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 .
Effective Filing Date
The present application, filed on December 10, 2021, is a 371 of PCT/CN2019/094956, filed on July 6, 2019. Therefore, the effective filing date of the present application is determined to be July 6, 2019.
Election/Restrictions
Newly submitted claims 31 and 32 are directed to inventions that lack unity with the invention originally claimed for the following reasons:
The compositions (products) recited by claims 31 and 32 lack unity with the methods originally claimed because there is no shared technical feature between all of the claims as amended. Claims 31 and 32 recite a composition comprising an isolated mixture of: “at least two primer pairs” (claim 31) or “at least two primer pairs and their corresponding TaqMan probes” (claim 32). In contrast, claim 14 appears to require using all four primer pairs (see new 112(b) rejection below.
In the alternative case wherein claim 14 is interpreted as requiring using at least two of the four primer pairs (i.e. a shared technical feature with claims 30 and 31), unity is lacking a posteriori, as a combination of two of the four primer pairs does not make a contribution over the prior art. As described in the July 15, 2025 rejections of record, Zhang et al. teach primers and probes for SCT hypermethylation that are identical to the claimed SEQ ID NOs: 4-8 (Zhang et al., Table S16 and below). Zhang et al. additionally teach that HOXA9 hypermethylation is a lung cancer biomarker that performs similarly well to SCT (Zhang et al., page 357, column 1, paragraph 2). Lin et al. teach primers for HOXA9 hypermethylation that are identical to the claimed SEQ ID NOs: 5-6. Further, Tsou et al. teach “In lung cancer patients, hypermethylation is quantitatively detectable in a variety of samples ranging from tumor material to blood and sputum. However, to date [~2007] the penetrance of DNA methylation at any single locus has not been high enough to provide great clinical sensitivity… markers should be developed individually… combined into a lung cancer hypermethylation panel that can be used for detection of all lung cancers” (Tsou et al., page 2, column 2, paragraph 1). Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have prepared a composition for diagnosing lung cancer by detecting DNA hypermethylation comprising the claimed primers and probes taught by Zhang et al. and Lin et al. because of the teaching of Lin et al. that combining well performing hypermethylation markers of lung cancer would provide for an improved panel comprising a small number of genes with improved sensitivity, specificity, and detection of all stages of lung cancer (Tsou et al., page 2, column 2, paragraph 1).
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, newly added claims 31 and 32 are withdrawn from consideration as being directed to product claims, a nonelected Group II invention; whereas claims 14-30, Group I invention, are directed to method claims currently under examination. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claim Status and Action Summary
Applicant canceled claims 1-13 in the response filed on May 27, 2025 and added new claims 14-30. Claims 31 and 32 are newly added in the response filed October 15, 2025 and are withdrawn as being drawn to a non-elected invention (see Election/Restriction section above). Claims 14-30 are under examination.
Any objections and rejections not reiterated below are hereby withdrawn.
The objections to the specification have been withdrawn in view of the amended specification.
The rejection of record in the nonfinal office action dated July 15, 2025 under 35 U.S.C. 112(b) is withdrawn in view of the amendments to the claims.
The rejection of record in the nonfinal office action dated July 15, 2025 under 35 U.S.C. 102(a)(1) is withdrawn in view of the amendments to the claims. In particular, the claim 14 now requires simultaneously amplifying and detecting at least two (or in the alternative interpretation, all four) of the recited target genes (see 112(b) section) .
Claim Rejections - 35 USC § 112(a) – New Matter
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.
Claim 14 is rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim 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, at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claim 14, as amended, recites “a hypermethylation status is determined to be present if the amplification result exceeds a predetermined threshold established by Receiver Operating Characteristic (ROC) curve analysis of amplification results from a population of subjects with lung cancer and a population of subjects with benign diseases”. The response asserts that support for the claim amendments can be found in the original specification at paragraphs 0078-079 and in figures 1-4. These citations and the remainder of the specification have been thoroughly reviewed, however, no reference to this limiting claim is present in the originally filed specification. Therefore, this claim term constitutes new matter. Applicant is required to cancel the new matter in the reply to this Office Action.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following 112(b) rejections are new grounds of rejection necessitated by the amendments to the claims.
