increased production of IL-1β and systemic neutrophilia (page 2, paragraph 1). Pasparakis teaches that the serious safety concerns resulted in several companies terminated their programs but Pasparakis teaches novel therapeutic approaches to tackle immune related disorders via inhibition of IKK signaling that also overcomes the known adverse effects of such treatments (page 2, paragraphs 1-2). Pasparakis teaches that increased production of IL-1β by myeloid cells treated with IKK inhibitors depends largely on RIPK1 activity and that RIPK1 inhibition strongly diminished LPs-induced production of IL-1β arising from IKK inhibition (page 2, paragraph 4). Pasparakis teaches that the most serious known side effect of IKK inhibitors, namely the increased production of IL-1β by myeloid cells can be prevented by the inhibition of RIPK1 and that diseases associated with a pathological or deregulated immune response, such as increased IL-1β from IKK inhibition, can be treated (page 2, paragraph 4). Pasparakis teaches that necrostatin-1 stable is a preferred RIPK1 inhibitor (page 6, paragraph 4; page 7, paragraph 1). Pasparakis teaches that ML120B (also known as MLN120B as evidenced by Med Chem Express; page 3, synonyms) is a preferred IKK inhibitor (page 9, paragraph 3).
Regarding claim 1, Pasparakis fails to teach treating cancer and administering a BCL-2 inhibitor.
Huang teaches methods to overcome resistance to regulated cell death in human cancers, particularly that of hematological cancers (abstract). Huang teaches that leukemia represents a class of hematologic malignancies that is characterized by dysregulation of cell death pathways and treatment-related resistance (abstract; page 1, column 1, paragraph 1). Huang teaches that the majority of chemotherapeutic and targeted drugs that kill leukemia cells operated via triggering apoptosis and thus there is a need for novel therapeutic strategies to reactivate nonapoptotic cell death programs in refractory leukemia (abstract). Huang teaches that necroptosis is a regulated form of necrosis modulated by intracellular signaling pathways and is a potential solution to overcoming apoptosis resistance in leukemia (abstract; page 1, column 2, paragraphs 1-2). Huang teaches that RIPK1 is a critical regulator of necroptosis (page 2, column 1, paragraph 1). Huang teaches that the RIPK1 is polyubiquitinylated, which then contributes to the recruitment of a number of proteins, such as IKK, and subsequently facilitates the NF-κB cell survival pathway (page 3, column 2, paragraph 2; page 4, column 1, paragraph 1). Huang teaches that this change drives the expression of downstream proteins directly involved in apoptosis inhibition, such as BCL-2 (page 4, column 1, paragraph 1). Huang teaches that RIPK1 phosphorylation by IKK prevents RIPK1 kinase-dependent formation of the death complex (page 4, column 2, paragraph 1). Huang teaches that the induction of necroptosis may overcome drug resistance in several major types of leukemia, such as obatoclax, which is a BCL-2 inhibitor (Table 1, page 8; page 7, column 1, paragraph 2). Huang teaches that antiapoptotic BCL-2 protein family members are often associated with chemotherapy resistance (page 9, column 1, paragraph 4). Huang teaches that venetoclax is a small molecule that is orally bioavailable that specifically targets BCL-2 and recently approved by the FDA (page 9, column 2, paragraph 2). Huang teaches that venetoclax shows a manageable safety profile and induced substantial responses in patients with relapsed chronic lymphoblastic leukemia (CLL) including those with poor prognostic features (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1). Huang teaches that apoptosis evasion represents a hallmark of human cancers, particularly of leukemia, therapeutic induction of necroptosis opens new directions for treatment strategies in apoptosis-resistant leukemia (page 10, column 1, paragraph 5; page 10, column 2, paragraph 1).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify the method of Pasparakis to 1) treat a hematological cancer because RIPK1 is a critical regulator of necroptosis and RIPK1 phosphorylation by IKK prevents RIPK1 kinase-dependent formation of the death complex as taught by Huang; and 2) incorporate a BCL-2 inhibitor to circumvent apoptotic/necroptotic resistance mechanisms in hematological cancer as taught by Huang. One or ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Pasparakis teaches treating diseases associated with a dysregulated immune response, such as autoimmune disorder, inflammatory diseases, or pathological immune responses as adverse effects of medical treatments via the combined use of a RIPK1 inhibitor and IKK inhibitor in a subject.
