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 .
Election/Restrictions
Applicant’s election without traverse of group I, claims 1, 3-4, 7, 13-23, and 26 and species mutation, increased copy number, SINE, Selinexor in the reply filed on 05/27/2026 is acknowledged.
Claims 7, 15, and 24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 05/27/2026.
Claims 1, 3-4, 13-14, 16-23, and 26 are under examination with regard to mutation results in elevated expression. Claim 4 is under examination with regard to increased copy number of XPO1. Claim 13 is under examination with regard to SINE. Claim 14 is under examination with regard to Selinexor.
Claim Rejections - 35 USC § 112(b)
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 3-4 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 3 recites a method for sensitizing a SCLC patient to chemotherapy comprising administering to the SCLC patient an effective amount of XPO1 inhibitor separating, sequentially, or simultaneously with the chemotherapy, wherein the chemotherapy comprises a topoisomerase inhibitor and wherein the SCLC patient comprises at least one mutation that results in elevated expression or activity. It is unclear if the claim is a method for sensitizing a SCLC patient to chemotherapy or a method of administer XPO1 inhibitor. There are no method steps that are directed to a method for sensitizing a SCLC patient to chemotherapy and it is unclear how this is achieved with the active process steps of the claims., None of the active process steps sensitize a SCLC patient to chemotherapy and it is unclear if one necessarily accomplish what is intended for the method by practicing the recited method steps. If the claim is intended to sensitive a SCLC patient to chemotherapy, it appears there is an omitted step. Claim 3 is indefinite because the limitation in the preamble is not recited in the process steps, the metes and bounds of the claim are vague and indefinite and it is unclear if one necessarily accomplishes what is intended for the method by practicing the recited method steps.
Claim 4 depends from claim 3 and is indefinite for the reasons applied to claim 3.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 18 and 22 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 18 depends from claim 1 and recites specific chemotherapeutic agents. Claim 22 depends from claim 18. Claim 1 requires the chemotherapy comprises a topoisomerase inhibitor. None of the chemotherapeutics recited in claim 18 encompass a topoisomerase inhibitor and therefore does not further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)-Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-4, 13-14, 16-23, and 26 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 drawn to a method for selecting a SCLC patient that has received or is receiving chemotherapy for treatment with an XPO1 inhibitor comprising detecting the presence of at least one mutation that results in elevated expression or activity of exportin-1 (XPO1) in a sample and administering an effective amount of XPO1 inhibitor, wherein the chemotherapy comprises a topoisomerase inhibitor (claim 1). Claim 3 requires sensitizing a SCLC patient to chemotherapy by administering an effective amount of XPO1 inhibitor, wherein the SCLC patient comprises at least one mutation that results in elevated expression or activity of XPO1. Dependent claims require the mutation is an increased copy number of XPO1. Dependent claims require the patient has not previously received chemotherapy or is chemoresistant SCLC, exhibits stage I-IV SCLC, and has a specific SCLC subtype. Dependent claims require chemotherapeutic agents that are not topoisomerase inhibitors and comprise a large genus of chemotherapeutics (claim 18) and require administration of XPO1 or chemotherapeutics by orally, intranasally, parenterally, intravenously, intramuscularly, intraperitoneally, intramuscularly, intraarterially, subcutaneously, intrathecally, intracapsularly, intraorbitally, intratumorally, intradermally, transtracheally, intracerebroventricularly, or topically (claim 21-22).
The claims encompass determining any one or mutations in any gene or any genomic location that results in elevated expression or activity of XPO1 (claim 1 and 3) and any one or mutations that result in increased copy number of XPO1(claim 4).
The claims do not define the mutation in terms of any structural or sequence such as type of mutation (insertion, deletion, substitution, translocation) the number of nucleotides encompassed by the mutation, or the identity of the nucleotides (A, G, T or C) in the mutation or describe any sequence of the mutation. The claims only describe the mutation in terms of function, increased expression or activity of XPO1. Accordingly the claimed genus of at least one mutation that results in elevated expression or activity of XPO1 is considered to be significantly large given the fact that the claims encompass any single or multiple nucleotide insertion, deletion or addition at any position of any gene that will results in elevated expression or activity of XPO1. The activity of XPO1 comprises a large genus of activities, including protein transport, nuclear export of p53, FOXO,Rev and U snRNAs, control of cellular processes, regulating NFAT and AP-1.