Claims 14-30 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 14 recites a step requiring: “simultaneously amplify and quantitatively detect a hypermethylation status of at least two of four target genes, the four target genes comprising HOXA9, SHOX2, SCT, and HOXA7, using [specific primers for all four of the recited target genes]”.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 14 recites the broad recitation “simultaneously amplify and quantitatively detect at least two of four target genes, the four target genes comprising…”, and the claim also recites “using [a combination of 8 primers (i.e. simultaneously amplifying and detecting all four target genes)] which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. It is unclear whether the claim is intended to be limited to the narrower embodiment wherein all four target genes are simultaneously amplified and detected using primers for all four target genes, or if the claim is intended to encompass the broader embodiment wherein at least two of the four target genes are simultaneously amplified and detected.
Claim 14 recites “four target genes, the four target genes comprising HOXA9, SHOX2, SCT, and HOXA7”. The metes and bounds of the claim are unclear, as it is unclear whether the claim is intended to be limited to the closed group consisting of “HOXA9, SHOX2, SCT, and HOXA7” or if the claim is intended to encompass an open group: “the four target genes comprising HOXA9, SHOX2, SCT, and HOXA7”. If the claimed group “the four target genes” is intended to encompass target genes in addition to the four genes required by the claim, it appears that the phrase “the four target genes” is contradictory to the scope of the group of target genes encompassed by the claim.
Claims 15-30 are rejected under 112(b) as indefinite because they depend from claim 14 and thus must include the indefinite limitations of claim 14.
Claims 27-30 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 27 recites “The method of claim 14, wherein the quantitative multiplex RT-PCR for the HOXA7 gene amplifies a target sequence comprising the nucleotide sequence of SEQ ID NO: 16.” However, the primers required by claim 14 (SEQ ID NO: 1 and 2) are primers that are complementary to a portion of bisulfite-converted sequence of the HOXA7 gene. SEQ ID NO: 16 is a portion of the naturally occurring sequence of the HOXA7 gene. Furthermore, the amplicon produced using the non-bisulfite converted equivalents of the recited primers is comprised within SEQ ID NO: 16. Therefore, the amplicon produced by the primers recited by claim 14 would not produce an amplicon with a sequence comprising SEQ ID NO: 16), as: i) SEQ ID NO: 16 encompasses all of the recited amplicon and ii) the recited primers amplify the bisulfite-converted sequence derived from SEQ ID NO: 16, rather than the recited naturally occurring sequence of SEQ ID NO: 16 (see UCSC genome browser figure below). For these reasons, the ordinary artisan would not be apprised of the metes and bounds of the claim as presently written.
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Regarding claim 28, the recited SEQ ID NO: 17 is 100% identical to a naturally occurring 1002 bp long sequence comprising a portion of the SCT gene (see below). For the same reasons as claim 27 is rejected as indefinite, claim 28 is also indefinite. In particular, the bisulfite-converted primers would not amplify a target sequence comprising the entirety of the naturally occurring sequence of SEQ ID NO: 17.
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Regarding claim 29, the recited SEQ ID NO: 18 is 100% identical to a naturally occurring 1002 bp long sequence comprising a portion of the SHOX2 gene (see below). For the same reasons as claim 27 is rejected as indefinite, claim 29 is also indefinite. In particular, the bisulfite-converted primers would not amplify a target sequence comprising the entirety of the naturally occurring sequence of SEQ ID NO: 18.
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Regarding claim 30, the recited SEQ ID NO: 19 is 100% identical to a naturally occurring 700 bp long sequence comprising a portion of the HOXA9 promoter, an intron of the HOXA10-HOXA9 gene, and the HOXA10-AS gene encoding an antisense long non-coding RNA (see below), all of which are overlapping in the hg38 genome assembly. For the same reasons as claim 27 is rejected as indefinite, claim 30 is also indefinite. In particular, the bisulfite-converted primers would not amplify a target sequence comprising the entirety of the naturally occurring sequence of SEQ ID NO: 19.
