DETAILED ACTION
Status of Application
Claims 1-21 are pending
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election without traverse of Group I, claims 1-7, 9, 12, 14, 17-18, 20-21, drawn to a method for inducing cell death or reducing cell survival of a rhabdomyosarcoma or neoplastic cell, and the election of small molecules (e.g., SU6668 and MSC1094308) as a single distinct species of inhibitory agents as submitted in communication filed on 11/07/2025 is acknowledged.
In view of the election of a single distinct species of inhibitory agents wherein only of small molecules (e.g., SU6668 and MSC1094308) are required, and the fact that claims 8, 10-11, 13, 15-16, 19 are directed to distinct species of inhibitory agents that have non-elected species, these claims are directed to non-elected inventions.
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 § 818.03(a)).
Claims 1-7, 9, 12, 14, 17-18, 20-21 are at issue and are being examined only to the extent they encompass the elected invention.
Priority
Acknowledgment is made of applicant’s claim for domestic priority under 35 U.S.C. 119 (e) to provisional Application No. 63/035,454 filed on 06/05/2020.
This is the US national application which entered the national stage from Application No. PCT/US2021/035976 filed on 06/04/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/02/2022, 04/11/2024, 04/11/2024, and 10/10/2025 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings submitted on 12/02/2022 have been reviewed and are accepted by the examiner for examination purposes.
Claim Objections
Claims 1, 3, 4,12, and 17 are objected due to the recitation of “VPS4A” or “VPS4B”. Abbreviations unless otherwise obvious and/or commonly used in the art, should not be recited in the claims without at least once reciting the entire phrase for which the abbreviation is used. Appropriate correction is required.
Claims 2, 3, 12, and 17 are objected due to the recitation of “ULK3”, “CHMPIA”, “CHMPIB”, “VTA1”, and “IST1”. Abbreviations unless otherwise obvious and/or commonly used in the art, should not be recited in the claims without at least once reciting the entire phrase for which the abbreviation is used. Appropriate correction is required.
Claims 7 and 18 are objected due to the recitation of “SMAD4” and “CDH1”. Abbreviations unless otherwise obvious and/or commonly used in the art, should not be recited in the claims without at least once reciting the entire phrase for which the abbreviation is used. Appropriate correction is required.
Claim 17 is objected due to the recitation of “CHMP4B”, “ITCH”, and “ISG15”. Abbreviations unless otherwise obvious and/or commonly used in the art, should not be recited in the claims without at least once reciting the entire phrase for which the abbreviation is used. Additionally, claim 17 is objected to due to failing to indicate the recipient of the administration of the agent. It should recite “administering to a subject having cancer an agent that inhibits…”. Appropriate correction is required.
Claim 3 is objected to due to the recitation of “thereby inducing or promoting cell death or reducing cell survival of the neoplastic cell” being repeated twice. To enhance clarity and to be consistent with commonly used claim language, the repetition of “thereby inducing or promoting cell death or reducing cell survival of the neoplastic cell” should be removed. Appropriate correction is required.
Claim 5 is objected to due to the recitation of “neoplastic cell is a brain, bladder, bile, blood, breast, duct, colon, colorectal, esophageal, gastric, germ cell, liver, ovarian, pancreatic, uterine, or lung cancer cell”. To enhance clarity and to be consistent with commonly used claim language, the comma between “breast” and “duct” should be removed. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 6, 7, 9, 17, 18, 20, 21 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.
Claim 1 (claims 2, 7, and 9 dependent thereon) is indefinite in the recitation of “A method for inducing cell death or reducing cell survival of a rhabdomyosarcoma cell characterized by a loss of VPS4B expression, the method comprising contacting the cell with an agent that inhibits the expression or activity of VPS4A, thereby inducing cell death or reducing cell survival of the rhabdomyosarcoma cell; or comprising contacting the cell with an agent that inhibits the expression or activity of VPS4B, thereby inducing cell death or reducing cell survival of the rhabdomyosarcoma cell.” for the following reasons. The purpose of VPS4B inhibition in a rhabdomyosarcoma cell characterized by a loss of VPS4B expression is unclear in the absence of a statement indicating what the purpose of the VPS4B inhibition is for. For examination purposes, “a method for inducing cell death or reducing cell survival of a rhabdomyosarcoma cell characterized by a loss of VPS4B expression, the method comprising contacting the cell with an agent that inhibits the expression or activity of VPS4A, thereby inducing cell death or reducing cell survival of the rhabdomyosarcoma cell” will only be examined. Correction is required.
