FINAL ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is responsive to the Amendments filed 23 December 2025 and 22 May 2026. Claim 17 has been amended, claims 1-16 and 18 have been canceled, and claims 27-34 have been added. All prior rejections of claims 1-3, 5-8, and 12-16 are moot in view of the cancelation of those claims. Claims 25-26, 29, and 32-34 remain/are withdrawn, and claims 17, 19-21, 27-28, and 30-31 are under consideration herein. Applicant’s amendments and arguments have been thoroughly reviewed, and the rejection of claim 19 under 35 USC 112(b), in view of the amendment of independent claim 17 such that the terminology in claim 19 finds basis in claim 17. Additionally, Applicant’s amendments to the specification/substitute specification filed 22 May 2026 have overcome the remaining issues related to compliance with the sequence rules (see also the Interview Summary mailed 15 April 2026 and Applicant’s remarks of 22 May 2026).
Claims 17, 20-21, 27-28, and 30-31 remain rejected for the reasons given below, which include new grounds of rejection necessitated by Applicant’s amendments. Claim 19 is objected to (see paragraph 9 below). Any rejections and/or objections not reiterated in this action have been withdrawn. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
Applicant’s election without traverse of the species of the E4-E2 fusion comprising SEQ ID NO: 22 and the primer pair of SEQ ID NO: 3 and SEQ ID NO: 4 in the reply filed on 23 September 2025 is again acknowledged. Claims 17, 19-21, 27-28, and 30-31 are currently under consideration herein as directed to the elected species.
Claims 25-26, 29, and 32-34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 25 September 2025.
Claim Interpretation
Regarding claim 17 and claims dependent therefrom, it is noted that the reference to “step a.” in line 5 has been interpreted as referring back to the previously recited activity of “a. detecting…..” (such that an indefiniteness issue is not raised, despite the lack of prior use of the term “step”; however, please see also the objection below).
Also regarding claim 17 and claims dependent therefrom (and with particular reference to new dependent claims 27 and 30-31), it is noted that the limitation “the detection” in a) of claim 1 has been interpreted as referring to the “detecting” of a) of the claim, as this is the only reasonable interpretation of the claim language (and similarly the limitation “the detection” in claim 27 is also interpreted as referring back to and further limiting this “detecting”). It is also noted that the specification states that (see paragraph 85 of the corresponding published application):
As used herein, the term “detecting” refers to detection of a level of a fusion (e.g., the fusion of a BCL2L14 polynucleotide sequence and a ETV6 polynucleotide) that is at least about 5% (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 2000%, at least about 3000%, or at least about 5000%) or at least about 5 times (e.g., at least about 6 times, at least about 7 times, at least about 8 times, at least about 9 times, at least about 10 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, or at least about 100 times) higher as compared to a sample from a subject in general or a study population (e.g., healthy control).
Based on this definition as well as the language of the claims and the content of the specification as a whole (in which the term “detecting” is employed only in reference to physical/active types of “detecting” nucleic acid or protein products), the term “detecting a BCL2L14/ETV6 gene fusion in the/a sample” has been interpreted as requiring the detecting of the physical presence of such a fusion in a (biological) sample at a level that is “at least about” 5% or 5 times higher “as compared to a sample from a subject in general or a study population”.
Claim Objections
Claims 17, 19-21, 27-28, and 30-31 are objected to because of the following informalities: claim 17 includes recitation of a period within the body of the claim, specifically in the limitation “step a.”. As discussed in MPEP 608.01(m), periods may not be used within the body of the claim (except as part of abbreviations). Appropriate correction is required; it is suggested that Applicant simply amend the claim to recite “a)” in lieu of “a.” (as well as “b)” in lieu of “b.”, in the interest of consistency).
Claim Rejections - 35 USC § 112(b)/second paragraph
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claims 27 and 30-31 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.
Claims 27 and 30-31 are indefinite over the recitation in claim 27 of the limitation "the biological sample" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim, because claim 17, from which claim 27 depends, references a “sample”, but not a “biological sample”. It is not clear whether the recitation of “the biological sample” in claim 27 is simply a reference to the “sample” of claim 17, or whether the method of claims 27 and 30-31 require another type of sample (a “biological sample”). Further clarification is therefore required to ensure that the boundaries of the claims are clear.
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.
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claim(s) 17, 20-21, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Chinnaiyan et al (US 2013/0096021 A1 [18 April 2013; filed 27 Sept. 2012]; cited in IDS) in view of Nik-Zainal et al (US 2019/0345562 [14 Nov 2019; filed 22 Dec 2017]; previously cited).
Chinnaiyan et al disclose methods of detecting gene fusions “as diagnostic markers and clinical targets for breast cancer” (see entire reference, particularly the Abstract and Summary at paragraphs 10-12). Among the methods taught by Chinnaiyan et al are methods comprising performing a nucleic acid (or protein) detection assay on a biological sample from a subject to detect/identify a BCL2L14-ETV6 fusion, which methods may further comprise determining a “treatment course of action based on the presence or absence of the gene fusion”, and administering an inhibitor targeting the fusion when detected (see paragraphs 12, 63, 184 [noting the reference to Table 1], claims 10-14, and Tables 1, 4-5, and 10).