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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.
Claims 15-17 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to include all the limitations of the claim upon which it depends.
This is a new grounds of rejection necessitated by the amendments to the claims.
Claims 15-17 depend from claim 14, which requires “simultaneously amplify and quantitatively detect a hypermethylation status of at least two of the four target genes… using [primers for all four target genes]”. Claim 15 recites “the presence of a hypermethylation status of SCT is indicative of the presence of lung cancer…” (i.e. only one, not at least two of the recited genes, as required by claim 14). Claim 16 requires using a forward… and… reverse primer for SCT consisting of… SEQ ID NOs 4 and 5 (i.e. only one, not at least two of the recited genes, as required by claim 14). Claim 17 requires using a forward… and… reverse primer for SCT consisting of… SEQ ID NOs 7 and 8 (i.e. only one, not at least two of the recited genes, as required by claim 14).
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.
Claims 26-30 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends.
This rejection has been updated as necessitated by the amendments to the claims.
The claims recite intrinsic properties of the naturally occurring gene(s) required by claim 14.
Regarding claim 26, the claim requires only that “the step of performing quantitative multiplex RT-PCR targets at least one CpG island within each of the at least two of the four genes”. The presence of a CpG island which can be methylated is an intrinsic property of the recited genomic sequences. Furthermore, claim 14 requires amplifying and detecting a hypermethylation status of all of the four genes using a pair of specific primers for each of the four genes. Therefore, the requirement that the RT-PCR step targets at least one CpG island is not a further limitation upon claim 14, as claim 14 already recites amplifying and detecting the target sequences using the specific primer pairs recited by claim 14.
Similarly, claims 27-30 require only that the “quantitative multiplex RT-PCR for the… gene amplifies a target sequence comprising the nucleotide sequence of [SEQ ID NO: 16-19, respectively]”. Seq ID NO: 16-19 are the naturally occurring sequences within the genes recited by claim 14 that comprise the recited amplicons (see below, example for HOXA7). Therefore, claims 26-30 do not recite any method steps in addition to those required by claim 14, upon which claim 26 depends. Rather, these claims seem to recite intrinsic characteristics of the human genes (the nucleotide sequence of a portion of each gene) required by claim 14 and the consequence of the method steps wherein sequences are “amplified and… detected” using the primers recited by claim 14.
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Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
Response to arguments
The response asserts that claims 26-30 as amended properly depend from claim 14. The rejections above have been updated or added as necessitated by the amendment to the claims.
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 14-30 are rejected under 35 U.S.C 101 because the claimed invention is directed to non-statutory subject matter.
This rejection has been updated as necessitated by the amendments to the claims. This rejection is made over the broadest reasonable interpretation of indefinite claim 14 that requires simultaneous amplification and detection at least two of four target genes (i.e. requiring the use of at least any two of the recited primer pairs)
35 U.S.C. 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. §2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Step I
The claimed invention is directed to a process that involves a natural principle and judicial exceptions.
Step 2A Prong I
The claims are taken to be directed to a natural phenomenon and mental steps.
Claim 14 is directed to a “method of diagnosing lung cancer in a human subject” by detecting the presence of a hypermethylation status of at least two of the genes: SCT, HOXA7, SHOX2, and HOXA9.
Claim 14 is directed to a process that involves the judicial exception of a law of nature/natural phenomenon (i.e. the natural correlation between hypermethylation of a gene or genes and the presence of lung cancer in a human subject) and an abstract idea (a comparison to a control).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exceptions for the reasons that follow.
