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 preliminary amendment filed 9/15/2023 is acknowledged. Claims 3, 5-9, 12, 14-18 have been amended. Claims 1-18 are pending and under examination.
Priority
This application is a 371 of PCT/US2022/020767 filed 03/17/2022 which claims benefit of 63/162,314 filed 03/17/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/12/2024 and 1/21/2025 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings were received on 9/15/2023 is acknowledged. These drawings are found acceptable by the examiner.
Specification
The disclosure is objected to because of the following informalities:
(a) The use of the terms “NanoString” “nCounter”, at pages 3, 5, 9, 17-20, and 22-24, “CoMMpass” at pages 3, 7, 8, 20, 22 and 23, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Appropriate correction is required.
Claim Rejections - 35 USC § 112: Indefiniteness
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 1-18 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.
(a) Claims 1-18 are indefinite in the claims 1 and 10 because the claims do not provide a clear nexus between the steps such that a clear interpretation can be ascertained. Specifically, the claims recite a method for treating a mammal having multiple myeloma (MM). wherein said method comprises: (a) identifying a mammal as having a biological sample with an altered level of expression of one or more markers as compared to a level of expression from a corresponding mammal that does not have late-stage MM or refractory/resistant (RR) MM. However, it is unclear how one is to establish a person not having late-stage MM or refractory/resistant MM. It cannot be determined the criteria for establishing what constitutes a reference or control sample as it relates to determining the absence of the sample’s stage of MM. Further it cannot be determined if treatment is intended to be for late stage or refractory/resistant MM or MM at any stage. Clarification is required.
(b) Claims 9 and 18 contain the trademark/trade name “NanoString” and “nCounter”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a type of technology and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 112: Enablement
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 1-18 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 identifying a mammal having late stage multiple myeloma (MM), and/or having MM that is resistant to treatment with immunomodulatory drugs (IMiD) and proteasome inhibitor (PI) based on the identification of a set of biomarkers associated with IMiD and PI resistance and disease progression in MM, it does not reasonably provide enablement for a method of treating any MM as instant claimed and administering to said mammal a composition comprising chimeric antigen receptor – (CAR –) T cells or a histone deacetylase (HDAC) inhibitor. 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.
Claim 1 and those dependent therefrom are directed to a method for treating a mammal having multiple myeloma (MM), wherein said method comprises: (a) identifying a mammal as having a biological sample with an altered level of expression of one or more markers as compared to a level of expression of the one or more markers in a biological sample from a corresponding mammal that does not have late stage MM or refractory/resistant (RR) MM, wherein said one or more markers are selected from the group consisting of CRBN, CEP55, DIRAS1, SKA2, CD53, PSMA7 and PSMD14, thereby identifying said mammal as having or being likely to have late stage MM or RR MM, and (b) administering to said mammal a composition comprising chimeric antigen receptor (CAR-) T cells or a histone deacetylase (HDAC) inhibitor.
The claim 10 and those dependent therefrom are directed to a method for treating a mammal having multiple myeloma (MM), wherein said method comprises: identifying a mammal as having a biological sample with an altered level of expression of one or more markers as compared to a level of expression of the one or more markers in a biological sample from a corresponding mammal that does not have late stage MM or refractory/resistant (RR) MM, wherein said one or more markers are selected from the group consisting of CRBN, CEP55, DIRAS1, SKA2, CD53, PSMA7 and PSMD14, and wherein the method comprises administering to said mammal a composition comprising chimeric antigen receptor (CAR-) T cells or a histone deacetylase (HDAC) inhibitor, wherein one or more symptoms of said MM is reduced in said mammals.
The claims are sufficiently broad to encompass any type of treatment of any stage of MM with a composition comprising chimeric antigen receptor (CAR-) T cells or a histone deacetylase (HDAC) inhibitor.
The specification teaches that the invention discloses a set of biomarkers associated with immunomodulatory drug (IMiD) and proteasome inhibitor (PI) in MM that was identified using NanostringTM nCounterTM technology. The specification teaches it was discovered that a subset of genes ((identified in Appendix A) were linked to clinical drug resistance, poor survival and disease progression following treatment with one or more IMiDs and/or one or more PIs. The specification teaches methods and materials for treating a mammal identified as having, or as being likely to have, advanced MM and/or RR MM wherein said treatment comprises anti-MM agents such as for example, a daratumumab based regime such as Dpd (daratumumab, pomalidomide, and dexasmethasone) chimeric antigen receptor T cell (CAR – T cells) against a target such as, without limitations, BCMA, GPCR5, or FCRH5, histone deacetylase (HDAC) inhibitors, or panobinostate-based therapies (e.g., PI and Panobinostat) (pages 14-15). The specification teaches that effective doses can vary, the effective amount of a composition can vary and the frequency of administration of a MM treatment can vary and be any frequency and any duration.
The specification however, while mentioning the use of CAR-T cells and HDAC inhibitor as a potential treatment options for MM, no guidance is provided concerning the use of CAR-T cells or HDAC inhibitor in the treatment of MM. In the examples beginning at page 16, the specification teaches NanoStringTM profiling to identify genes differentially expressed between newly diagnosed and late/RR stage MN and further analysis of the survival data in MM sequencing datasets. The specification teaches MM cell proliferation and drug response after modulating of PRR11 expression and PBK1 activity, validation and quality control of NanoStringTM expression profiling in MM, identification of differentially expressed genes in drug resistant patients, clinical and functional analysis of top identified genes, identifying predictive probes and establishing a predictive model. The specification teaches in the example 5 wherein the predictive model as shown in the Figure 14, represents four IMiD sensitivity candidate genes (CRBN, CEP55, DIRAS1 and SKA2) and three PI sensitivity candidate genes (CD53, PSMA7 and PSMD14) as significant predictors of disease stages (p < 0.05) (pages 23-24).
