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 .
Claim Status
Currently, claims 1-10, 14-16, 18-19 are pending in the instant application. Claims 11-13, 17, and 20 have been canceled and claims 1-3, 5, 7-10, 14-15 are withdrawn. This action is written in response to applicant' s correspondence submitted 03/06/2026. All the amendments and arguments have been thoroughly reviewed but were found insufficient to place the instantly examined claims in condition for allowance. The following rejections are either newly presented, as necessitated by amendment, or are reiterated from the previous office action. Any rejections not reiterated in this action have been withdrawn as necessitated by applicant' s amendments to the claims. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action. This action is FINAL.
Claims 4, 6, 16, 18-19 are under examination with respect to Merlin and mRNA expression.
Withdrawn Rejections/Objections
The objection of claim 4 is withdrawn in view of the amendment to the claims.
The improper Markush rejection of claims 4, 6, 11-12, 16-19 is withdrawn in view of the amendment to the claims.
The rejection of claims 18-19 under 35 USC 112(b) is withdrawn in view of the amendment to the claims.
Claim Rejections - 35 USC § 112- New Matter
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 4, 6, 16, 18-19 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. This is a new matter rejection
Claim 4 has been amended to recite administering to the patient an effect amount of ferroptosis inducer monotherapy. This amendment changes the scope of the claims and is not supported by the disclosure and raises the issue of new matter. The specification teaches administering an effective amount of ferroptosis-inducing agent (see para 6). The specification teaches that “a”, “an” and “the” include plural unless the content clearly distracts otherwise (see para 149). The specification taches the compositions of therapeutics can be administered in combination with one or more additional therapeutic compounds (see para 159). The specification does not teach ferroptosis inducer monotherapy. The specification does not disclose or contemplate treating and administering only ferroptosis inducer or disclose any monotherapy. The specification teaches one or more additional therapeutic compounds and envisions more than one by the teachings of “a”, “an”, and “the”. Because the disclosure does not teach monotherapy, this amendment to the claims introduces new matter.
Additionally the amendment to the claims to recite treating lung, liver, colon, and breast epithelial cancer by administering ferroptosis inducer wherein mRNA expression of Merlin is reduced changes the scope of the claims and introduces new matter. While the specification teaches ferroptosis in colon, breast, lung and liver epithelial cell lines (para 249-250) and teaches decreased Merlin expression can promote metastasis (para 323) these embodiments do not disclose treating lung, liver, colon, breast epithelial cancer with reduced merlin expression with a ferroptosis inducer. The specification does demonstrate treating the epithelial cancer with erastin (see para 251) but it does not teach that treatment was administered in biological samples with reduced Merlin expression. For these reasons the amendment to the claims is new matter.
Maintained Rejections
Claim Rejections - 35 USC § 112- Enablement
Claims 4, 6, 16, 18-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating metastasis in mesothelioma by administering an effective amount of sorafenib wherein mRNA expression of merlin in a biological sample obtained from a patient is reduced compared to a sample obtained from a healthy subject, does not reasonably provide enablement for treating any therapy resistant metastasis prone cancer by administering any ferroptosis inducing agent. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. This rejection was previously presented and ahs been rewritten to address the amendment to the claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
Scope of the Claims/Nature of the Invention
The claims are drawn to a method for treating a therapy resistant, metastasis prone cancer in a patient. The claims recite a step of administering to the cancer patient an effective amount of ferroptosis-inducing agent wherein mRNA expression of elected gene Merlin is reduced compared to control sample or predetermined threshold.
The claims encompass any therapy resistant metastasis prone cancer wherein mRNA expression of merlin is reduced to a control sample or predetermined threshold. The claims encompass any predetermined threshold.
The claims encompass any ferroptosis inducing agent.
Dependent claims encompass epithelial cancer comprising mesothelioma, breast, colon, liver, and lung.
Dependent claims including ferroptosis inducing agent is class1 or class 2 ferroptosis inducer. Additional claim recites specific ferroptosis inducing agents including erastin, erastin derivative, sorafenib, and artemisinin derivative.
