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 1-27 and species E9-E2 fusion; SEQ ID NO 28-33, SEQ ID NO 35, SEQ ID NO 38-51; SEQ ID NO 53; SEQ ID NO 7 and SEQ ID NO 8 in the reply filed on 11/4/2025 is acknowledged.
Claims 8, 10, 28-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 11/4/2025.
Claims 1-7, 9, 11-27 are under examination. Claim 2 and 18 are under examination with respect to E9-E2. Claim 3 and 19 are under examination with respect to SEQ ID NO 28-33, 35, 38-51. Claim 4 and 26 are under examination with respect to SEQ ID NO 53. Claim 7 and 9 are under examination with respect to SEQ ID NO 7 and 8.
Comment Regarding Drawings
It is noted that the Drawings filed 8/29/2022 have been accepted despite the lack of SEQ ID Nos noted below, as the required sequence identifiers may be added to the specification (i.e. replacement of the drawing itself is not required if the SEQ ID Nos are added to the description of the figure).
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claims 14 and 15 are objected to because of the following informalities: the claims recite “The method claim 1” which is not grammatically correct. The claims should recite “The method of claim 1”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 7 is 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 7 recites the limitation "a first of the one or more primers or probes" and “a second of the one or more primers or probes” in line 1-3 of the claim. There is insufficient antecedent basis for this limitation in the claim. Claim 7 depends from claim 5 and claim 1. Claim 1 does not require any primer or probe. Claim 5 recites a reaction mixture comprising two primer, a first and second primer but does not require any probe or one or more primer or probes.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-3, 5-6, 11-16, are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a natural phenomenon/law of nature without significantly more.
The claims recite an anbstract idea that is a mental process. Claim 1 recites diagnosing a subject with increased sensitivity to a MEK inhibitor and detecting an RAD51AP1-DYRK4 gene fusion wherein the detection indicates the subject has increased sensitivity to the MEK inhibitor and the subject is diagnosted with increased sensitivity to MEK inhibitor. The rectitation of diagnosing is a mental conclusion drawn regarding the detection of a naturally occuring gene fusion. Such detecting and diagnosing may be performed mentally and encompasses a step that can be accomplished mentally be evaluating data and using critical thinking process wherein one mentally reads information in a database or report regarding the fusion and determines sensitivity of MEK inhibitor.
The claims are directed to a law of nature. Claim 1 recites diagnosing a subject with increased sensitivity to a MEK inhibitor and detecting an RAD51AP1-DYRK4 gene fusion wherein the detection indicates the subject has increased sensitivity to the MEK inhibitor and the subject is diagnosted with increased sensitivity to MEK inhibitor. The recited relationship of the detection of RAD51AP1-DYRK4 fusion and increased sensitivity to MEK inhibitor is a natural phenomenon that exists apart from any human action. This type of correlation is a consequence of a natural process.
This judicial exception is not integrated into a practical application because the only active steps of the claim are obtaining a biological sample and detecting the gene fusion. Both of these steps are data gathering steps that constitute insignificant extra-solution activity, there are no actions required by the claims that constitute any type of application/implementation of the judicial exceptiosn recited within the claims.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the active steps of the claims, whether considered individually or in combination, constituted well-understood, routine and conventional activity before Applicant’s effective filing date (see Liu, cited below). With further regard to dependent claim 2-3, these claims simpley recite further characteristic of a naturally occuring gene fusion; no pratical application is set and nothing significantly more than a jidical exception is present in the claims. It is noted that the particular elected gene fusion E9-E2 (probe comprising SEQ ID NO 53) is a recitation of a naturally occuring fursion sequence. Claims 5-6 recite more particular types of data gathering and are routine and conventional in the art. Primers and probes were well-known, routein and conventional in the art. Claims 12-14, recite a particular type of subject and is not significnalty more than the judicial exception. Claims 15-16 recite further active steps of administering, there is no requirement that administering correspond to an implementation or application of the judicial exception. For example, the administering may be performed prior to obtaining a sample for testing.
The additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide inventive concept necessary to render the claims patient eligible. There is no combination of elements in this step that distinguishes it from well-understood, routine and conventional data gathering activity engaged in by scientists prior to applicant’s invention and at the time the application was filed. Many cited prior art references in this record demonstrate that these techniques were conventional at the time of the invention. The prior art of Liu demonstrate detecting RAD51AP1-DYRK4 and E2-E9 fusion. Thus the prior art and specification demonstrates it was routine, well-known and conventional in the art to detect gene fusion in a sample. The dependent claims do not provide significantly more to the claims outside of the judicial exception as they encompass conventional techniques as described in the instant specification as noted above.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 11-14, 25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liu (2019, cited on IDS, AACR meeting 2019Mar 29-Apr3).