With further regard to the “detecting” of a) of independent claim 17, as well as the recitations of breast cancer/triple negative breast cancer in claims 20-21, Chinnaiyan et al teach that samples for use in their methods may be obtained from any source, including preferred samples of breast biopsy samples or other breast tissue samples (see, e.g., paragraphs 54 and 78-79). Chinnaiyan et al further teach a variety of well-known methods that may be applied to detecting their disclosed gene fusions, including nucleic acid sequencing, hybridization, amplification, etc. (see, e.g., paragraphs 80-110), and disclose performing their methods on biological samples from subjects with triple negative breast cancer (see paragraphs 58, 181, and 184 [noting the reference to Table 1], as well as paragraph 192); it is also noted that Table 1 reports detection of a BCL2L14-ETV6 fusion in a triple negative breast cancer tumor (see Table 1, and see also Example 2 at Table 10). Regarding the recitation “wherein the detection indicates the subject has increased resistance to a paclitaxel”, this “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 MPEP 2111.04). Additionally, the requirements of this “wherein” clause are inherently met as a result of the performance of the active step of “detecting a BCL2L14/ETV6 gene fusion in a sample obtained from the subject” of a).
Chinnaiyan et al do not teach an “administering” meeting the requirements of claim 17 and its dependent claims. Further, Chinnaiyan et al do not disclose detecting an “E4-E2 fusion” (i.e., the elected species of fusion), as is now recited in independent claim 17 (and new dependent claim 28).
Nik-Zainal et al teach detection and classification of breast (and ovarian) cancers as deficient in homologous repair (“HR-deficient”) based on the detection of “rearrangement signatures” that occur as “hotspots” in the cancer genome (see entire reference, particularly the Abstract and the Summary at paragraphs 4-5). Nik-Zainal et al teach that detection of such rearrangement signatures may “inform decisions on treatment, since some agents are more effective against” such cancers (paragraph 4; see also paragraphs 11-15). Regarding the elected E4-E2 fusion construct, Nik-Zainal et al teach a breast cancer rearrangement signature hotspot, “B4”, that includes both BCL2L14 and ETV6; see paragraphs 65, 77, 87-107, and Table 1 at page 20, noting that Nik-Zainal et al generally disclose testing for any possible rearrangements/fusions/ breakpoints involving their disclosed hotspots. Among the types of treatments taught by Nik-Zainal et al as exhibiting greater efficacy against HR-deficient cancers – i.e., those characterized by the “hotspots” discussed by Nik-Zainal et al - as compared to HR-proficient cancers are administration of the PARP inhibitors olaparib and talazoparib, and the platins carboplatin and cisplatin, i.e., therapies as specified in b) of independent claim 17 (see, e.g., paragraphs 128-132).
In view of the teachings of Chinnaiyan et al and Nik-Zainal et al, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed a method of treating breast cancer, including triple negative breast cancer, comprising a “detecting” and “administering” as set forth in amended independent claim 17 (which methods further meet the requirements of dependent claims 20-21 and 28). While neither of the references explicitly reports detecting such an E4-E2 fusion in particular, the teachings of Chinnaiyan et al establish that fusions of BCL2L14/ETV6 occur in the context of triple negative breast cancer, and Nik-Zainal et al disclose grouping these two genes together in a breast cancer rearrangement signature “hotspot”, which would have motivated one of ordinary skill in the art to have conducted detection/testing with regard to any such fusion (including an E4-E2 fusion as set forth in claims 17 and 28), regardless of the specific fusion points involved (and given the detailed guidance of both references, an ordinary artisan also would have had a reasonable expectation of success in detecting any such fusions). An ordinary artisan would have been motivated to have conducted such “detecting” for the benefit of characterizing the specific genetic structure(s) underlying a subject’s breast cancer, thereby facilitating, e.g., more appropriate treatment of the subject (as is suggested by both the teachings of Nik-Zainal et al and the teachings of Chinnaiyan et al). Further, given thecancer rearrangement signature hotspot, “B4”, that includes both BCL2L14 and ETV6 - it also would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the methods suggested by Chinnaiyan et al and Nik-Zainal et al so as to have employed any of these known breast cancer therapies in treating such subjects, and thereby to have performed methods meeting all the requirements of the claims. An ordinary artisan would have been motivated to have made such a modification for the benefit of more appropriately treating the cancer/breast cancer/triple negative breast cancer of a subject exhibiting a BCL2L14/ETV6 fusion, as is suggested by the teachings of both references.
Applicant traverses the prior rejection of claims based on the same combination of references on the following grounds.