The specification however does not provide any teaching or working examples of an effective mode of treatment comprising a composition comprising chimeric antigen receptor (CAR-) T cells or a histone deacetylase (HDAC) inhibitor. No specific guidance is provided in the specification or claims for treatment of any stage of MM as encompassed by the claims
Regarding treatment of any multiple myeloma, the prior art provides little guidance concerning successful treatment of the cancer. There is no guidance in the specification or prior art to dosing or regimens to be employed to successfully treat any MM at any stage with a composition comprising CAR – T cells or HDAC inhibitor. In post-dated art, Zhang et al (Front. Immunol. 14: 1101495, pages 01 – 13, February 2023) teaches despite the encouraging outcomes of anti-BCMA CAR T cells therapy in RR MM, it usually exhibits short-term efficacy and many MM patients still experience disease reoccurrence or progression. Zhang teaches that the resistance mechanisms are closely related to the interactions among anti-BCMA CAR-T cells, tumor cells and the complicated tumor microenvironment, involving antigen escape and CAR – T cell exhaustion (see abstract and section 2 at page 2). Zhang concludes that while Car T cell therapy has achieved impressive outcomes fin RR MM and it side effects generally controllable, there are still several challenges to be addressed, such as relapse after anti-BCMA CAR T cell therapy, high manufacturing costs and the longer manufacturing cycle of autologous CAR - T cell products limit their accessibility. Thus, further improvement is required. Zhang states that due to the resistance to CAR -T cell therapy and persistent high-risk factors, subsequent anti-myeloma therapy is also of great clinical significance (see “Conclusion” at page 9).
Xiao et al (World Journal of Clinical Oncology, 16 (8): 108768, 1-6, August 2025) teaches HDACs has been recognized as promising anti-cancer agents, but emerging evidence indicates that unintended pro-metastatic effects may offset the therapeutic benefits (abstract). With regards to a treatment option for MM, Xiao teaches the activating of phosphatidylinositol 3-kinase (ADKT/mTOR/p65) signaling pathway for enhance efficacy in multiple myeloma. The reference concluded by teaching that they emphasize the importance of mechanism-based drug design and combination treatment approaches. Furthermore, traditional HDAC exhibit severe adverse effects in clinical applications, including off-target toxicities and limited therapeutic efficacy against solid tumors. Xiao teaches that considering the differential expression levels of specific HDACs across various malignancies, patient stratification is critical for successfully applying HDAC therapies (bottom of page 3 to top of page 4 and section entitled “Conclusion). Thus, post-dated art suggests it would be difficult to administer a composition comprising chimeric antigen receptor (CAR-) T cells or a histone deacetylase (HDAC) inhibitor to effectively treat any stage of multiple myeloma without further information and guidance. Therefore, in view of the foregoing, undue experimentation is required to make and use the claimed invention commensurate fully in scope.
Claim Rejections - 35 USC § 103
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.
12. Claim(s) 1-5, 9-13 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hasskarl et al (WO 2020097403, citation made of record on IDS filed 11/12/2024) in view of Knudsen (US 20180087113, March 2018).
Regarding claims 1 and 10, Hasskarl et al teach a method for treating a mammal having multiple myeloma (MM) ([0026], [0032], [0208]), wherein said method comprises: (a) identifying a mammal as having a biological sample with an altered level of expression of one or more markers, wherein said one or more markers comprise CRBN ([0282], and (b) administering to said mammal a composition comprising chimeric antigen receptor-(CAR-) T cells (0279], [0330] – [0332]) (see also abstract, [0546], [0675], [0688] and claims 24-27, 54 and 91).
Regarding claims 2 and 11, Hasskarl et al teach wherein said mammal is a human ([0495]).
Regarding claim 3 and 12, Hasskarl et al teach wherein said biological sample is a blood sample obtained from said mammal ([0496]).
Regarding claims 4 and 13, Hasskarl et al teach wherein said blood sample is a plasma sample [0496]).
Hasskarl does not expressly teach wherein the comparison of the expression levels of the markers in the biological sample that corresponds to a mammal that does not have late stage MM or refractory/resistant MM.
Regarding claims 1-4 and 10-13, Knudsen teaches a method for predicting drug responsiveness in cancer patients, wherein the cancer comprises multiple myeloma and wherein the method comprises steps of identifying a mammal as having a biological sample with an altered level of expression of one or more markers in a biological sample, wherein the one or more markers comprises CD53 [0105] as compared to sample sensitive or resistant to treatment and used to determine a cancer patients responsiveness to treatment [0105] and administering to said mammal a composition comprising a histone deacetylase inhibitor ([0012], [0046] – [0047]) and wherein said symptoms are reduced ([0057]. Knudsen teaches that the multiple myeloma may encompass Stage I, Stage II or Stage III multiple myeloma {0058]. Knusen additionally teaches wherein the sample may encompass blood, serum or plasma [0059].
Regarding claims 9 and 18, Knudsen et al teach wehrien the analysis comprises NanoStringTM nCounterTM technologies ([0061]-[0062]).
It would have been prima facie obvious to one or ordinary skill in the art at the time of the effectively filing date of the claimed invention to have been motivated to have modified the method of HassKarl to encompass a comparison of expression levels of the markers in a biological sample that corresponds to a mammal that does not resistant MM. The ordinary artisan would have been motivated to do so for the obvious advantages of monitoring or detecting drugs resistance responsiveness in future therapeutic treatments as taught by Knudsen.
Conclusion
13. No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CYNTHIA B WILDER whose telephone number is (571)272-0791. The examiner can normally be reached Flexible.
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/CYNTHIA B WILDER/ Primary Examiner, Art Unit 1681