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 .
Priority
The instant application is a national stage entry of PCT application PCT/CN2021/120300, filed 03/24/2023 under 35 USC 371. Acknowledgment is made of applicant's claim for foreign priority based on an application CN202011015709.0 filed in People’s Republic of China on 09/24/2020.
Claim Objections
Claims 8, 10 and 23 are objected to because of the following informalities: claims 8, 10 and 23 recite “LND-212854”, which is an inhibitor of the BMP receptor ALK (Specification, p11, parag 5). However, the name of the chemical should be “LDN-212854” (see Specification Table 3, p20).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 26 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.
From M.P.E.P. § 2163, the analysis of whether the specification complies with the written description requirement calls for the examiner to compare the scope of the claim with the scope of the description to determine whether applicant has demonstrated possession of the claimed invention from the standpoint of one of skill in the art at the time the application was filed. For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. For claims drawn to a genus, possession may be shown (for example) through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus, and is an inverse function of the skill and knowledge in the art. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to
reflect the variation within the genus. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly. If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, para. 1.
Instant claim is directed to a method for treating a hematological malignant tumor, a hematological non-malignant tumor, a solid tumor, an immune system disease, a genetic or metabolic disease in a subject, comprising administering to the subject hematopoietic stem cells, wherein the hematopoietic stem cells are cultured in a cell culture medium comprising one or more compound(s) selected from the group consisting of a tubulin polymerization inhibitor, LDN-212854, AZD0364, SCH772984, pimasertib, trametinib, JWR-1-endo, TTNPB, JNK-inhibitor IX and CHIR99021. The claim covers a genus of solid tumors (in any parts of the body), a genus of immune system diseases, genetic diseases or metabolic diseases (with any structure or function changes in immune system or metabolic system having different symptoms, etiologies, or mechanisms (known or unknown), and/or any gene mutation caused diseases in any system of the body), as well as a genus of treating (e.g., managing symptoms, controlling the disease, or preventing complications of an exist immune system disease, genetic disease or metabolic disease). The issue at hand is whether or not Applicant has possession of the full scope of the genus of solid tumors, immune system diseases, genetic diseases or metabolic diseases and the treating of said solid tumors, immune system diseases, genetic diseases or metabolic diseases at the time the application was filed.
In the instant case, Applicant has failed to provide disclosure of species which are representative of the full scope of the genus of the claimed solid tumors, immune system diseases, genetic diseases or metabolic diseases and the treating of said solid tumors, immune system diseases, genetic diseases or metabolic diseases. The specification only discloses human CD34+ HSPCs treated with Colchicine, Vinblastine sulfate or Lexibulin for a short time and then transplant into NPG (NOD-scid Il2rg-/-) immunodeficient mice, and the transplantation efficiency is increased (see Example 5). The specification does not disclose any embodiments regarding to the treatment of any of solid tumors, immune system diseases, genetic diseases or metabolic diseases which would be encompassed within the pending claim. The specification does not identify any specie of solid tumors, immune system diseases, genetic or metabolic diseases being treated, any species of treating, or any predictably result in effect (e.g., structure or functionality change, or reduction or absence of the symptoms). As such, the instant specification does not provide a sufficient representative sampling of species of solid tumors, immune system diseases, genetic or metabolic diseases and the treating of said solid tumors, immune system diseases, genetic or metabolic diseases encompassed in instant claim.
Furthermore, Applicant has failed to provide disclosure of relevant, identifying characteristics, such as the functional characteristics (be able to treat solid tumors, immune system diseases, genetic or metabolic diseases) coupled with known or disclosed structure of the compounds including a tubulin polymerization inhibitor, LDN-212854, AZD0364, SCH772984, pimasertib, trametinib, IWR-1-endo, TTNPB, JNK-inhibitor IX and CHIR99021 (e.g., the common structure of these compounds for the claimed function). The specification does not disclose any information regarding the structures of the compounds, as well as any treating effects of the claimed compounds. Applicant has failed to establish a known structure- function relationship wherein the genus of structures of the compounds including a tubulin polymerization inhibitor, LDN-212854, AZD0364, SCH772984, pimasertib, trametinib, IWR-1-endo, TTNPB, JNK-inhibitor IX and CHIR99021 is capable of providing for the function as claimed with any predictability. Thus, one of ordinary skill in the art, in looking to the instant specification, would not be able to determine that Applicant was in possession of the invention, as claimed, at the time the invention was made.