The reply summarizes the rejection and the factual inquiries that guidance an obviousness determination (Reply page 7), as well as rationales that may support a conclusion of obviousness (Reply page 7 bridging to page 8). Applicant argues that the examiner’s rejection relies on an “obvious to try” rationale, requiring the Office to establish “finite number of identified, predictable solutions, with a reasonable expectation of success” (Reply page 8). The Reply also summarizes what is required by amended independent claim 17 (Reply page 8 bridging to page 9), and argues that the cited art fails to teach increased paclitaxel resistance, the claimed fusion and associated paclitaxel resistance, and administering a taxane alternative (Reply page 9).
These arguments have been thoroughly considered but are not persuasive. Initially, it is noted that the new limitations of amended independent claim 17 are addressed above in the rejection of that claim (which addresses each of the limitations noted in Applicant’s traversal, including the “wherein” language related to paclitaxel resistance and administration of a taxane alternative). Further, the rejection does not simply rely on an “obvious to try” rationale; rather, the references themselves teach and suggest recombination between the two genes in question in association with breast cancer, with Chinnaiyan et al reporting detection of a BCL2L14-ETV6 fusion in a triple negative breast cancer tumor, and Nik-Zainal et al’s teaching an HR-deficient breast cancer rearrangement signature hotspot, “B4”, that includes both BCL2L14 and ETV6 (as discussed in the rejection). While the examiner agrees that specific fusion constructs are not disclosed by the cited references – it is noted that those claims reciting such specific constructs (e.g., claim 19) as well as specific primers (claims 30-31) have not been rejected over the prior art – given the guidance and specific teachings of the references, the invention as claimed would have been obvious to an ordinary artisan before the effective filing date of the claimed invention (and with further regard to the issue of a “finite number” of identified predictable solutions, while there would clearly be a large number of possible fusions between the two genes in questions, that number is in fact finite, and any such fusions could also be readily predicted and identified with a reasonable expectation of success [for example by sequencing and sequence comparisons]). Accordingly, these arguments are not found persuasive with regard to claims 17, 20-21, and 28.
Claim(s) 27 is rejected under 35 U.S.C. 103 as being unpatentable over Chinnaiyan et al in view of Nik-Zainal et al, as applied to claims 17, 20-21, and 28, above, and further in view of Reeve et al WO9947706A1 [Sept 1999]; previously cited).
The relevant teachings of Chinnaiyan et al and Nik-Zainal et al are set forth above. While Chinnaiyan et al teach a variety of methods that may be employed in detecting their disclosed fusions, including nucleic acid sequencing (as noted above), Chinnaiyan et al do not teach a detecting/detection that employs a reaction mixture including primers meeting the requirements of (new) claim 27.
Reeve et al teach compositions, including arrays, comprising all possible “N mer” oligonucleotides or subsets thereof “where N is preferably from 5 to 10, particularly 8 or 9” (see entire reference, particularly pages 4-5; quotation from page 5, lines 10-11). Reeve et al teach that their N mers may be DNA, RNA, PNA or “mimetics or mixtures thereof” (see page 5, lines 12-13), and state that the molecules may be in solution (page 4) or "immobilised at a spaced location on a surface of a support” (page 5). Reeve et al disclose the use of their reagents in sequencing by hybridization, and particularly in determining difference between target and reference sequences (see entire reference, particularly, e.g., pages 2-3). The method disclosed by Reeve et al comprises incubating together "under hybridisation conditions" target nucleic acid obtained from a sample and an oligomer composition of Reeve et al to determine the nucleic acid sequence of a target (see pages 2-7). Further, the compositions of Reeve et al encompass, e.g., the use of all possible 10mers, such that the compositions of Reeve et al inherently include multiple primers meeting the requirements of claim 27 (as the claims simply require primers “complementary to” the recited target sequences). The sequencing method of Reeve et al thus includes the use of primers meeting the requirements of applicant’s claims. It is also noted that Reeve et al disclose embodiments of their invention in which target sequences are amplified using compositions of labeled Nmers (see, e.g., pages 3-4), as well as embodiments of their methods in which each of their oligonucleotides includes a label, and in which the labeled oligonucleotides are hybridized and the labels subsequently observed and measured (see, e.g., pages 2-3 and 5-6).
In view of the teachings of Reeve et al, 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 et al so as to have substituted the sequencing method of Reeve et al for that taught by Chinnaiyan et al, and thereby to have performed a method meeting the requirements of instant claim 27. As both the sequencing methodologies taught by Chinnaiyan et al and that taught by Reeve et al were sequencing methods known to those of ordinary skill in the art at the time the invention was made, an ordinary artisan would have recognized such a modification as the simple substitution of one known sequencing technique for another to achieve the predictable result of sequencing (and thereby identifying and detecting) the target fusions taught by Chinnaiyan et al.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DIANA B JOHANNSEN whose telephone number is (571)272-0744. The examiner can normally be reached Monday-Friday, 7:30 am-3:30 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached at (571) 272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682
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