-Pasparakis teaches several autoimmune diseases, such as systemic lupus erythematosus, and that the cells associated with the diseases to be treated with the claimed invention are a myeloid cell, such as bone marrow myeloid progenitor cell, monocyte or macrophage,
-Pasparakis teaches that IKK are key regulatory signaling molecules that coordinate the activation of NF-κB,
-Pasparakis teaches that the IKK complex and its catalytic subunits IKKα/IKK1 and IKKβ/IKK2 are essential for activation of NF-κB,
-Pasparakis teaches that IKK inhibitors have great potential but that IKKβ knockout or inhibition resulted in increased production of IL-1β and systemic neutrophilia,
-Pasparakis teaches that the serious safety concerns resulted in several companies terminated their programs but Pasparakis teaches novel therapeutic approaches to tackle immune related disorders via inhibition of IKK signaling that also overcomes the known adverse effects of such treatments,
-Pasparakis teaches that increased production of IL-1β by myeloid cells treated with IKK inhibitors depends largely on RIPK1 activity and that RIPK1 inhibition strongly diminished LPs-induced production of IL-1β arising from IKK inhibition,
-Pasparakis teaches that the most serious known side effect of IKK inhibitors, namely the increased production of IL-1β by myeloid cells can be prevented by the inhibition of RIPK1 and that diseases associated with a pathological or deregulated immune response, such as increased IL-1β from IKK inhibition, can be treated,
-Pasparakis teaches that necrostatin-1 stable is a preferred RIPK1 inhibitor,
-Pasparakis teaches that ML120B (also known as MLN120B as evidenced by Med Chem Express; page 3, synonyms) is a preferred IKK inhibitor,
-Huang - teaches methods to overcome resistance to regulated cell death in human cancers, particularly that of hematological cancers,
-Huang teaches that leukemia represents a class of hematologic malignancies that is characterized by dysregulation of cell death pathways and treatment-related resistance,
-Huang teaches that the majority of chemotherapeutic and targeted drugs that kill leukemia cells operated via triggering apoptosis and thus there is a need for novel therapeutic strategies to reactivate nonapoptotic cell death programs in refractory leukemia,
-Huang teaches that necroptosis is a regulated form of necrosis modulated by intracellular signaling pathways and is a potential solution to overcoming apoptosis resistance in leukemia,
-Huang teaches that RIPK1 is a critical regulator of necroptosis,
-Huang teaches that the RIPK1 is polyubiquitinylated, which then contributes to the recruitment of a number of proteins, such as IKK, and subsequently facilitates the NF-κB cell survival pathway,
-Huang teaches that this change drives the expression of downstream proteins directly involved in apoptosis inhibition, such as BCL-2,
-Huang teaches that RIPK1 phosphorylation by IKK prevents RIPK1 kinase-dependent formation of the death complex,
-Huang teaches that the induction of necroptosis may overcome drug resistance in several major types of leukemia, such as obatoclax, which is a BCL-2 inhibitor,
-Huang teaches that antiapoptotic BCL-2 protein family members are often associated with chemotherapy resistance,
-Huang teaches that venetoclax is a small molecule that is orally bioavailable that specifically targets BCL-2 and recently approved by the FDA,
-Huang teaches that venetoclax shows a manageable safety profile and induced substantial responses in patients with relapsed chronic lymphoblastic leukemia including those with poor prognostic features, and
-Huang teaches that apoptosis evasion represents a hallmark of human cancers, particularly of leukemia, therapeutic induction of necroptosis opens new directions for treatment strategies in apoptosis-resistant leukemia.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive a method of treating hematological cancer via a RIPK1 inhibitor, an IKK inhibitor, and a BCL-2 inhibitor.
