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 .
Applicant’s election without traverse of group I in the reply filed on 7/23/25 is acknowledged.
Claims 15, 17, and 19-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/23/25.
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.
Claims 1-3, 5, 6, 8, 10, 11, and 13 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 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.
The claims are directed to delivery of any agent that inhibits Aldh3a2 activity or expression; and any agent that induces ferroptosis.
The specification does not adequately describe the structure required for the each of these functions. Without further guidance, one would not be able to recognize which agents necessarily have the structure to result in inhibition of Aldh3a2 or induction of ferroptosis. The agents are not required to have any specific structural relationship with any specific target sequence, but rather can act in any manner via any mechanism on any target that has a secondary effect of inhibition of Aldh3a2 or induction of ferroptosis. The minimal species of the specification are not representative of the entire claimed genus.
With regards to shRNAs that inhibit the expression of Aldh3a2, the specification does not adequately describe the structure required for the shRNA to result in inhibition of expression of any Aldh3a2. The shRNAs are not required to have any specific structural relationship with any specific target sequence, but rather can be targeted (complementary to) to any target that has a secondary effect of inhibition of Aldh3a2. The minimal species of the specification that are shRNAs that are specific for Aldh3a2 and are complementary to a specific Aldh3a2 sequence are not representative of the entire claimed genus.
With regards to GPX4 inhibitors, the specification does not adequately describe the structure required for the agent to result in inhibition of any GPX4. The inhibitors are not required to have any specific structural relationship with any specific target sequence, but rather can be targeted to any target that has a secondary effect of inhibition of GPX4. The minimal species of the specification (RSL3, ML162, and DPI10) are not representative of the entire claimed genus.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"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." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The claims are rejected under the written description requirement for failing to disclose adequate species to represent the claimed genus.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
With respect to siRNAs, as single species of RNAi agents, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) teaches that duplexes of 21-23 nt RNAs are the sequence specific mediators of RNAi and that even single mismatches between the siRNA duplex and the target mRNA abolish interference (abstract and page 6888).
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species within each of the instantly recited genuses that function as claimed. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Response to Arguments
Applicant argues that the Office has failed to set forth evidence or substantive reasoning to support the broad interpretation of the claims and the finding of lack of written description support for this broad interpretation of the claims. Moreover, the only reference cited by the Office in connection with this § 112(a) rejection was Elbashir et al., which appears to be cited to establish that a "single mismatch between the siRNA duplex and the target mRNA abolish interference." Office Action at 7. However, no effort is expended to attempt to tie this statement to the disclosure of the present application, including the two shRNAs exemplified to inhibit Aldh3a2 expression, the general knowledge in the field of shRNA design as a whole and the existing well-known sequences of the Aldh3a2 gene and Aldh3a2 RNA transcripts. Applicants assert that the reduction to practice of the two Aldh3a2 shRNAs, coupled with the well-known sequences of Aldh3a2 sequences, would lead one of skill in this art to determine that the Inventors had possession of the claimed method that utilizes an agent which inhibits Aldh3a2 activity or expression, such as a shRNA that inhibits Aldh3a2 expression.
Contrary to applicant’s arguments, in absence of further description of the structure required for the function, one would not be able to envision which agents are capable of inhibiting Aldh3a2 activity or expression. The claims are not even limited to Aldh3a2 shRNAs or siRNAs, but rather any agent that is are capable of inhibiting Aldh3a2 activity or expression. The claims encompass any agent that is specific for any target that has the secondary effect of inhibiting Aldh3a2 activity or expression; as well as any drug or small molecule that may have the recited function; which is a genus of agents that has not been adequately described in the specification.
With regards to Elbashir et al., this reference is sufficient to demonstrate that even the single species of agents, siRNAs, have not been adequately described. It is well known in the siRNA art that not any siRNA that is complementary to a given target (i.e. Aldh3a2) will have the function of inhibiting the activity or expression of the target. The minimal species of the specification are not representative of the entire claimed genus. Certainly the two Aldh3a2 shRNAs of the instant specification that have a strand that is fully complementary to a specific target sequence are not representative of the entire claimed genus of agents of any structure that have the recited function. One would not be able to readily recognize which agents are necessarily included or excluded from the recited genus.
Applicant argues that in regard to the second agent which induces ferroptosis, such as by inhibiting GPX4, the Office has failed to give weight to the entirety of the teachings of the specification, as well as what was conventional knowledge in this field. For example, the specification teaches that the second agent may be Erastin, DPI2, BSO, SAS naperisone, SRS, RSL3, DPI7, DPI10, FIN56, sorafenib, artemisinin, Nrf2, LSH, TFR1 or a xCT modulator. Moreover, at the time of filing, a person of skill in this art would have understood that many ferroptosis inducers were already known and conventional in the art, such as those outlined in Table 1 of evidentiary reference Du ("Recent progress in ferroptosis: inducers and inhibitors." Cell death discovery 8.1 (2022): 501).