Claim 6 recites the limitation " wherein the neoplastic cell is a pancreatic cancer cell, renal cell carcinoma, pancreatic ductal adrenocarcinoma, sarcoma cell, osteosarcoma cell or a rhabdomyosarcoma cell". There is insufficient antecedent basis for the renal cell. Correction is required.
Claim 7 recites the limitation "wherein the rhabdomyosarcoma or neoplastic cell is further characterized by a loss of SMAD4 or CDH1" in the first line of the claim. There is insufficient antecedent basis for the neoplastic cell. Correction is required.
Claim 17 (claims 18, and 20-21 dependent thereon) is indefinite in the recitation of “wherein the subject is selected if the cancer is determined to have VPS4A dependency, wherein dependency is determined using a multivariate model, wherein levels of a VPS4B maker ….and ISG15 marker are used as inputs to the model” due to it being unclear what levels of CHMP4B, ITCH, or ISG15 markers are required for VPS4A dependency. It is also unclear as to what is a VPS4B marker, CHM4B marker, ITCH marker or a ISG15 marker. It is unknown if the term “marker” is equivalent to VPS4B, CHM4B, ITCH, and ISG15 (e.g., VPS4B marker = VPS4B), or if the term “marker” refers to an unknown compound whose presence is indicative of the presence of VPS4B, CHM4B, ITCH, or ISG15 (e.g., VPS4B marker = unknown compound that correlates with the presence of VPS4B). In addition, while the claim states that a model will determine dependency, this does not provide any insight as to what VPS4A dependency is. Moreover, while the claim requires a generic multivariate model that requires several inputs, it is unclear if a patient that has been found to have a cancer that is VPS4B dependent by another method would be excluded from the scope of the claim. For examination purposes, no patentable weight will be given to the term “wherein the subject is selected….as inputs in the model”. Correction is required.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
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 1-7, 9, 12, 14, 17-18, 20-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow.
Claims 1-7, 9 are directed in part to an in vitro or in vivo method for inducing cell death or reducing survival of rhabdomyosarcoma cells or any neoplastic cell by contacting said cells with a genus of agents having any structure, wherein said agents are inhibitors of the expression or activity of VPS4B, VPS4A, ULK3, CHMPIA, CHMPIB, VTA1, and/or IST1, including SU6668 and/or MSC 1094308. See claim rejections under 35 USC § 112(b) for claim interpretation.
Claims 12-14, 17-21 are directed in part to a method of treating a patient suffering from a neoplasia or cancer by administering a genus of agents having any structure, wherein said agents inhibit the expression and/or activity of VPS4B, VPS4A, ULK3, CHMPIA, CHMPIB, VTA1, and/or IST1, including SU6668 and/or MSC 109430. See claim rejections under 35 USC § 112(b) for claim interpretation.
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for the Federal Circuit has held that “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials”. As indicated in MPEP § 2163, the written description requirement for a claimed genus may be satisfied 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 that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
There is no structural limitation with respect to the members of the genus of agents required by the claimed process. While the specification in the instant application discloses the agents SU6668 and MSC 1094308, it provides no clue as to the structural elements required in any agent that can inhibit ULK3, CHMPIA, CHMPIB, VTA1, IST1, VPS4A, or VPS4B to promote cell death, nor does it teach which structural elements of any cancer or neoplastic cell that agent can be used on. Please note that the agent encompasses any chemical compound, protein or nucleic acid that can inhibit the expression of the genes encoding the recited proteins. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which compounds have ULK3, CHMPIA, CHMPIB, VTA1, IST1, VPS4A, or VPS4B inhibition activity, or a structure/function correlation that would allow one of skill in the art to determine which types of cancer and neoplastic cells can be targets of a particular agent that inhibits the activity of ULK3, CHMPIA, CHMPIB, VTA1, IST1, VPS4A, or VPS4B.