Regarding claim 2, Pasparakis teaches administering necrostatin-1 stable and ML120B (page 6, paragraph 4; page 7, paragraph 1; page 9, paragraph 3; page 19, paragraph 3). Huang teaches administering venetoclax in patients with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1). Accordingly, the combination of Pasparakis and Huang teaches administering necrostatin-1 stable, ML120B, and venetoclax to treat a hematological cancer.
Regarding claim 3, Pasparakis teaches administering ML120B, an IKK inhibitor (page 9, paragraph 3; page 19, paragraph 3).
Regarding claim 4, Pasparakis teaches administering necrostatin-1 stable and ML120B (page 6, paragraph 4; page 7, paragraph 1; page 9, paragraph 3; page 19, paragraph 3), which are small molecules. Huang teaches administering venetoclax (a small molecule) in patients with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1).
Regarding claim 7, Pasparakis teaches administering necrostatin-1 stable and ML120B (page 6, paragraph 4; page 7, paragraph 1; page 9, paragraph 3; page 19, paragraph 3). Huang teaches administering venetoclax in patients with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1). Accordingly, the combination of Pasparakis and Huang teaches administering the combination of necrostatin-1 stable, ML120B, and venetoclax to treat a hematological cancer.
Regarding claim 8, Pasparakis teaches administering necrostatin-1 stable (page 6, paragraph 4; page 7, paragraph 1; page 19, paragraph 3), which is a RIPK1 inhibitor.
Regarding claim 9, Pasparakis teaches administering ML120B (page 9, paragraph 3; page 19, paragraph 3), which is an IKK inhibitor.
Regarding claim 10, Huang teaches administering venetoclax (a BCL-2 inhibitor) in patients with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1).
Regarding claim 12, Huang teaches administering venetoclax in patients with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1), which is a hematological cancer.
Regarding claim 13, Huang teaches administering venetoclax in patients with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1). Huang also teaches treating acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, myelodysplastic syndrome, chronic myelomonocytic leukemia, and lymphoma (page 8, column 1, paragraph 1; page 9, column 1, paragraph 2).
Regarding claim 14, Huang teaches administering venetoclax in patients (a human) with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1).
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.
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6. Claim 1-4, 7-10, and 12-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 4-8, and 13 of U.S. Patent No. 12,678,447 in view of Huang (J. Experiment. Clinic. Cancer Res.¸2018, 37(310), 1-15) as evidenced by Med Chem Express (“MLN120B,” Med Chem Express, 2026, < www.medchemexpress.com/MLN120B.html?utm_source=google&utm_medium=CPC&utm_campaign=Small%20Molecules2&utm_term=HY-15473&utm_content=MLN120B&gad_source=1&gad_campaignid=24085468214&gclid=EAIaIQobChMI0b72qNTDlgMVkHBHAR2RKx1LEAAYASAAEgIgyvD_BwE>, accessed 28 Aug 2026).
U.S. Patent No. 12,678,447 claims a method of treating a deregulated immune response in a subject via administering the IKK inhibitor, MLN120B (which is ML120B as evidenced by Med. Chem. Express; page 3, synonyms) and the RIPK1 inhibitor, necrostatin-1 stable (claims 1 and 13). ‘447 claims a method of concomitant inhibition of RIPK1 and IKK (claims 4 and 8).
Regarding claim 1, 447 fails to teach treating cancer and administering a BCL-2 inhibitor.