Contrary to applicant’s arguments, in absence of further description of the structure required for the function, one would not be able to envision which agents are capable of inducing or inhibiting GPX4. The claims encompass any agent that is specific for any target that has the function of inducing ferroptosis; as well as any drug or small molecule that may have the recited function; which is a genus of agents that has not been adequately described in the specification. For example, Zhang et al. (Cell Death and Disease (2023) 14:340) teach that certain chemotherapeutics induce ferroptosis. The species of the specification are not representative of the entire claimed genus. Contrary to applicant’s arguments, without further description of the structure required for the function, one would not be able to envision the entire genus of possible compounds that induce ferroptosis. One would not be able to readily recognize which agents are necessarily included or excluded from the recited genus.
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.
Claim(s) 1-3, 5, 6, 8, 10, 11, and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tsvetkov et al. (US 2018/0353445 A1), in view of Bradbury et al. (WO 2019/113004 A1), and Sillar et al. (Int. J. Mol. Sci. 2019, 20, 6003, 1-20).
Tsvetkov et al. teach: [0011] methods comprise contacting cancer cells that have reduced expression or activity of one or more 19S subunits with a BCL2 family inhibitor, an ALDH inhibitor (e.g., disulfiram), or a bis(thio-hydrazide amide) (e.g., elesclomol). Also described herein are methods of treating cancer that take advantage of such vulnerabilities. In some aspects, the methods comprise administering a BCL2 family inhibitor (e.g., ABT-263), an ALDH inhibitor (e.g., disulfiram), a bis(thio-hydrazide amide) (e.g., elesclomol) to a subject in need of treatment for a cancer that has reduced expression or activity of one or more 19S subunits relative to a reference level.
Tsvetkov et al. teach: [0012] In some aspects, described herein is a method of treating a subject in need of treatment for cancer comprising administering to the subject one or both of: (a) a proteasome inhibitor; and (b) a BCL2 family inhibitor (e.g., ABT-263), ALDH inhibitor (e.g., disulfiram), or bis(thio-hydrazide amide) (e.g., elesclomol), so that the subject is exposed to both the proteasome inhibitor and the BCL2 family inhibitor (e.g., ABT-263). ALDH inhibitor (e.g., disulfiram), or bis(thio-hydrazide amide) (e.g., elesclomol). In some embodiments the compound of (b) is a BCL2 family inhibitor (e.g., ABT-263). In some embodiments the compound of (b) is an ALDH inhibitor (e.g., disulfiram). In some embodiments the compound is a bis(thio-hydrazide amide) (e.g., elesclomol).
Tsvetkov et al. teach: [0950] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present invention is not intended to be limited to the Description or the details set forth therein. Articles such as “a”. “an” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” or “and/or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
Therefore, it would have been obvious to combine agents of Tsvetkov et al. as a matter of design choice.
Tsvetkov et al. teach: [0524] In some embodiments, a compound that selectively inhibits growth of cancer cells that have reduced expression or activity of one or more 19S subunits is an aldehyde dehydrogenase (ALDH) inhibitor. Aldehyde dehydrogenases catalyze the irreversible oxidation of aldehydes to their corresponding carboxylic acid, thereby protecting cells from aldehyde-induced cytotoxicity.
Tsvetkov et al. teach: [0525] In some embodiments an ALDH inhibitor inhibits the expression and/or activity of one or more members of the ALDH3 family (ALDH3A1, ALDH3A2, ALDH3B1, and ALDH3B2).
Therefore, Tsvetkov et al. teach a method of inducing cell death of cancer cels via contacting the cells with an inhibitor of ALDH3a2 (instant claims 1 and 2).
It is noted that instant claims 2 and 3 recite outcomes rather than method steps and are therefore considered to necessarily flow from the recited method steps.
Tsvetkov et al. teach that the inhibitor can be an RNAi agent, more specifically a shRNA [0123]-[0124].
Tsvetkov et al. teach: [0127] In some embodiments an RNAi agent is a vector an expression vector) suitable for causing intracellular expression of one or more transcripts that give rise to a siRNA, shRNA, or miRNA in the cell. Such a vector may he referred to as an “RNAi vector”. An RNAi vector may comprise a template that, when transcribed, yields transcripts that may form a siRNA (e.g., as two separate strands that hybridize to each other), shRNA, or miRNA precursor (e.g., pri-miRNA or pre-mRNA) (instant claim 8).
Tsvetkov et al. teach: [0042] In certain embodiments of any method or composition described herein relating to a cancer or cancer cell, the cancer or cancer cell type is a carcinoma. In certain embodiments of any method or composition described herein relating to a cancer or cancer cell, the cancer or cancer cell type is a hematologic malignancy. In certain embodiments of any method or composition described herein relating to a cancer or cancer cell, the cancer or cancer cell type is acute myeloid leukemia (instant claims 5 and 6).
