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 .
Status of Claims
Applicant’s amendment filed 06/26/2026 is acknowledged. Claims 23-24 and 27-29 have been amended. Claims 1-22, 25-26, and 30-63 have been cancelled. Claims 23-24 and 27-29 are pending in the instant application and the subject of this non-final office action.
Claim Objections
Claims 27 and 29 are objected to because of the following informalities:
Claim 27: On pg. 7, near the bottom, the claim recites “the probe … fusion of PV ALB”. This should read “the probe … fusion of PVALB” without the space in the gene name.
Claim 29: At the top of pg. 11, the claim recites “The nucleic acid … probe, primer … fusion of CD44 with NRG1 … has 95% or more complementary sequence with… a sequence comprised SEQ ID NO: 158”. SEQ ID NO: 158 appears to be a typo (it is a protein sequence).
Claims 27 and 29: The claims recite “a sequence comprised by …”. Each occurrence of this phrase should be changed to “a sequence within …” or similar.
Appropriate correction is required.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP 2111.
Regarding claim 23, the “detection assay” has been interpreted as a detection assay kit as only structures have been recited in the claims.
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.
Claim 23-24 and 27-29 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.
Regarding claim 23, the claim recites “A detection assay comprising a probe, primer, or primer pair for detection of a fusion comprising … a portion of exon 5 of CD44, or allelic variant of exon 5, and a portion of exon 2 of NRG1, or an allelic variant of exon 2 ...”.
The term “a portion” renders the claim indefinite because the preamble limitation reciting the portions that must be detected acts as a functional limitation on the probe or primer(s), and it is unclear how much, i.e., the scope of the target sequence(s) must be capable of being detected by the claimed structure in order to meet the limitation of the claim. See MPEP 2173.05(g), which recites that the use of functional language in a claim may fail “to provide a clear-cut indication of the scope of the subject matter embraced by the claim” and thus be indefinite.
Claims 24 and 27-29 are indefinite for depending on claim 23 and not rectifying the deficiency.
Regarding claim 24, the claim recites “the fusion as detected comprises: the fusion of … with … comprising or consisting of SEQ ID NO …, and preferably includes the nucleic acids at positions …”.
First, the term “preferably” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed inventions.
Second, it is unclear what the positions are in reference to. For example, the fusion of CD44 with NRG1 comprising or consisting of SEQ ID NO: 11, is 110 nucleotides long. Under an interpretation of preferably as “optionally”, it is unclear how the fusion is intended to optionally include positions 52 and 53 while comprising or consisting of the entire sequence. If, in contrast, the nucleic acid probe, primer, or primer pair is intended to include the two nucleic acids, the claim does not currently recite this.
Claims 27-29 are indefinite for depending on claim 24 and not rectifying the deficiency.
Regarding claim 27, the claim recites “specifically hybridizes to, or has 95% or more complementary sequence identity with, a sequence comprised by exon … from …, or a sequence located 5’ of exon … and/or to a sequence comprised by exon … from …, or a sequence located 3’ of exon …”.
First, because the claim restates the “to” following the “and/or” it is unclear whether the third and fourth listed sequence options may only specifically hybridize or may also have 95% or more complementary sequence identity with.
Second, the recitation the regions with “or”, “and/or”, “or” renders the claim unclear. In particular, it is not clear whether the “and/or” extends only to the “a sequence located 5’ of exon … and/or to a sequence comprised by exon … from …” (as would be implied by the commas) or whether the “and/or” is intended to encompass both sets of the “or” pairs such that the artisan may choose to combine an “and” of, for example, a sequence comprised by the first exon and a sequence 3’ of the second exon and meet the limitation of the claim.
Claims 28 is indefinite for depending on claim 27 and not rectifying the deficiency.
Regarding claim 29, the claim recites “specifically hybridizes to, or has 95% or more complementary sequence identity with a sequence comprised by SEQ ID NO … and/or to a sequence comprised by …”. As in claim 27, it is unclear whether the 95% or more complementary sequence is intended to apply only to the first region or to both regions given, at least, the second “to”.
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.
Claims 24 and 27-29 are 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. 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.
Regarding claims 24 and 27-29, claim 24 recites “The nucleic acid probe, primer or primer pair for detection of a polynucleotide fusion according to claim 23, wherein the fusion as detected comprises …”. Claim 23, in contrast, recites “A detection assay comprising a nucleic acid probe, primer or primer pair for the detection of the prices of a polynucleotide fusion comprising … a portion of exon 5 of CD44 … and a portion of exon 2 of NRG1 …”.