Claim Rejections - 35 USC § 112(a)
Scope of enablement
Claim 26 is 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 a hematological malignant tumor, or a hematological non-malignant tumor, does not reasonably provide enablement for treating ANY solid tumors, immune system diseases, genetic diseases or metabolic diseases in a subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in Jn re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Nature of the Invention and Breadth of the claims:
The disclosure of the instant claim is directed to a method for treating a hematological malignant tumor, a hematological non-malignant tumor, a solid tumor, an immune system disease, a genetic or metabolic disease in a subject, comprising administering to the subject hematopoietic stem cells, wherein the hematopoietic stem cells are cultured in a cell culture medium comprising one or more compound(s) selected from the group consisting of a tubulin polymerization inhibitor, LDN-212854, AZD0364, SCH772984, pimasertib, trametinib, JWR-1-endo, TTNPB, JNK-inhibitor IX and CHIR99021. The claim broadly embraces a genus of solid tumors, immune system diseases, genetic diseases or metabolic diseases, thus scope of the claims cover any solid tumors (including benign and malignant, i.e., skin cancer, lung cancer, liver cancer), any immune system diseases (i.e., type 1 diabetes, asthma), genetic diseases (i.e., Down syndrome, Fragile X syndrome) or metabolic diseases (i.e., diabetes, thyroid disorders), as well as a genus of treating said diseases. Any body structure or function changes caused by genes and/or immune system and/or metabolic system are covered by the claims. The claims do not limit the scope of the changes as having any common symptom, etiology, or mechanism (known or unknown). Moreover, the method also comprises a genus of treating (e.g., managing symptoms, controlling the disease, or preventing complications of an exist solid tumor, immune system disease, genetic disease or metabolic disease). The breadth of the claims is thus extremely broad.
Guidance of the Specification and The Existence of Working Examples:
The specification discloses the claimed compounds for culturing the hematopoietic stem cells. Specifically, the specification discloses adding the compounds to the cell culture medium (Example 2), culturing the hematopoietic stem cells and detecting the CD184 protein expression (Example 3) and cell viability (Example 4), as well as transplanting the compound-treated hematopoietic stem cells into NPG (NOD-scid Il2rg-/-) immunodeficient mice (Example 5) and resulting in the increased transplantation efficiency. However, none of working examples 2-5 show the treating of any solid tumors, immune system diseases, genetic diseases or metabolic diseases, or the treating result/effect of said compounds to the solid tumors, immune system diseases, genetic diseases or metabolic diseases. These examples, while only showing the effect of compounds to the CD184 expression and cell viability, do not support the treating of solid tumors, immune system diseases, genetic diseases or metabolic diseases by said compounds.