The claims encompass a large genus of agents which are structurally unrelated. A sufficient written description of a genus of agents may be achieved by a recitation of a representative number of agents defined by their mechanism of action or a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. However, in the instant case, there is no recited structural feature which is representative of all the members of the genus of agents recited in the claims, and there is no information as to which are the structural elements of the agents that are essential for the recited inhibition activity, or a correlation between structure and function which would provide those unknown structural features. Furthermore, while one could argue that the species disclosed is representative of the structure of all the members of the genus of agents required, it is noted that the art teaches examples of how even highly structurally similar agents can have different inhibition activities. For example, Bennet et al. (Antiviral Research, Volume 136, December 2016, pages 51-59) teach that the analog of a cancer therapeutic does not effectively work as a cancer therapeutic (Page 51, Abstract, line 3-4). Therefore, since minor structural differences may result in changes affecting mechanism of action, and no additional information correlating structure with the desired functional characteristics has been provided, one cannot reasonably conclude that the species disclosed, including SU6668 and MSC 1094308, are representative of the structure of all the agents that can inhibit ULK3, CHMPIA, CHMPIB, VTA1, IST1, VPS4A, or VPS4B that is required by the claimed process.
The claims encompass in vivo methods, that include treating a subject with agents that inhibit ULK3, CHMPIA, CHMPIB, VTA1, IST1, VPS4A, or VPS4B. While the specification discloses an in vitro method to induce cell death in rhabdomyosarcoma cells and pancreatic cancer cells with a doxycycline-inducible RNAi system that uses shRNA, the specification is silent with regard to an in vivo method to induce cell death or a method for treatment a subject having neoplasia with any agent that inhibits the expression or activity of ULK3, CHMPIA, CHMPIB, VTA1, IST1, VPS4A, or VPS4B including SU6668 and/or MSC 109308. Furthermore, while one could argue that the in vitro method disclosed can be extrapolated to an in vivo environment, it is noted that the art teaches examples of how in vitro results are not necessarily replicated in vivo. For example, Dinic et al. (Life, Volume 14, December 2024, pages 1-33) teach that there are discrepancies between in vitro drug responses and clinical outcomes (page 14, last paragraph).
Therefore, since the discrepancies between in vitro drug responses and clinical outcomes may result in differences in neoplasia cell survival in a subject, and no additional information correlating in vitro studies with the desired goal of improving any cancer subject’s outcomes has been provided, one cannot reasonably conclude that the in vitro studies disclosed are representative of the abilities to treat cancer in vivo using any agent that is required by the claimed process.
Due to the fact that the specification only discloses in vitro studies using an RNAi system that inhibits VPS4A or VPS4B, and discloses two small compound agents that inhibit ULK3, the lack of description of any additional agents that inhibits the expression and/or activity of the recited proteins, and the lack of description of in vivo methods to treat any type of neoplasia or cancer with an agent that inhibits the expression and/or activity of the recited proteins, one of ordinary skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
Claims 1-7, 9, 12, 14, 17-18, 20-21 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 an in vitro method to induce cell death of a rhabdomyosarcoma cell with a doxycycline-inducible RNAi system that uses the shRNA of SEQ ID NO: 42, 43, 44, 45 or 46, and an inhibitor of ULK3 selected from SU6668 and MSC 109308, does not reasonably provide enablement for (a) an in vitro or in vivo method for inducing cell death or reducing survival of rhabdomyosarcoma cells or any neoplastic cell by contacting said cells with an agent having any structure, wherein said agent is an inhibitor of the expression or activity of ULK3, CHMPIA, CHMPIB, VTA1, IST1, VPS4A, or VPS4B, including SU6668 and MSC 1094308, or (b) a method for treating a patient suffering from a neoplasia or cancer by administering an agent having any structure, wherein said agent inhibits the expression and/or activity of ULK3, CHMPIA, CHMPIB, VTA1, IST1, VPS4A, or VPS4B, including SU6668 and/or MSC 109308. 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/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2nd 1400 (Fed. Cir. 1988)) as follows: 1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3) the presence and absence of working examples, 4) the nature of the invention, 5) the state of prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) the breadth of the claims. The factors which have led the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, are addressed in detail below.