The specification discloses only three locations of mutations within the XPO1 gene that result in a gain of function mutation, E571, R749, and D624 however the specification does not identify the mutation that results in a gain of function only the location of amino acid residue (see para 81). The specification does not describe any mutation in XPO1 or in any other gene that would results in increased expression of XPO1 gene or activity of XPO1 gene. The specification does not disclose any copy number variation of XPO1. The specification discloses only how to generally identify mutations by sequencing but does disclose how to identify a mutation that results in increased expression or activity of XPO1 (see pg. 38-40).
While the specification discloses three locations of mutations in XPO1 that result in a gain of function mutation, the specification does not describe the activity of XPO1 that results from the location of the mutations. The specification does not describe any increased activity of XPO1 nor any mutation in XPO1 or any gene that results in increased activity of XPO1 other than the stated gain of function. The specification does not describe any copy number of XPO1 that results in increased expression or activity of XPO1. The specification does not teach or describe sensitizing a SCLC patient to chemotherapy.
The claims additionally encompass administering topoisomerase inhibitor with an XPO1 inhibitor to treat SCLC in patients with at least one mutation that results in elevated expression or activity of XPO1. The claims encompass a large genus of XPO1 inhibitors that are not described. The claims encompass any SINE compound, inhibitory nucleic acid targeting XPO1, and any anti-exportin antibody. While claim 18 does not further limit claim 1, if it was amended to properly depend from claim 1, the specification does not describe the large genus of chemotherapeutics listed in claim 1 with administering XPO1 for SLCL. The genus of chemotherapeutics listed are not all therapeutics to treat SCLC and the specification does not describe the chemotherapeutic agents listed in claim 18 in combination with XPO1 to treat SCLC. For example accatin III is not a drug, altretamine is a chemotherapeutic that treats ovarian cancer, mannosfulan is an alkylating agent but is not approved for cancer treatment.
While the specification identifies XPO1 as a target for cisplatin sensitization in SCLC (See ex), the specification does not describe any other chemotherapeutic sensitization or combination of therapy other than cisplatin and selinexor with XPO1 to treat SCLC. The specification describes cisplatin and Selinexor, the combination of cisplatin, Selinexor and etoposide, and irinotecan with Selinexor or KPT-185 to treat SCLC (ex 5 and 6). The specification further teaches high XPO1 expression levels in SCLC but does not teach any mutation or copy number variant that results in the high XPO1 expression (see ex 4)
Thereby, while the specification has adequately described cisplatin and Selinexor, the combination of cisplatin, Selinexor and etoposide, and irinotecan with Selinexor or KPT-185 to treat SCLC and described increased expression of XPO1 in SCLC, the specification has not adequately described a representative number of XPO1 inhibitors or chemotherapeutics to treat SCLC in a combination with a representative number of XPO1 inhibitors. The specification has not described any mutation that results in any increased expression or activity of XPO1 nor described any copy number that results in increased expression XPO1.
No members of the claimed genus of mutations that results in increased expression or activity of XPO1 have been sufficiently described in terms of any other relevant identifying characteristics. No additional members of the claimed genus of XPO1 inhibitors, other than selinexor, chemotherapeutics and XPO1 inhibitors have been sufficiently described in terms of any other relevant identifying characteristics. Relevant to the lack of particular structural limitations in the rejected claims, MPEP 2163 states:
The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art.
Additionally, the specification does not disclose a clear structure-function relationship between the mutations and activity of XPO1. There is no showing or evidence which links particular nucleotide locations or amino acid changes in any gene with increased XPO1 expression or activity. While the specification discloses a location of three mutations in XPO1 that results in gain of function, there is no indication of the function that is correlated to the location of the mutations, what the change of the mutation is, the specification only describes the position of the mutation but does not describe the mutation.. In the absence of any real structure-function relationship in a representative number of mutations that result in increased expression and activity of XPO1 and in the absence of a representative number of species of the claimed genus of mutation and NCSC cancer, chemotherapeutics, XPO1 inhibitors there is insufficient descriptive support for the currently claimed genus of mutations that result in XPO1 increased activity and expression, broad genus of any XPO1 inhibitor in combination with any chemotherapeutics. While limitations from the specification are not read into a claim, a claim must be read in view of the specification.