The claims encompass methods wherein any mesothelioma, breast, colon, liver, and lung epithelial cancer is administering any ferroptosis inducing agent to a subject that has a reduced merlin expression. The scope of ferroptosis inhibitors is broad. The term ferroptosis inhibitor reads on any compound or substance that inhibits iron dependent death at any activity rate (low, medium or potent inducer) or at any process of the signaling pathway.
In order to be enabled to practice the present invention, the skilled artisan would have to accept that by administering any ferroptosis inducer that any therapeutic effect of therapy of mesothelioma, breast, colon, liver, and lung cancer could be achieved. However in light of the fact that the specification fails to provide the skilled artisan with any direction or guidance as to method of treating any mesothelioma, breast, colon, liver, and lung epithelial cancer with any ferroptosis inducer in any cancer patient with any reduced merlin expression in general could be achieved the presence specification is viewed as lacking an enabling disclose of the entire scope of the claimed invention.
The nature of the invention requires a reliable correlation between the expression level of merlin in any therapy resistant metastasis prone cancer in any patient and treating the patient with any ferroptosis inducing agent.
Teachings in the Specification and Examples
The specification teaches an animal model that encompasses mesothelioma (see para 240). The specification does not teach any other animal model or provide guidance of treatment in any other subject with any other cancer.
In example 4, the specification teaches heterozygous deletion of Merlin encoding gene NF2 has been detected with high frequency in malignant mesothelioma. The specification teaches analysis of human malignant mesothelioma cell lines were assessed. The specification teaches 6 out of 10 cell lines were merlin defective (see para 276). The specification does not teach analysis of any subjects with malignant mesothelioma, breast, colon, liver, or lung. The specification only discloses analysis in 10 cell lines.
Example 6 teaches inhibition of Merlin increases tumor proliferation and invasive capability and renders tumor sensitivity to GPX4 inhibition. This example describes developing mice that comprise mesothelioma and metastasis. The specification asserts that these results indicate that Merlin status in mesothelioma tumor tissues might be useful as a biomarker to predict tumor metastasis and responsiveness to induction of ferroptosis cell death (see para 312).
The specification teaches treating HTC cells targeting Lats1 and 2 into nude mice and treating within IKE. The specification teaches that IKE is an erastin analog that is amendable for in vivo use because of increased solubility and stability (see para 314). The specification reaches that IKE reduced tumors when Lats1/2 were inhibited, however the specification does not teach that IKE reduces tumors when Merlin was inhibited.
The specification does not teach treating a subject with reduced Merlin with any ferroptosis inducing agent. The specification does not teach treating a subject with any cancer other than malignant mesothioma. The specification does not teach treating a subject with any breast, colon, liver, and lung epithelial cancer.
State of the Art and the Unpredictability of the Art
While methods of measuring mRNA levels are known in the art, methods of correlating mRNA levels with a phenotype (such as therapy resistant metastasis prone cancer or responsive to ferroptosis inducing agent) are highly unpredictable. The unpredictability will be discussed below.
The claims require administering an effective amount of ferroptosis inducing agent to a subject with a reduced Merlin expression for treating therapy resistant metastasis prone cancer. The specification provides no evidence of treating a therapy resistant cancer. The specification further provides no evidence of treating a subject with reduced Merlin expression and ferroptosis inducing agent. While the specification teaches administering to mouse xenografts IKE or erastin, the specification does not teach these models comprise reduced Merlin expression or provide any resistant therapy metastasis cancer. There is no guidance in the specification for treating the genus of therapy resistant metastasis cancer with the genus of ferroptosis inducing agents. In the absence of evidence to the contrary this is highly unpredictable.
Larraufie (Bioorganic & Medicinal Chemistry Letters 25 (2015):4787-4792 teaches erastin exhibits modest water solubility and potency, precluding its use in vivo (See pg. 4788, 1st column). Sehm (Oncotarget, vol 7, 2016, pp. 36021-36033) teaches SAS treatment does not affect experimental tumor growth and treated animal revealed comparable tumor volume as untreated controls (see abstract).