Huang teaches methods to overcome resistance to regulated cell death in human cancers, particularly that of hematological cancers (abstract). Huang teaches that leukemia represents a class of hematologic malignancies that is characterized by dysregulation of cell death pathways and treatment-related resistance (abstract; page 1, column 1, paragraph 1). Huang teaches that the majority of chemotherapeutic and targeted drugs that kill leukemia cells operated via triggering apoptosis and thus there is a need for novel therapeutic strategies to reactivate nonapoptotic cell death programs in refractory leukemia (abstract). Huang teaches that necroptosis is a regulated form of necrosis modulated by intracellular signaling pathways and is a potential solution to overcoming apoptosis resistance in leukemia (abstract; page 1, column 2, paragraphs 1-2). Huang teaches that RIPK1 is a critical regulator of necroptosis (page 2, column 1, paragraph 1). Huang teaches that the RIPK1 is polyubiquitinylated, which then contributes to the recruitment of a number of proteins, such as IKK, and subsequently facilitates the NF-κB cell survival pathway (page 3, column 2, paragraph 2; page 4, column 1, paragraph 1). Huang teaches that this change drives the expression of downstream proteins directly involved in apoptosis inhibition, such as BCL-2 (page 4, column 1, paragraph 1). Huang teaches that RIPK1 phosphorylation by IKK prevents RIPK1 kinase-dependent formation of the death complex (page 4, column 2, paragraph 1). Huang teaches that the induction of necroptosis may overcome drug resistance in several major types of leukemia, such as obatoclax, which is a BCL-2 inhibitor (Table 1, page 8; page 7, column 1, paragraph 2). Huang teaches that antiapoptotic BCL-2 protein family members are often associated with chemotherapy resistance (page 9, column 1, paragraph 4). Huang teaches that venetoclax is a small molecule that is orally bioavailable that specifically targets BCL-2 and recently approved by the FDA (page 9, column 2, paragraph 2). Huang teaches that venetoclax shows a manageable safety profile and induced substantial responses in patients with relapsed chronic lymphoblastic leukemia (CLL) including those with poor prognostic features (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1). Huang teaches that apoptosis evasion represents a hallmark of human cancers, particularly of leukemia, therapeutic induction of necroptosis opens new directions for treatment strategies in apoptosis-resistant leukemia (page 10, column 1, paragraph 5; page 10, column 2, paragraph 1).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify the method of ‘447 to 1) treat a hematological cancer because RIPK1 is a critical regulator of necroptosis and RIPK1 phosphorylation by IKK prevents RIPK1 kinase-dependent formation of the death complex as taught by Huang; and 2) incorporate a BCL-2 inhibitor to circumvent apoptotic/necroptotic resistance mechanisms in hematological cancer as taught by Huang. One or ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘447 claims a method of treating a deregulated immune response in a subject via administering the IKK inhibitor, MLN120B (which is ML120B as evidenced by Med Chem Express) and the RIPK1 inhibitor, necrostatin-1 stable,
-‘447 claims a method of concomitant inhibition of RIPK1 and IKK,
-Huang - teaches methods to overcome resistance to regulated cell death in human cancers, particularly that of hematological cancers,
-Huang teaches that leukemia represents a class of hematologic malignancies that is characterized by dysregulation of cell death pathways and treatment-related resistance,
-Huang teaches that the majority of chemotherapeutic and targeted drugs that kill leukemia cells operated via triggering apoptosis and thus there is a need for novel therapeutic strategies to reactivate nonapoptotic cell death programs in refractory leukemia,
-Huang teaches that necroptosis is a regulated form of necrosis modulated by intracellular signaling pathways and is a potential solution to overcoming apoptosis resistance in leukemia,
-Huang teaches that RIPK1 is a critical regulator of necroptosis,
-Huang teaches that the RIPK1 is polyubiquitinylated, which then contributes to the recruitment of a number of proteins, such as IKK, and subsequently facilitates the NF-κB cell survival pathway,
-Huang teaches that this change drives the expression of downstream proteins directly involved in apoptosis inhibition, such as BCL-2,
-Huang teaches that RIPK1 phosphorylation by IKK prevents RIPK1 kinase-dependent formation of the death complex,
-Huang teaches that the induction of necroptosis may overcome drug resistance in several major types of leukemia, such as obatoclax, which is a BCL-2 inhibitor,
-Huang teaches that antiapoptotic BCL-2 protein family members are often associated with chemotherapy resistance,
-Huang teaches that venetoclax is a small molecule that is orally bioavailable that specifically targets BCL-2 and recently approved by the FDA,
-Huang teaches that venetoclax shows a manageable safety profile and induced substantial responses in patients with relapsed chronic lymphoblastic leukemia including those with poor prognostic features, and
-Huang teaches that apoptosis evasion represents a hallmark of human cancers, particularly of leukemia, therapeutic induction of necroptosis opens new directions for treatment strategies in apoptosis-resistant leukemia.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive a method of treating hematological cancer via a RIPK1 inhibitor, an IKK inhibitor, and a BCL-2 inhibitor.