Liu teaches large scale analysis of breast cancer RNAseq data from TCGA. Liu teaches ER+ breast tumor tissues were screened by RT-PCR. Liu teaches tumor specific RAD51AP1-DYRK4 fusion overexpressed in luminal B tumors (claim 11-13). Liu teaches detection of RAD51AP1-DYRK4 expression (see results). Liu teaches E9-E2 chimeric fusion (see experimental design) (claim 2-3). By teaching the E9-E2 chimeric fusion of RAD51AP1-DYRK4, Liu teaches SEQ ID NO 28-33, SEQ ID NO 35, SEQ ID NO 38-51.
It is noted that independent claim 1 recites “wherein the detection indicates the subject has increased sensitivity to the MEK inhibitor and the subject is diagnosed with increased sensitivity to the MEK inhibitor”, the wherein language simply states what is indicated by the result of the detecting, as this claim language does not require steps to be performed, it is not limiting of claim scope (see MPE 2111.04). Additionally the requirement of the wherein clause are inherently met as a result of the performance of the active step of detecting a RAD51AP1-DYRK4 gene fusion in the sample and the diagnosis referenced in the wherein clause and preamble constitute instructional limitations added to a method known in the art, i.e. non-functional descriptive material that is not given patentable weight (see MPEP 2111.05). Furthermore the recitation in the preamble of “diagnosing a subject” in the context of the present claim does not result in a manipulative difference (such that patentable weight is not given), as the recitation “subject is diagnosed” simply states a conclusion regarding the subject that results from the active “detecting” of the claim (see MPEP 2111.02(II)).
Claims 25 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhuo (US2017009304, cited on IDS).
Zhuo teaches a set of isolated polynucleotides encoding a fusion transcript (see para 6). Zhuo teaches the sequence comprises SEQ ID NO 882561 which comprises SEQ ID NO 53. Additionally, nucleotides 1-74 of SEQ ID NO 882561 comprises nucleotides 1-74 of SEQ ID NO 38 (exon 9 of RAD51AP1) and nucleotides 75-99 of SEQ ID NO 882561 comprise nucleotides 150-126 of SEQ ID NO 35 (exon 2 of DYRK4). Zhou teaches obtaining a sample and detecting fusion in cancer patients (see para 39).
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 1-7, 9, 11-14, 25-27 are rejected under 35 U.S.C. 103 as being unpatentable over Chinnaiyan (US20130096021 A1) in view of Liu (2019, cited on IDS).
Chinnaiyan teaches methods of cancer diagnosis and therapy by detecting gene fusions as diagnostic markers in breast cancer (see para 10). Chinnaiyan teaches a probe that detects the gene function, a pair of primers that amplify the fusion junction, a first primer that hybrids to a 5’ member and a second primer that hybridizes to the 3’ member of the gene fusion (see para 11). Chinnaiyan teaches the reagent is labeled (see para 11). Chinnaiyan teaches a step of determining the fusion and determining the treatment course based on the presence or absence of the gene fusion in breast cancer (see para 12). Chinnaiyan teaches obtaining samples from a subject including fluid and tissues (see para 54). Chinnaiyan teaches detection of gene fusion by hybridization or amplification (see detection methods). Chinnaiyan teaches a method of detecting gene fusion in a sample from a breast cancer patient. Chinnaiyan teaches probes specific for gene fusion point, detection by primers that are complementary to the 5’ and 3’ gene fusion point, and detection by a detectable label. Chinnaiyan does not teach detection of the gene fusion, RAD51AP1-DYRK4 or luminal B tumors.
However, RAD51AP1-DYRK4 gene fusion is a known gene fusion in breast cancer. Liu teaches large scale analysis of breast cancer RNAseq data from TCGA. Liu teaches ER+ breast tumor tissues were screened by RT-PCR. Liu teaches tumor specific RAD51AP1-DYRK4 fusion overexpressed in luminal B tumors. Liu teaches detection of RAD51AP1-DYRK4 expression (see results). Liu teaches E9-E2 chimeric fusion (see experimental design). By teaching the E9-E2 chimeric fusion of RAD51AP1-DYRK4, Liu teaches SEQ ID NO 28-33, SEQ ID NO 35, SEQ ID NO 38-51.
In view of the teaching of Liu, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have modified the method of Chinnaiyan to include analysis of additional known gene fusions including RAD51AP1-DYRK4 in breast cancer patients. The skilled artisan would have been motivated with an expectation of success to include analysis of additional known gene fusions, including RAD51AP1-DY4K4 because both Chinnaiyan and Liu teach gene fusions in breast cancer patients, including luminal B breast cancer patients and teach the use of gene fusions for guiding therapy.