Zhou (Signal Transduction and Targeted Therapy, 2024, 9:55, pp. 1-33) teaches there is a lack of well-established animal models to evaluate cancer ferroptosis in vivo. Zhou teaches the current models rely on IKE and cysteines to treat xenograft tumors however timing and frequency of administration vary in practice and side effects of long term administration and potential drug resistance are not well understood. Additionally generating CRISPR-Cas9 mediated GPX4 knockout cancer cells for xenograft fails to evaluate the efficacy and safety effects of ferroptosis drugs. Zhou teaches that ferroptosis in cancer is complex and in some cases ferroptosis induction initially promotes tumor formation but later leads to tumor cell demise and suppression. Zhou teaches it is crucial to determines the appropriate therapeutic time window for FINs. Zhou teaches the lack of effective and specific frugs that can safely induce ferroptosis in cancer cells is a challenge. Zhou teaches the in vivo potential of several compound that induce ferroptosis is limited due to poor bioavailability and insufficient targets. Zhou teaches reducing the toxicity of FINs remains a challenge in clinical oncology. Zhou teaches these challenges are needed to develop ferroptosis anticancer strategies. (See pg. 22, 1st column).
Thus in the absence of evidence to the contrary it is highly unpredictable to administer an effective amount of ferroptosis inducing agent to a patient with reduced Merlin expression to treat a therapy resistant metastasis prone cancer in a patient.
Quantity of Experimentation:
For the reasons discussed above, it would have required undue, unpredictable experimentation of a trial- and-error nature to practice the recited methods in the full,
broad scope encompassed by the rejected claims. The type of experimentation required
is not routine and the subsequent data analysis is sophisticated. Furthermore, the outcome of the tasks is entirely unpredictable based on the limited data and analysis provided in the instant specification.
Conclusions:
Herein, although the level of skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
Response to Arguments
The response traverses the rejection on page 7 of the remarks mailed 03/06/2026. The response asserts the claims have been amended to replace metastasis prone cancer with epithelial cancer. This response has been reviewed but not found persuasive. The amendment to the claims to recite epithelial cancer is not enabled. The specification teaches only disclosing analysis of the claimed epithelial cancers in cancer cell lines. The specification does not teach Merlin expression in the claimed epithelial cancers and treatment with ferroptosis inducer monotherapy. While the specification asserts decreased Merlin expression can promote metastasis see para 310, this does not provide guidance for treating epithelial cancer cells with decreased Merlin expression with any ferroptosis inducer, as broadly claimed. For these reasons and reasons of record this rejection is maintained.
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.
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.
Claims 4, 6, 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Pachter (US20160346282A1) in view of Sekido (Pathology Internation, 2011, 61:331-344). This rejection was previously presented and ahs been rewritten to address the amendment to the claims.
The claims are enabled to the extent of the specification in order to provide compact prosecution Pachter in view of Sekido is provided as it teaches the enabled scope of the claims.
Pachter teaches a method for treating a subject having cancer by administering a combination of therapies (See para 4-5). )Pachter teaches the combined therapy can be administered sequentially, including administering one therapy 8 weeks or more before the second therapy (see para 43). Because Pachter teaches sequential therapy that includes 8 or more weeks apart, each therapy can be considered to be a monotherapy. Pachter teaches the cancer is metastasis and comprises any tumor that exhibits a decreased merlin expression, including mesothelioma, breast, lung, liver, and rectal cancer (see para 9). Pachter teaches administration with a targeted therapy including sorafenib (class 1 ferroptosis inducer) (see para 78) (claim 18-19). Patcher teaches the cancer is resistant to standard therapy (see para 68). Because Patcher taches administering to the metastasis prone cancer an effective amount of ferroptosis inducing agent (sorafenib) and teaches the cancer has a decreased merlin expression this will encompass obtaining a sample from a patient and comparing to a control sample or predetermined threshold to determine that the cancer has a decreased merlin expression. Patcher does not teach how decreased expression of merlin was determined.