Claims 27 and 27-29 fail to require each of the limitations of the claim upon which they depend because they do not require that the nucleic acid probe, primer, or primer pair be a part of a detection assay.
For this reason, the claims fail to comply with 112(d).
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 23-24 and 27-29 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) without significantly more. The claim(s) recite(s) natural product(s). This judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The following three inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter?
Yes, the claims are directed to a product (composition of matter).
Step 2A, prong 1. Does the claim recite a law of nature, a natural phenomenon, or an abstract idea (recognized judicial exceptions)?
Yes, the claims each recite a natural phenomenon/natural product under the broadest reasonable interpretation.
Claim 23 recites a detection assay (interpreted as a product/kit) comprising a nucleic acid probe, primer, or primer pair with the intended use limitation that it must be for the detection of particular gene fusions or allelic variants thereof. As has been established in the courts, see MPEP 2106.04(c)(II)(A), the appropriate counterparts for primers and probes are corresponding segments of the naturally occurring gene sequence. The intended use limitation may act as a functional limitation that imparts a structural constraint (e.g., a primer must be within an amplifiable range given the known limitations of polymerases to enable detection of such a fusion, if using DNA as a template or a probe must be, broadly, within that region of the chromosome).
Claims 24 and 27-29 recite a nucleic acid probe, primer, or primer pair according to claim 23 also directed to detect particular gene fusions. Claims 27-29 recite regions of the genes, or SEQ ID NOs thereof, that the probe or primer(s) must be able to specifically hybridize to or have a level of complementary sequence identity with.
By reciting nucleic acid products directed to bind to regions encompassed by the human genome (e.g., pg. 9, para 3), the claims recite a natural product. See MPEP 2106.04(b)(II) discussing naturally and non-naturally occurring products that lack markedly different characteristics from any naturally occurring counterpart: Ambry Genetics, 774 F.3d at 760, 113 USPQ2d at 1244 ("Contrary to Myriad's argument, it makes no difference that the identified gene sequences are synthetically replicated. As the Supreme Court made clear, neither naturally occurring compositions of matter, nor synthetically created compositions that are structurally identical to the naturally occurring compositions, are patent eligible.").
In the instant case, the probe or primer(s) are directed to sequence(s) capable of binding to the genome or a transcript such that the gene fusions could be detected.
As discussed in MPEP 2106.04(c)(II)(C)(2): In Ambry Genetics, the court identified claimed DNA fragments known as "primers" as products of nature, because they lacked markedly different characteristics. Because the characteristics of the claimed primers were innate to naturally occurring DNA, they lacked markedly different characteristics from nature and were thus product of nature exceptions.
Where a probe and/or primer(s) may overlap a gene fusion that is due to the naturally occurring phenomenon of translocations such that the underlying gene fusion would also be reflected in a cell’s genome/transcriptome, such probe and/or primer(s) would remain a natural product.
Step 2A, prong 2. Is the judicial exception(s) integrated into a practical application?
No, the judicial exception is not integrated into a practical application. None of claims 23-24 or 27-29 require additional elements beyond the probe or primer(s).
Step 2B. Does the claim amount to significantly more?
No, the claims do not amount to significantly more.
As recited in MPEP 2106.05(I), an inventive concept "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself." Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016).
None of claims 23-24 or 27-29 require additional elements beyond the probe or primer(s), which are natural products.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 23-24 and 27-29 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Blume (US 2005/0244851 A1; published 11/03/2005).
Regarding claims 23-24 and 27-29, Blume teaches nucleic acids probes that have 100% sequence identity to, i.e., specifically hybridize to, sequences within instant SEQ ID NO: 130 (i.e., exon 6 of NRG 1 as defined by claim 28), including Blume SEQ ID NO: 4858472; 3’ of instant SEQ ID NO: 130/NRG1 exon 6 relative to instant SEQ ID NO: 155, including Blume SEQ NO: 4858522; within instant SEQ ID NO: 65 (i.e., exon 5 from CD44, as defined in claim 28), including Blume SEQ ID NO: 3398155; 5’ of instant SEQ ID NO: 65/CD44 exon 5 relative to instant SEQ ID NO: 99, including Blume SEQ ID NO: 3398099. See alignment visualization in Appendix A.
As claim 29 recites the structures that the probe for detection of the fusion of CD44 with NRG1 specifically hybridizes to, or has 95% or more complementary sequence identity with, a sequence comprised by SEQ ID NO: 99 and/or to a sequence comprised by SEQ ID NO: 155 and Blume teaches probes that encompass each of these regions, these probes are interpreted as being capable of detecting such fusions.