It is acknowledged that the specification also teaches the general methodology for detecting mutations in genes. However, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. Thereby, a showing of how to potentially identify mutations is not sufficient to establish that Applicants were in possession of the invention as broadly claimed.
With respect to the present invention, there is no record or description which would demonstrate conception of a representative number of mutations that result in an increased expression or activity of XPO1 in SCLC that are linked to selecting and sensitizing patients for treatment. There is no record or description of a representative number of XPO1 inhibitors of the large genus claimed. Therefore, the claims fail to meet the written description requirement because the claims encompass a significantly large genus of mutations in any gene that results in increased expression or activity of XPO1 and XPO1 inhibitors which are not described in the specification that would be associated with effective SCLC therapy.
Claim Rejections - 35 USC § 112(a)- 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, 3-4, 13-14, 16-23, and 26 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 small cell long cancer in a patient comprising detecting an increased expression of XPO1 and administering an effective amount of selinexor, selinexor in combination with cisplatin or cisplatin, Selinexor and etoposide, and irinotecan with Selinexor or KPT-185 to the patient with increased expression of XPO1, does not reasonably provide enablement for selecting or sensitizing a patient by detecting presence of at least one mutation that results in elevated expression or activity of XPO1, detecting copy number of XPO1, and administering XPO1 inhibitor with a chemotherapy. 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.
Nature of the Invention and breadth of the claims
The claimed methods are drawn to selecting SCLC patient for treatment with XPO1 inhibitor and sensitizing a SCLC patient to chemotherapy and comprise detecting the presence of at least one mutation that results in elevated expression or activity of exportin-1 (XPO1), including increased copy number of XPO1 and administering an effective amount of XPO1 and a topoisomerase inhibitor.
The claims generically encompass the analysis of any mutation in any gene that results in XPO1 increased expression or activity. The claims encompass administering any XPO1 inhibitor. Dependent claims require increased copy number of XPO1.
The claims thus require knowledge of reliable and robust association between the presence of any mutation that results in increased expression of XPO1 and activity of XPO1 with treatment and sensitizing SCLC to chemotherapy. The claims require a reliable association of any XPO1 inhibitor with any combination of chemotherapy or topoisomerase inhibitor to treat SCLC, including any subtype.
Direction provided by the specification and working example
The instant specification provides example wherein samples were analyzed to determine combination of cisplatin and selinexor (ex 3 and 5), irinotecan and selinexor (ex 6) and XPO1 expression in SCLC was observed (ex 4). Relevant to the methods of the pending claims, the data of the specification (e.g.: example 4) indicate that increased expression of XPO1 is detected in SCLC.
Relevant to the breadth of the claims, there is no analysis of mutations in any gene, including XPO1 that result in increased expression or activity of XPO1. There is no analysis of any increased copy number of XPO1. There is no analysis of sensitizing a SCLC patient to chemotherapy by administering XPO1 inhibitor in patients that have at least one mutation that results in elevated expression or activity of XPO1. The specification teaches only that increased expression of XPO1 is associated with SCLC. While the specification asserts that gain of function mutations of XPO1 include E571, R749 and D624, there is no data or analysis that a mutation at these positions will result in a gain of function of XPO1 and what the gain of function would be, increased expression of XPO1 nor any data or analysis of any mutation that results in increased expression of XPO1 or activity of XPO1 in SCLS. There is no analysis of mutations associated with increased expression or activity of XPO1 or any therapeutic outcome in SCLC. Additionally there is no analysis of treating SCLC with XPO1 in combination with any chemotherapeutic agent except cisplatin or topoisomerase inhibitor. The chemotherapeutic agents listed in claim 18 encompass many different agents that do not treat SCLC or are even know to treat cancer. For example accatin III is not a drug, altretamine is a chemotherapeutic that treats ovarian cancer, mannosfulan is an alkylating agent but is not approved for cancer treatment.