However Sekido teaches inactivation of merlin in malignant mesothelioma cells. Sekido teaches downregulation of Merlin in malignant mesothelioma cell lines. Sekido teaches quantitative RT-PCR using Taqman probes and to detect decreased mRNA expression relative to predetermined threshold (see figure 3).
Therefore it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to improve the method of Pachter to include RT-PCR to detect decreased merlin expression as taught by Sekido. The ordinary artisan would have been motivated to improve the method of treating cancer that comprises a decreased merlin expression as taught by Pachter with PCR analysis of the tumor to detect decreased merlin expression as taught by Sekido because Pachter does not teach how tumors with decreased merlin expression were determined. The ordinary artisan would have had a reasonable expectation of success to use PCR amplification of mRNA in the method of Pachter because Pachter teaches tumors with decreased merlin expression without teaching how expression was determined and Sekido teaches decreased merlin expression in cancer by PCR analysis. Because both Pachter and Sekido teach decreased merlin expression for the analysis of cancer, it would have been obvious to one skilled in the art to include an additional known method in the art, the method of PCR amplification to detect decreased merlin expression as taught by Sekido in the method of Pachter in order to achieve the predictable result of detecting decreased merlin expression in cancer.
Response to Arguments
The response traverses the rejection on pages 8-10 of the remarks mailed 03/06/2026. The response asserts the claims have been amended to recite ferroptosis inducer monotherapy. The resp9onse asserts Pachter fails to teach or suggest ferroptosis inducer monotherapy in any patient with epithelial cancer. The response asserts that Pachter does not teach that ferroptosis inducers can be solely administered in an amount that is therapeutically effect to treat epithelial cancer. The response asserts that Pachter described combination therapy methods with FAK inhibitor and MEK inhibitor and targeted therapy such as sorafenib to treat patients with epithelial cancers. The response asserts that Pachter does not provide motivation for monotherapy or select epithelial cancer with reduced Merlin mRNA expression. The response asserts that Sekido fails to teach or suggest any therapy for epithelial cancer that exhibit reduced Merlin mRNA expression. These remarks have been thoroughly reviewed but not found persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., ferroptosis inducers administered solely to treat epithelial cancers) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The claims recite a method for treating “comprising” administering “a” ferroptosis inducer monotherapy. The specification teaches that “a”, “an” and “the” include plural (see para 149). The specification taches the compositions of therapeutics can be administered in combination with one or more additional therapeutic compounds (see para 159). Comprising is open language and allows for additionally therapies to be administered before or after the recited ferroptosis inducer monotherapy. The specification envisions “an” to include plurals and to include therapeutics to be administered in combination with one or more addito8inal therapeutics. Because the claims are comprising allowing for additional therapies, the claims are not limited only administering ferroptosis inducer monotherapy. Pachter teaches sequential administration and teaches administering one therapy followed by a second therapy 8 or more weeks later, as such Pachter teaches administering a ferroptosis inducer monotherapy as a second therapy after a first therapy has been administered. Additionally Pachter teaches the cancer is any tumor that exhibits a decreased merlin expression, including mesothelioma, breast, lung, liver, and rectal cancer (see para 9). As such Pachter teaches administering ferroptosis inducers to epithelial cancers comprising mesothelioma, breast, lung, and liver that have decreased merlin expression. It is noted that Sekido was cited to demonstrate measuring of decreased merlin expression and not cited to teach decreased merlin expression and treatment with ferroptosis inducer, which is taught by Pachter. For these reasons and reasons of record this rejection is maintained.
Conclusion
No claims are allowable.
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 SARAE L BAUSCH whose telephone number is (571)272-2912. The examiner can normally be reached M-F 9a-4p.
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/SARAE L BAUSCH/ Primary Examiner, Art Unit 1699
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