It is further noted that claim 27 recites that the probe may specifically hybridize to a sequence located 5’ of exon 5 (of CD44) and/or to a sequence located 3’ of exon 6 (of NRG1), which as discussed above, is taught by Blume, and is also interpreted as being able to detect such fusions.
As such, as each and every limitation of claims 23-24 and 27-29 is taught by Blume, the claims are anticipated by Blume.
Claims(s) 23-24 and 27-29 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Kohno (US 2015/0057335 A1; published 01/26/2015; as cited on the IDS dated 06/26/2026)
Regarding claims 23-24 and 27-29, Kohno teaches a kit for detecting a fusion gene comprising polynucleotides designed to enable specific amplification of a CD74-NRG1 or a SLC3A2-NRG1 fusion polynucleotide (para [0561]).
Kohno teaches the primer SEQ ID NO: 18 (Table 1), which aligns, as shown below, within instant SEQ ID NO: 155.
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251
1739
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Greyscale
As the claims, in their narrowest form, require a primer that specifically hybridizes to SEQ ID NO: 155, where NRG1 is chosen and the primer is taught for the detection for a fusion gene, it is understood to be capable of detecting a CD44-NRG1 fusion gene. Such would also be understood as meeting the limitations of the kit in claim 23 that requires a primer for the detection of the presence of fusions with a portion of exon 6 of NRG1.
As each and every limitation of claims 23-24 and 27-29 is taught by Kohno, the claims are anticipated by Kohno.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 23-24 and 27-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-9, 11-15, 16-26 of copending Application No. 18566980 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 23 of ‘980 recites a kit for determining the presence or absence of an NRG1 fusion polynucleotide in a liquid biopsy sample comprising (a) a pair of forward and reverse polynucleotide primers which specifically hybridize to the NRG1 fusion polynucleotide and/or (b) a polynucleotide probe which specifically hybridizes to the NRG1 fusion polynucleotide.
‘980 claim 13 recites a method for determining the presence or absence of an NRG1 fusion polynucleotide in a sample … wherein the presence or absence of the NRG1 fusion polynucleotide is determined by sequencing the NRG1 fusion polynucleotide or using a polynucleotide probe which specifically hybridizes to the NRG1 fusion polynucleotide.
‘980 claim recites that the NRG1 fusion polynucleotide is a CD44-NRG1 fusion polynucleotide which comprises the sequence of SEQ ID NO: 469 or a fragment comprising at least 20 contiguous nucleotides of SEQ ID NO: 469, including at least the positions of SEQ ID NO: 469.
As shown in Appendix B, ‘980 SEQ ID NO: 469 the 5’ and 3’ portions are, respectively, comprised by instant SEQ ID NO: 99 and instant SEQ ID NO: 155.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized a polynucleotide probe that is designed to specifically hybridize to the sequence of SEQ ID NO: 469 (i.e., the inner regions of instant SEQ ID NO: 99 and SEQ ID NO: 155), as such is taught as suitable for the same purpose as the probes of the kit. There would have been a strong expectation for success as the kit and method are taught for the same purpose, for the same NRG1 fusions, and utilize the same class(es) of oligonucleotides.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
van Dongen (van Dongen JJ, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia. 1999 Dec;13(12):1901-28) teaches designs and testing (i.e., optimization) of primers for RT-PCR detection of a variety of fusion gene transcripts (entire document, e.g., Abstract).
Skotheim (Skotheim RI, et al. A universal assay for detection of oncogenic fusion transcripts by oligo microarray analysis. Mol Cancer. 2009 Jan 19;8:5) teaches using oligonucleotide microarrays to screen all known oncogenic fusion transcripts in a single experiment using exon-wise measurements of individual fusion partners with an array of oligonucleotide probes that includes all combinations of exon-exon junctions (Abstract). Skotheim teaches that this microarray method enables objective and automated genome-wide analysis in which all known as well as predicted fusion genes are assessed without requiring any a priori knowledge as to the likelihood of the clinical or genetic diagnosis (pg. 4, Discussion, para 1). Skotheim teaches that scaling up to include all known fusion genes as well as sets of novel candidate genes can easily be achieved (pg. 4, Discussion, para 3, spanning pg. 8).
Skotheim also teaches a chimeric probe set (pg. 4, col 2, para 1; Fig. 2B and 3B).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Emma R Hoppe whose telephone number is (703)756-5550. The examiner can normally be reached Mon - Fri 11:00 am - 7:00 pm.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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