Regarding claim 2, ‘447 teaches administering necrostatin-1 stable and ML120B (claims 1 and 13). Huang teaches administering venetoclax in patients with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1). Accordingly, the combination of ‘447 and Huang teaches administering necrostatin-1 stable, ML120B, and venetoclax to treat a hematological cancer.
Regarding claim 3, ‘447 teaches administering ML120B, an IKK inhibitor (claims 1 and 13).
Regarding claim 4, ‘447 teaches administering necrostatin-1 stable and ML120B (claims 1 and 13), which are small molecules. Huang teaches administering venetoclax (a small molecule) in patients with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1).
Regarding claim 7, ‘447 teaches administering necrostatin-1 stable and ML120B (claims 1 and 13). Huang teaches administering venetoclax in patients with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1). Accordingly, the combination of ‘447 and Huang teaches administering the combination of necrostatin-1 stable, ML120B, and venetoclax to treat a hematological cancer.
Regarding claim 8, ‘447 teaches administering necrostatin-1 stable (claims 1 and 13), which is a RIPK1 inhibitor.
Regarding claim 9, ‘447 teaches administering ML120B (claims 1 and 13), which is an IKK inhibitor.
Regarding claim 10, Huang teaches administering venetoclax (a BCL-2 inhibitor) in patients with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1).
Regarding claim 12, Huang teaches administering venetoclax in patients with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1), which is a hematological cancer.
Regarding claim 13, Huang teaches administering venetoclax in patients with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1). Huang also teaches treating acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, myelodysplastic syndrome, chronic myelomonocytic leukemia, and lymphoma (page 8, column 1, paragraph 1; page 9, column 1, paragraph 2).
Regarding claim 14, Huang teaches administering venetoclax in patients (a human) with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1).
7. Claims 1, 10, and 12-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10-11 of co-pending Application No. 19/157,194 in view of Huang (J. Experiment. Clinic. Cancer Res.¸2018, 37(310), 1-15).
This is a provisional nonstatutory double patenting rejection.
U.S. Application No. 19/157,194 claims a compound for use in the treatment of a condition in a subject via administering a RIPK1 inhibitor and an IKK inhibitor (claims 1 and 10). ‘194 specifically claims the RIPK1 inhibitor is necrostatin-1 stable (claim 11).
Regarding claim 1, 194 fails to teach treating cancer and administering a BCL-2 inhibitor.
Huang teaches methods to overcome resistance to regulated cell death in human cancers, particularly that of hematological cancers (abstract). Huang teaches that leukemia represents a class of hematologic malignancies that is characterized by dysregulation of cell death pathways and treatment-related resistance (abstract; page 1, column 1, paragraph 1). Huang teaches that the majority of chemotherapeutic and targeted drugs that kill leukemia cells operated via triggering apoptosis and thus there is a need for novel therapeutic strategies to reactivate nonapoptotic cell death programs in refractory leukemia (abstract). Huang teaches that necroptosis is a regulated form of necrosis modulated by intracellular signaling pathways and is a potential solution to overcoming apoptosis resistance in leukemia (abstract; page 1, column 2, paragraphs 1-2). Huang teaches that RIPK1 is a critical regulator of necroptosis (page 2, column 1, paragraph 1). Huang teaches that the RIPK1 is polyubiquitinylated, which then contributes to the recruitment of a number of proteins, such as IKK, and subsequently facilitates the NF-κB cell survival pathway (page 3, column 2, paragraph 2; page 4, column 1, paragraph 1). Huang teaches that this change drives the expression of downstream proteins directly involved in apoptosis inhibition, such as BCL-2 (page 4, column 1, paragraph 1). Huang teaches that RIPK1 phosphorylation by IKK prevents RIPK1 kinase-dependent formation of the death complex (page 4, column 2, paragraph 1). Huang teaches that the induction of necroptosis may overcome drug resistance in several major types of leukemia, such as obatoclax, which is a BCL-2 inhibitor (Table 1, page 8; page 7, column 1, paragraph 2). Huang teaches that antiapoptotic BCL-2 protein family members are often associated with chemotherapy resistance (page 9, column 1, paragraph 4). Huang teaches that venetoclax is a small molecule that is orally bioavailable that specifically targets BCL-2 and recently approved by the FDA (page 9, column 2, paragraph 2). Huang teaches that venetoclax shows a manageable safety profile and induced substantial responses in patients with relapsed chronic lymphoblastic leukemia (CLL) including those with poor prognostic features (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1). Huang teaches that apoptosis evasion represents a hallmark of human cancers, particularly of leukemia, therapeutic induction of necroptosis opens new directions for treatment strategies in apoptosis-resistant leukemia (page 10, column 1, paragraph 5; page 10, column 2, paragraph 1).