A correlation that preexists in the human is an unpatentable phenomenon. The association between the amount of DNA methylation (i.e. hypermethylation) at a particular genetic locus or loci and the presence of lung cancer is a law of nature/natural phenomenon. The “isolating”, “converting”, “performing a round of PCR”, and “detecting” steps recited by claim 14 which tell users of the process to determine the presence of lung cancer amount to no more than an “instruction to apply the natural law”. These “isolating”, “converting”, “performing a round of PCR”, and “detecting” steps constitute insignificant extra-solution activity, namely mere data gathering that are required to perform the “method of diagnosing…” recited by claim 14. Even if the step(s) were to require something more such as to verbalize the discovery of the natural law, this mere verbalization is not an application of the law of nature to a new and useful end. The “isolating”, “converting” “performing a round of PCR”, “detecting”, and conditional “determined to be present if…” and “establishing a diagnosis… if ” steps do not require the process user to do anything in light of the correlation.
Claim 14 recites determining the presence of a hypermethylation status if the amplification result exceeds a predetermined threshold established by ROC curve analysis from… a population of subjects with lung cancer and a population of subjects with benign lung diseases (i.e. comparison to a positive and negative control) and establishing a diagnosis if an elevated level of methylation is quantified… as compared to a control.
A comparison to control is an abstract idea. (See MPEP 2106.04(a)(2)(III)(A); claims to “comparing BRCA sequences and determining the existence of alterations,” where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014).
These steps fail to provide the “practical assurance” sought by the Prometheus Court that the “process is more than a drafting effort designed to monopolize the law of nature itself.”
Step 2A Prong II
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception. Claims 15 and 18-20 recite detecting the presence of a hypermethylation status of specific single genes or specific combinations of the genes recited by claim 14. These limitations are not an integration of the exception into a practical application. Instead, these elements are data gathering steps (detecting a PCR product(s)) that are required to perform the method of diagnosing lung cancer. Claims 14, 16-17, and 21-25 further require the use of specific polynucleotide primers and probes to amplify and/or detect the hypermethylated, bisulfite-converted, sequences. These elements are similarly data gathering steps required to perform the method of diagnosing lung cancer. Finally, claims 26-30 recite intrinsic properties of the recited genes (“contain at least one CpG island which can be methylated… and comprise a sequence of [SEQ ID NO: 16-19, respectively]. Claims 26-30 do not recite any method steps.
Accordingly, the claims are directed to judicial exceptions.
Step 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non-patent eligible elements, are sufficient to “transform the nature of the claims into a patent eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
The claims are not sufficiently defined to provide a method which is significantly more than a statement of a natural principle for at least these reasons:
The claims do not add a specific limitation other than what is well-understood, routine, and conventional in the field.
The claims require isolating genomic DNA from a bronchial washing or a bronchial brush from a human subject, treating the genomic DNA with sodium bisulfite, performing PCR using primers complementary to the bisulfite converted genomic DNA sequences, and detecting the presence or absence of a PCR product(s). These steps are mere data gathering steps that amount to extra solution activity to the judicial exception. These data gathering laboratory techniques are equivalent to the well-known technique “methylation-specific PCR”. The claim does not recite a new, innovative method for such determination. Conducting methylation-specific PCR for these genes was well known in the art in the context of lung cancer diagnosis at the time the invention was made. The prior art, for example: Hulbert et al., teach detecting HOXA9 and HOXA7 hypermethylation by methylation specific PCR, and that said detection is indicative of lung cancer. Zhang et al. teaches SCT, HOXA9, AND SHOX2 hypermethylation (measured by methylation specific PCR) are all well-performing biomarkers of lung cancer. Additionally, the instant specification teaches that “One of ordinary skills in the art recognizes that the hypermethylation status of a gene can be determined in many ways, using widely known and well-established method, such as conventional PCR, quantitative real time PCR or high-throughput sequencing. For example, a method may comprise the following steps: (i) converting unmethylated cytosine to uracil in the genomic DNA using sodium bisulfite; (c) performing a round of PCR on said sodium bisulfite-treated genomic DNA to amplify, wherein the PCR primers are designed in such a way that if the CpG islands are methylated, successful amplification will occur and a PCR product can be detected, while on the other hand, if there is no methylation, the PCR primers will not anneal to the site and no PCR amplification will result.” (Specification, paragraph 0016). Additionally, the primers and probes of SEQ ID NOs 4-14 are not novel over the cited prior art. The primers and probes for MSP detection of SCT in the context of lung cancer diagnosis consisting of SEQ ID NOs 4-9 are 100% identical to primers and probes for MSP detection of SCT in the context of lung cancer diagnosis taught by Zhang et al. The primers and probes for MSP detection of SHOX2 in the context of lung cancer diagnosis consisting of SEQ ID NOs 10-12 are 100% identical to primers and probes for MSP detection of SHOX2 in the context of lung cancer diagnosis taught by Fleishhacker et al. The primers for MSP detection of HOXA9 in the context of lung cancer diagnosis consisting of SEQ ID NOs 13 and 14 are 100% identical to primers and probes for MSP detection of HOXA9 in the context of lung cancer diagnosis taught by Lin et al.