State of the Art and Predictability of the Art and the Amount of Experimentation Necessary:
The state of the prior art with respect to compounds including a tubulin polymerization inhibitor, LDN-212854, AZD0364, SCH772984, pimasertib, trametinib, JWR-1-endo, TTNPB, JNK-inhibitor IX and CHIR99021 as a supplement in the culture medium of hematopoietic stem cells for treatment of solid tumors, immune system diseases, genetic diseases or metabolic diseases are disclosed by several references. Xiao et al. (Cell Discovery ( 2019) 5:2) teach culturing human cord blood (CB) CD34+ cells with JNK-IN-8, an inhibitor of the JNK signaling pathway, can enhance the self-renewal of HSCs with a 3.88-fold increase in cell number (Abstract). Xiao et al. disclose the hematopoietic stem cells are used for stem-cell therapy for leukemia and other high-risk blood diseases (p1, left column). Xiao et al. do not teach the JNK pathway inhibitor treated hematopoietic stem cells are used for treating ANY solid tumors, immune system diseases, genetic diseases or metabolic diseases. Rossi et al. (US 2018/0187156 A1) teach a method of producing an expanded population of hematopoietic stem cells ex vivo by adding CHIR99021 (parag 0055) or LDN-212854 (parag 0485), Rossi et al. teach the treated hematopoietic stem cells can be used for some immune deficiency or autoimmune diseases (see parag 0534) or some genetic blood disorders (see parag 0535). Rossi et al. do not teach the CHIR99021 or LDN-212854 treated hematopoietic stem cells can be used to treat ANY solid tumors, immune system diseases, genetic diseases or metabolic diseases. Hintzsche et al. (Sci Rep. 2018 Jul 13;8(1):10901) teach adding vinblastine sulfate in the culture medium of hematopoietic stem cells to test the sensitivity of hematopoietic stem cells to the chemotherapeutic agent vinblastine sulfate. Low does of vinblastine sulfate do not change the cell viability and the frequencies of micronucleated cells (p2, results). Hintzsche et al. do not teach the vinblastine sulfate treated hematopoietic stem cells for the treatment of ANY solid tumors, immune system diseases, genetic diseases or metabolic diseases. There was no evidence at the time the invention was made that these claimed compounds would have any effect on any of the solid tumors (i.e., skin cancer, lung cancer, liver cancer), the immune system diseases (i.e., type 1 diabetes, asthma), genetic diseases (i.e., Down syndrome, Fragile X syndrome) or metabolic diseases (i.e., diabetes, thyroid disorders). There was no known link between, at least these types of solid tumors, immune system diseases, genetic diseases or metabolic diseases, and the claimed compounds. None of the known effects of the compounds would have been expected to have an effect on the underlying causes or symptoms of any of the solid tumors, immune system diseases, genetic diseases or metabolic diseases.
In conclusion, in view of breadth of the claims and absence of a strong showing by Applicant, in the way of specific guidance and direction, and/or working examples demonstrating the same, such invention as claimed by Applicant is not enabled commensurate with full scope. An artisan of skill would have required undue experimentation to practice the invention with a reasonable expectation of success.
Claim Interpretation
Instant claim 8 recites a preamble “for improving CD 184 protein expression on the surface of hematopoietic stem cells in a subject”, instant claim 10 recites a preamble “for improving transplantation efficiency or homing ability of hematopoietic stem cells in a subject”, instant claim 26 recites a preamble “for treating a hematological malignant tumor, a hematological non-malignant tumor, a solid tumor, an immune system disease, a genetic or metabolic disease in a subject”, each preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation to be given patentable weight and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020). See MPEP 2111.02.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 8, 10, 23 and 26 are rejected under 35 U.S.C. 102(a)(1)and 102(a)(2) as being anticipated by Rossi et al. (US 2018/0187156 A1, published in 2018).
Rossi et al. teach producing, expanding, enriching, and/or maintaining hematopoietic stem cells ex vivo by treating the cells with an agent(s) that exhibits two or more activities selected from modulation of histone methylation; inhibition of TGFβ signaling; inhibition of p38 signaling; activation of canonical Wnt signaling; and modulation of histone acetylation (Abstract).
Regarding claims 8, 10 and 23, Rossi et al. teach a method of producing an expanded population of hematopoietic stem cells ex vivo by contacting a population of hematopoietic stem cells with (a) a first agent selected from the group consisting of an LSD1 inhibitor IV RN-1, LSD1 inhibitor II S2101, LSD1 inhibitor LSD1-C76, LSD1 inhibitor III CBB1007, LSD1 inhibitor I, and Tranylcypromine, and (b) a second agent selected from the group consisting of ALK5 inhibitor II (E-616452), LY364947, A83-01, Trichostatin A, SB203580, CHIR99021, DMHl, sodium acetate, and istodax (romidepsin) (parag 0055). Rossi et al. also teach "contacting" a population of cells with one or more agents can be achieved in a variety of ways, including the one or more agents may be added to the cell culture medium sequentially (see parag 0391). Herein the use of CHIR99021 reads on a method comprising supplementing CHIR99021 to a medium for culturing the hematopoietic stem cells (claims 8 and 10) and a cell culture medium comprising CHIR99021 (claim 23).