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify the composition of ‘194 to 1) treat a hematological cancer because RIPK1 is a critical regulator of necroptosis and RIPK1 phosphorylation by IKK prevents RIPK1 kinase-dependent formation of the death complex as taught by Huang; and 2) incorporate a BCL-2 inhibitor to circumvent apoptotic/necroptotic resistance mechanisms in hematological cancer as taught by Huang. One or ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘194 claims a compound for use in the treatment of a condition in a subject via administering a RIPK1 inhibitor and an IKK inhibitor,
-‘194 specifically claims the RIPK1 inhibitor is necrostatin-1 stable,
-Huang - teaches methods to overcome resistance to regulated cell death in human cancers, particularly that of hematological cancers,
-Huang teaches that leukemia represents a class of hematologic malignancies that is characterized by dysregulation of cell death pathways and treatment-related resistance,
-Huang teaches that the majority of chemotherapeutic and targeted drugs that kill leukemia cells operated via triggering apoptosis and thus there is a need for novel therapeutic strategies to reactivate nonapoptotic cell death programs in refractory leukemia,
-Huang teaches that necroptosis is a regulated form of necrosis modulated by intracellular signaling pathways and is a potential solution to overcoming apoptosis resistance in leukemia,
-Huang teaches that RIPK1 is a critical regulator of necroptosis,
-Huang teaches that the RIPK1 is polyubiquitinylated, which then contributes to the recruitment of a number of proteins, such as IKK, and subsequently facilitates the NF-κB cell survival pathway,
-Huang teaches that this change drives the expression of downstream proteins directly involved in apoptosis inhibition, such as BCL-2,
-Huang teaches that RIPK1 phosphorylation by IKK prevents RIPK1 kinase-dependent formation of the death complex,
-Huang teaches that the induction of necroptosis may overcome drug resistance in several major types of leukemia, such as obatoclax, which is a BCL-2 inhibitor,
-Huang teaches that antiapoptotic BCL-2 protein family members are often associated with chemotherapy resistance,
-Huang teaches that venetoclax is a small molecule that is orally bioavailable that specifically targets BCL-2 and recently approved by the FDA,
-Huang teaches that venetoclax shows a manageable safety profile and induced substantial responses in patients with relapsed chronic lymphoblastic leukemia including those with poor prognostic features, and
-Huang teaches that apoptosis evasion represents a hallmark of human cancers, particularly of leukemia, therapeutic induction of necroptosis opens new directions for treatment strategies in apoptosis-resistant leukemia.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive a method of treating hematological cancer via a RIPK1 inhibitor, an IKK inhibitor, and a BCL-2 inhibitor.
Regarding claim 10, Huang teaches administering venetoclax (a BCL-2 inhibitor) in patients with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1).
Regarding claim 12, Huang teaches administering venetoclax in patients with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1), which is a hematological cancer.
Regarding claim 13, Huang teaches administering venetoclax in patients with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1). Huang also teaches treating acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, myelodysplastic syndrome, chronic myelomonocytic leukemia, and lymphoma (page 8, column 1, paragraph 1; page 9, column 1, paragraph 2).
Regarding claim 14, Huang teaches administering venetoclax in patients (a human) with relapsed chronic lymphoblastic leukemia (page 9, column 2, paragraph 2; page 10, column 1, paragraph 1).
Conclusion
No claim is allowed.
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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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