State of the art, level of skill in the art, and level of unpredictability
While the state of the art and level of skill in the art with regard to identification of mutation in samples is high, the unpredictability in associating any particular alteration with a specific phenotype, or identifying a particular mutation with increased expression or increased activity in cancer with therapy, as is encompassed by the claims, is even higher. The unpredictability is demonstrated by the related art and the instant specification.
Conforti (Cancer Res, 2017, 77(20), pp5614-5627) teaches therapeutic effects of XPO1 inhibition in cancer. Conforti teaches XPO1 is expressed in thymoma carcinoma cell lines and is inhibited by selinexor. Conforti teaches XPO1 gene amplification confers acquired resistance to selinexor. Conforti teaches 3,.5 fold more copies of XPO1 gene were detected in resistant cells to selinexor (see pg. 5620, XPO1 gene amplification confers acquired resistance). Conforti demonstrates that increased copy number of XPO1 results in resistance to selinexor not sensitivity to XPO1 inhibitors.
Jardin (Am J Hematology, 2016, vol 91, pp 923-930) teaches that there was no correlation between the XPO1 mutation status and level of XPO1 mRNA expression (see pg. 926). Jarden teaches the functional relevance of E571K variant of XPO1 is unknown (see pg. 929).
Nagasaka (Lung Cancer, 2021, 160:92-98) teaches mutation of XPO1 E571 is a recurrent phenomenon in hematological malignances. Nagaska teaches overexpression of XPO1 is common in hematological malignancies. Nagaska teaches XPO1 amplified in NSCLC and linked to poor survival however the underlying mechanism is not known. XPO1 amplification has been associated with drug resistance with topoisomerase II an galectin-3 (see pg. 93). Nagaska teaches there is no overlap of XPO1 mutations and amplification, both mutation and amplification were rare occurrences. Nagaska teaches early failures with XPO1 inhibitors such as leptomycin B. Nagaska teaches the efficacy of immunotherapy is unclear in a setting with XPO1 mutant NSCLC tumor. Nagaska teaches a very low XPO1 mutation in a large cohort (see pg. 96).
The prior art demonstrates the unpredictability of identifying mutations in any gene that result in increased expression or activity of XPO1, including copy number gain of XPO1 and response to therapy in cancer, including XPO1 inhibitors. Additionally the art demonstrates that in human subjects the detection of XPO1 mutations is extremely low. This is relevant because the instant specification does not teach analysis of any mutations in any subjects with SCLC or teach analysis of any copy number identified in subjects with SCLC. The specification discloses a working example of human subjects to detect expression of XPO1 however does not teach analysis of mutations or copy numbers of XPO1, which is distinct from expression of XPO1.
Quantity of experimentation required
A large and prohibitive amount of experimentation would be required to make and use the claimed invention. Given that the claims generically encompass any mutation that results in increased expression or activity of XPO1 and administering any XPO1 inhibitor to a patient with SCLC, one would have to perform large case: control studies, and validation of any results, to determine which mutations occur and which mutations are associated with increased expression or activity of XPO1 and may be reliably and robustly associated with selecting treatment or sensitizing a SCLC patient and which XPO1 inhibitors would treat a subject for SCLC with a mutation that results in increased XPO1 expression or activity. Even for the particular copy number gain and positions disclosed in the specification as consistent with the Election (i.e.: copy number gain), given the lack of mutation change or copy number described to be associated with increased expression or activity of XPO1b or SCLC, one would have to perform an analysis to see if even those mutations are robustly and reliably associated with SCLC and response to therapy.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention and breadth of the claims, the state of the art, the level of skill in the art and its high level of unpredictability, and the particular guidance in the specification including the examples, it is the conclusion that an undue amount of experimentation would be required to make and use the invention as claimed.
Conclusion
No claims are allowable.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Fereydoun Sajjadi can be reached at 571-272-3311. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SARAE L BAUSCH/
Primary Examiner, Art Unit 1699
Prosecution Insights