Because the claim may reasonably be interpreted broadly as requiring only “at least two of four target genes”, the claim encompasses embodiments wherein only those primers and probes that are known in the art (i.e. those taught by Zhang et al. and Fleishhacker for SCT and SHOX2) are used.
Additionally, because claim 14 is written in conditional format, “a hypermethylation status is determined if…” and “establishing a diagnosis… if…”, the claim encompasses embodiments comprising only amplifying and detecting nucleic acids by PCR.
Furthermore, the courts have recognized the following laboratory techniques as well-understood, routine, and conventional activity in the life science arts when claimed as insignificant extra-solution activity:
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546;
v. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
vi. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
Response to arguments:
The response asserts that the amended claims “are directed to the practical application via the improvement of the functioning of a computer and/or include such additional elements that transform the judicial exception into a patent-eligible concept.”
The response asserts that “the claims require performing quantitative multiplex polymerase chain reaction simultaneously amplifying and detecting all four target genes… using fifteen highly specific primers and probes”.
These arguments have been thoroughly reviewed and are not persuasive.
First, the claims do not recite a computer or any improvements to the functioning of a computer.
Furthermore, the arguments presented in the response are not commensurate in scope with the claims as presently amended. Claim 14 recites using primers SEQ ID NO 4 and 5 or SEQ ID NO 7 and 8 for SCT, and none of the claims recite using all four of these primers together. Furthermore, the claims recite performing RT-PCR using primers SEQ ID NO 4 and 5 with probe SEQ ID NO 6 (claim 21) or SEQ ID NO 7 and 8 with probe SEQ ID NO 9 (claim 22). In addition, the claims as written do not require combining all of the recited probes (SEQ ID NOs 3, 6, 9, 12, 15) into a single reaction (claims 22-25 only recite using one probe each). Finally, as was described in the 112(b) rejection above, it is unclear whether claim 14 requires the broader embodiment simultaneously amplifying and detecting a combination of at least any two target genes (i.e. using primers for two of the target genes) or the narrower embodiment requiring amplifying and detecting all four of the target genes.