The breadth of the claims. Claims 1-7, 9, 12, 14, 17-18, 20-21 broadly encompass (a) an in vitro or in vivo method for inducing cell death or reducing survival of rhabdomyosarcoma cells or any neoplastic cell by contacting said cells with an agent having any structure, wherein said agent is an inhibitor of the expression or activity of ULK3, CHMPIA, CHMPIB, VTA1, IST1, VPS4A, or VPS4B, including SU6668 and/or MSC 109308, or (b) a method for treating a patient suffering from a neoplasia or cancer by administering an agent having any structure, wherein said agent inhibits the expression and/or activity of ULK3, CHMPIA, CHMPIB, VTA1, IST1, VPS4A, or VPS4B, including SU6668 and/or MSC 109308. The enablement provided is not commensurate in scope with the claims due to the lack of knowledge regarding the structure/identity of the agents that can act as inhibitors of the expression or activity ULK3, CHMPIA, CHMPIB, VTA1, IST1, VPS4A, or VPS4B required by the claims, the types of neoplastic cells that can be the targets of these inhibitors so that cell death could be observed, and the types of cancer or neoplasia that each of these inhibitors can treat. In the instant case, the specification enables an in vitro method to induce cell death of a rhabdomyosarcoma cell with a doxycycline-inducible RNAi system that uses the shRNA of SEQ ID NO: 42, 43, 44, 45 or 46, and an inhibitor of ULK3 selected from SU6668 and/or MSC 109308
The amount of direction or guidance presented and the existence of working examples. The specification discloses an in vitro method to induce cell death of a rhabdomyosarcoma cell with a doxycycline-inducible RNAi system that uses the shRNA of SEQ ID NO: 42, 43, 44, 45 or 46, and an inhibitor of ULK3 selected from SU6668 and/or MSC 109308. However, the specification fails to provide any clue as to the structural elements required in any agent that can inhibit ULK3, CHMPIA, CHMPIB, VTA1, IST1, VPS4A, or VPS4B in the different types of cancers/neoplastic cells claimed. The specification does not teach those structural features that should be present in any inhibitor of ULK3, CHMPIA, CHMPIB, VTA1, IST1, VPS4A, or VPS4B that could be used to induce cell death in any type of cancer or neoplastic cell. No correlation between structure and function has been presented.
The state of prior art, the relative skill of those in the art, and the predictability or unpredictability of the art. The structure of an agent determines its structural and functional properties. While the art discloses a limited number of ULK3, CHMPIA, CHMPIB, VTA1, IST1, VPS4A, or VPS4B inhibitors, neither the specification nor the art provide a correlation between structure and function such that one of skill in the art can envision the structure of any agent that can inhibit ULK3, CHMPIA, CHMPIB, VTA1, IST1, VPS4A, or VPS4B in different cancer/neoplastic cells or rhabdomyosarcoma cells and can be used to induce cell death in said cells. In addition, the art is silent with treating cancer, neoplasia or inducing cell death in any neoplastic cell with SU6668 and/or MSC 109308. The art clearly teaches that analogues or derivatives of a compound are not necessarily functional analogues. For example, Bennet et al. (Antiviral Research, Volume 136, December 2016, pages 51-59) teaches that the analog of a cancer therapeutic does not effectively work as a cancer therapeutic (Page 51, Abstract, line 3-4)
The art clearly teaches that it is unpredictable if one agent known for treating a type of cancer can be used to treat another type of cancer. For example, Cristofanilli et al. (Annals of Oncology, Volume 19, October 2000, pages 1713-1719) teach that an agent used to treat leukemia was ineffective in treating metastatic breast cancer (page 1716, right column, last 2 lines). In addition, it is known in the art that it is unpredictable if those results found in vitro could be replicated in vivo. For example, Dinic et al. (Life, Volume 14, December 2024, pages 1-33) teach there are discrepancies between in vitro drug responses and clinical outcomes (page 14, last paragraph).
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification. While methods of determining agents’ ability to inhibit proteins activity were known in the art at the time of the invention, it was not routine in the art to screen by a trial and error process for an essentially infinite number of agents to find an agent with the desired inhibition activity and further determine which types of cells, neoplasia and/or cancer could be targeted with those agents that have the recited inhibition activity. In the absence of (i) a rational and predictable scheme for selecting those agents most likely to have the desired functional features, (ii) a correlation between structure and the recited inhibition activity, and (iii) a correlation between the structure of an agent having the recited inhibition activity and the type of neoplastic cell, neoplasia or cancer that could be targeted by said agent, one of skill in the art would have to test an infinite number of agents, as well as different types of cells and cancers to find those agents that have the desired functionality and the cells/diseases that can be targeted with said agents.
Therefore, taking into consideration the extremely broad scope of the claim, the lack of guidance, the amount of information provided, the lack of knowledge about a correlation between structure and the desired function, the high degree of unpredictability in the prior art regarding obtaining the results observed in vitro under in vivo conditions, the high degree of unpredictability regarding structural modifications and effects in function, and the high degree of unpredictability regarding treating different types of cancers with the same agent, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention. Thus, Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the invention in a manner reasonably correlated with the scope of the claims.
Conclusion
No claim is in condition for allowance
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/SYNPHANE L SHELTON/Examiner, Art Unit 1652
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652