Regarding claim 26, following the discussion above, Rossi et al. teach producing an expanded population of hematopoietic stem cells ex vivo by culturing hematopoietic stem cells with compounds such as CHIR9902 (see parag 0055, 0391). Rossi et al. also teach culturing step may be performed in order to expand, enrich, and/or maintain the population of hematopoietic stem cells prior to administration of the resulting cells to a patient (parag 0394). This teaching reads on administering to the subject hematopoietic stem cells which are cultured in the culture medium comprising a compound such as CHIR9902.
Claims 8-10, 23 and 28-37 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hintzsche et al. (Sci Rep. 2018 Jul 13;8(1):10901).
Hintzsche et al. compared the sensitivity of hematopoietic stem cells (HSC) with the genotoxicity testing cell line TK6 for chromosomal mutations. HSC were less sensitive than TK6 cells for the genotoxic effects of the model genotoxins and chemotherapeutic agents doxorubicin, vinblastine, methyl methanesulfonate (MMS) and equally sensitive for mitomycin C (MMC) (Abstract).
Regarding claims 8, 10 and 23, Hintzsche et al. teach hematopoietic stem cells (HSCs) were incubated at the same cell density of 2.5 × 104 cells in 250 μl culture medium supplemented with 2 mg/ml HSA with addition of 10 μl test substance solution (doxorubicin, vinblastine, mitomycin C) in a 96-well culture plate (see p9, parag 5). This teaching reads on supplementing vinblastine (vinblastine sulfate, see p9, parag 1) to a medium for culturing the hematopoietic stem cells. Vinblastine sulfate is a tubulin polymerization inhibitor.
Regarding claim 9, Hintzsche et al. teach adding 100 nM of vinblastine to the culture medium of the hematopoietic stem cells (p2, parag 5). 100 nM of vinblastine is in the range of 1 nM-100 µM.
Regarding claims 28-30, as discussed above, Hintzsche et al. teach hematopoietic stem cells (HSCs) were incubated at the same cell density of 2.5 × 104 cells in 250 μl culture medium supplemented with 2 mg/ml HSA with addition of 10 μl test substance solution (doxorubicin, vinblastine, mitomycin C) in a 96-well culture plate (see p9, parag 5). This teaching reads on supplementing vinblastine (vinblastine sulfate, see p9, parag 1) to a medium for culturing the hematopoietic stem cells.
Regarding claims 31-33, following the discussion above, Hintzsche et al. teach hematopoietic stem cells (HSCs) were incubated at the same cell density of 2.5 × 104 cells in 250 μl culture medium supplemented with 2 mg/ml HSA with addition of 10 μl test substance solution (doxorubicin, vinblastine, mitomycin C) in a 96-well culture plate (see p9, parag 5). This teaching reads on supplementing vinblastine (vinblastine sulfate, see p9, parag 1) to a medium for culturing the hematopoietic stem cells.
Regarding claim 34, following the discussion above, Hintzsche et al. teach adding 100 nM of vinblastine to the culture medium of the hematopoietic stem cells (p2, parag 5). 100 nM of vinblastine is in the range of 1 nM-100 µM.
Regarding claims 35-37, as discussed above, Hintzsche et al. teach hematopoietic stem cells (HSCs) were incubated at the same cell density of 2.5 × 104 cells in 250 μl culture medium supplemented with 2 mg/ml HSA with addition of 10 μl test substance solution (doxorubicin, vinblastine, mitomycin C) in a 96-well culture plate (see p9, parag 5). This teaching reads on supplementing vinblastine (vinblastine sulfate, see p9, parag 1) to a medium for culturing the hematopoietic stem cells.
Conclusion
No claims are allowed.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699