In performing the method of Chinnaiyan in view of Liu, the ordinary artisan would have designed primers and probes to known sequences, including primers to detect a known gene fusion based on the teaching of Chinnaiyan for primer and probe detection for gene fusions. Additionally designing primers and probes which are equivalent to those taught in the art is routine experimentation. The prior art teaches the parameters and objectives involved in the selection of oligonucleotides that function as probes and primers, see Chinnaiyan. Moreover there are many intranet web sites that provide free downloadable software to aid in the selection of primers drawn from genetic data recorded in a spreadsheet. The prior art is replete with guidance and information necessary to permit the ordinary artisan in the field of nucleic acid detection to design primer and probes. As discussed above, the ordinary artisan would have been motivated to have designed and tested new primers and probes to obtain additional oligonucleotides that would function to detect RAD51AP1-DY4K4 and identify oligonucleotides with improved properties. The ordinary artisan would have a reasonable expectation of success of obtaining probes and primers for the gene fusion, RAD51AP1-DY4K4 and E9-E2 as this gene fusion is taught by Liu. Thus for the reasons provided above, the ordinary artisan would have designed additional probes, including SEQ ID NO 53 and primer SEQ ID NO 7 and 8, using the teaching in the art at the time the invention was made.
It is noted that independent claim 1 recites “wherein the detection indicates the subject has increased sensitivity to the MEK inhibitor and the subject is diagnosed with increased sensitivity to the MEK inhibitor”, the wherein language simply states what is indicated by the result of the detecting, as this claim language does not require steps to be performed, it is not limiting of claim scope (see MPE 2111.04). Additionally the requirement of the wherein clause are inherently met as a result of the performance of the active step of detecting a RAD51AP1-DYRK4 gene fusion in the sample and the diagnosis referenced in the wherein clause and preamble constitute instructional limitations added to a method known in the art, i.e. non-functional descriptive material that is not given patentable weight (see MPEP 2111.05). Furthermore the recitation in the preamble of “diagnosing a subject” in the context of the present claim does not result in a manipulative difference (such that patentable weight is not given), as the recitation “subject is diagnosed” simply states a conclusion regarding the subject that results from the active “detecting” of the claim (see MPEP 2111.02(II)).
Claims 15-24 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (2019, cited on IDS) in view of Infante (European J of Cancer, 2013, 49:2077-2085) and De (Cancer Res, 2012, 72, P6-04-11, pp 1)
Liu teaches large scale analysis of breast cancer RNAseq data from TCGA. Liu teaches ER+ breast tumor tissues were screened by RT-PCR. Liu teaches tumor specific RAD51AP1-DYRK4 fusion overexpressed in luminal B tumors. Liu teaches detection of RAD51AP1-DYRK4 expression (see results). Liu teaches E9-E2 chimeric fusion (see experimental design). By teaching the E9-E2 chimeric fusion of RAD51AP1-DYRK4, Liu teaches SEQ ID NO 28-33, SEQ ID NO 35, SEQ ID NO 38-51. Liu does not teach administering a therapeutically effective amount of a MEK inhibitor, including trametinib.
MEK inhibitors to treat cancer were known in the art. Infante teaches treating solid tumors with trametinib. Infante teaches one patient with triple negative breast cancer who had received multiple prior anticancer regiments received trametinib and achieved partial response at first disease assessment and complete response at second assessment (see pg. 2082, 1st column). De teaches development of resistance to endocrine therapy is a clinical issue in ER+ breast cancer. De teaches combination of PIK-AKT-mTOR and MEk inhibitors should be effective in abrogating aromataste-inhibitor resistance in ER+ breast cancer.
It would have been prima facie obvious to include MEK inhibitor, including trametinib in the method of Liu because Liu teaches aggressive ER+ breast cancer population because Infante teaches trametinib achiever complete response in an aggressive form of breast cancer and De teaches the use of MEK inhibitors are effective in aggressive ER+ breast cancer. The ordinary artisan would have been motivated with an expectation of success to administer trametinib to patients with cancer, including patients with breast cancer and gene fusion, RAD51AP1-DYRK4. De and Infante teach MEK inhibitors, including trametinib are effective in treating aggressive cancers, including breast cancer and Liu teaches the presence of the gen fusion, RAD51AP1-DYRK4 is present in aggressive breast cancer patients.
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.
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/SARAE L BAUSCH/Primary Examiner, Art Unit 1699