Tsvetkov et al. teach: [0214] In some embodiments mammalian cells are used. In some embodiments mammalian cells are primate cells (human cells or non-human primate cells) (instant claim 13).
It would have been obvious to combine the shRNA inhibitor of ALDH3a2 with an agent that induces ferroptosis, more specifically RSL3 or ML162, because each of these agents were known to be useful for the same intended purpose of treating AML, as evidenced by Tsvetkov et al. (for shRNA inhibitor of ALDH3a2) and Bradbury et al. (for RSL3 and ML162) (instant claims 1, 10, and 11). It is noted that each of the references treat utilizing combination therapies. One would reasonably expect for each to induce cell death and inhibit the growth of cancer cells.
Bradbury et al. teach: The present disclosure describes methods of treatment (e.g., combination treatment) by ferroptotic induction, as well as compositions and dosing regimens that are part of such methods. Surprisingly, it is presently found that delaying administration of a ferroptosis-inducing agent until after starting hormone therapy results in enhanced ferroptotic induction in a subject. Thus, in certain embodiments, combination therapies are presented herein that include multiple administration steps whereby a ferroptosis-inducing agent is administered sometime after hormone therapy has begun (abstract) (instant claim 1).
Bradbury et al. teach that the cancer can be AML [0046] (instant claims 5 and 6).
Bradbury et al. teach: In certain embodiments, the agent comprises (e.g., is) an inhibitor of enzyme GPX4. In certain embodiments, the inhibitor of enzyme GPX4 comprises a member selected from the group consisting of RLS3 and ML162.[0015] (instant claims 10 and 11).
Bradbury et al. teach: [0106] Thus, in certain embodiments, ferroptotic induction is performed in combination with any one or more of immunotherapy, hormonal therapy, chemotherapy, radiotherapy (e.g., alpha-, beta-, or gamma-emitters) and/or small molecule drug administration.
With regards to the newly recited limitation that the cancer cells exhibit increased redox stress or excessive production of reactive oxygen species prior to contact, Sillar et al. teach that reactive oxygen species have been shown to be elevated in AML (abstract). Therefore, AML was known to have elevated reactive oxygen species, which is the cancer that is the subject of the instant rejection as taught by Tsvetkov et al.
Response to Arguments
Applicant argues that the Office has failed to address on the merits the limitations of claim 3, along with the limitations of claim 4, now forming part of claim 1. In particular, in place of pointing to teachings of the prior art that read on the limitations of claims 3 and 4, the Office reasons that the limitations would simply flow from the recited method steps of claim 1. Applicants respectfully disagree that these claims fail to further limit claim 1 or that the prior art even teaches the claimed method.
With regards to the limitations of claim 3, the claim is directed to intended outcomes rather than a method step. The intended outcomes are considered to flow from the recited method. Should the breadth of the recited method steps not achieve the recited outcomes, the claims are not enabled over the claimed scope.
Contrary to applicant’s assertion, the exact limitations of claim 4, which has now been cancelled, are not recited in amended claim 1. The amendment requires for the cancer cells to exhibit increased redox stress or excessive production of reactive oxygen species prior to contact, whereas previously recited claim 4 were directed to the uncontacted cancer cells, which implied that some cancer cells are contacted and some are not. The newly recited limitation more clearly requires for the limitation to apply to all of the cancer cells prior to the contacting step. This limitation has been addressed in the amended rejection by citing art that demonstrates that AML cells meet this limitation.
Applicant argues that claim 3 further limits claim 1 by requiring that agents that induce death of normal cells are not administered with the first and/or second agent. Contrary to applicant’s argument, claim 3 recites an outcome and therefore is considered to flow from the recited steps. The combination of the two recited agents would necessarily achieve the limitation of claim 3, absence evidence to the contrary. Additionally, the rejection is not directed to administering additional agents, so this limitation is met regardless.
Applicant argues that administering one active agent and not the other agent forming part of each of the combination therapies of Tsvetkov et al. and Bradbury et al. would render each combination therapy unsuitable for its intended purpose. Moreover, the Office has failed to establish that providing such combination therapies in addition to the claimed compounds in the method would not lead to cell death of normal cells. The rejection is not based upon administration of additional agents, but rather renders obvious delivery of an inhibitor of Aldh3a2 and an inhibitor of ferroptosis.
Contrary to applicant’s argument, Tsvetkov et al. clearly teach a method of treating a subject in need of treatment for cancer comprising administering to the subject “one” or both of the agents and does not require a specific combination for treatment. Bradbury et al. teach treatment by ferroptotic induction and teach that combination therapy can enhance ferroptotic induction; which is not a teaching of requiring an additional agent. It would have been obvious to combine two agents known to treat the same cancer, AML.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636