As is described in the updated 101 rejection above, claim 14 as presently written encompasses the use of only the well-understood, routine, and conventional primers for SCT and SHOX2 (taught by Zhang and Fleishhacker for the same purpose as they are presently claimed; diagnosing lung cancer by detecting DNA hypermethylation).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 14-30 are rejected under 35 U.S.C. 103 as being unpatentable over Dietrich et al., “Performance evaluation of the DNA methylation biomarker SHOX2 for the aid in diagnosis of lung cancer based on the analysis of bronchial aspirates” International Journal of Oncology 40: 825-832, 2012 in view of Zhang et al., “Validation of SCT Methylation as a Hallmark Biomarker for Lung Cancers” Journal of Thoracic Oncology Vol. 11 No. 3: 346-360 (March 2016), Hulbert et al., “Early Detection of Lung Cancer Using DNA Promoter Hypermethylation in Plasma and Sputum” Clin Cancer Res; 23(8), pages 1998-2005 (published April 15, 2017), Tsou et al., “Identification of a panel of sensitive and specific DNA methylation markers for lung adenocarcinoma” Molecular Cancer 2007, 6:70 (published October 29, 2007), Fleishhacker et al., US 2018/0298447 A1 (published October 18, 2018), Lin et al., US 2014/0235455 A1 (published August 21, 2014), Nawaz et al., “Development of a multiplex methylation specific PCR suitable for (early) detection of non-small cell lung cancer” Epigenetics, 9:8, 1138-1148 (published 2014), Tusna̒dy et al., “BiSearch: Primer-design and Search Tool for PCR on Bisulfite Treated Genomes” Nucleic Acids Research 33, e9 (2005), Rychlik, Nucleic Acids Research, Vol. 17, No. 21, Pg 8543-8551, 1989, Buck, Biotechniques, Vol. 27, pg. 528-536, 1999. and Genbank, AF24435.1 (published November 12, 2000), AF032095.2 (published December 3, 1999), AC004080.2 (published March 1, 2002).
This rejection has been updated as necessitated by the amendments to the claims.
Regarding claims 14 and 18-20, the claims encompass diagnosing lung cancer by simultaneously amplifying all four of the target genes HOXA9, SHOX2, SCT, and HOXA7 and detecting hypermethylation of at least two of the four target genes.
Dietrich et al. teaches methods of diagnosing lung cancer in a human subject comprising: isolating genomic DNA from bronchial aspirates (i.e. a bronchial washing sample), converting unmethylated cytosine to uracil by treating the genomic DNA with sodium bisulfite, and performing real time, methyl-specific PCR to amplify and detect the presence of a methylated biomarker (Dietrich et al., page 825, column 1). Dietrich et al. teaches SHOX2 DNA methylation is diagnostic for lung cancer (Dietrich et al., page 825, column 2) (i.e. at least one of the recited four genes). Dietrich et al. further teaches specific detection of the PCR product derived from bisulfite converted methylated DNA using a TaqMan probe specific to the bisulfite-converted target sequence (Dietrich et al., page 828, Figure 1).
Dietrich et al. does not teach that detecting a hypermethylation status of SCT is indicative of the presence of lung cancer in a subject.
However, Zhang et al. teach that hypermethylation of SCT, HOXA9, and SHOX2 are biomarkers of lung cancer. In particular, Zhang et al. teaches SCT hypermethylation is a highly discriminative biomarker for lung and other malignant tumors (Zhang et al., page 347, column 1, paragraph 2). Zhang et al. teach detecting SCT hypermethylation in lung cancer tissue samples by a methylation specific qPCR assay using primers and Taqman probes specific to the bisulfite-converted sequence of SCT (Zhang et al., page 349, column 1, paragraph 3).
Neither Dietrich et al. nor Zhang et al. teach that detecting a hypermethylation status of HOXA7 is indicative of the presence of lung cancer in a subject.
However, Hulbert et al. teach a method for diagnosing lung cancer comprising detecting hypermethylation of a multigene panel comprising HOXA7 and HOXA9 (Hulbert et al., table 2). Hulbert et al. teach simultaneous detection of the best performing biomarkers in order to improve the sensitivity and specificity compared to single detection assays (Hulbert et al., table 2 and abstract). Zhang et al. teach SCT, HOXA9, and SHOX2 are all well-performing hypermethylation biomarkers of lung cancer present in lung cancer specimens (i.e. biopsies) (Zhang et al., page 357, column 1, paragraph 2 and page 347, column 1 paragraph 1).
Furthermore, Tsou et al. teach that as early as 2007, it was recognized that “In lung cancer patients, hypermethylation is quantitatively detectable in a variety of samples ranging from tumor material to blood and sputum. However, to date the penetrance of DNA methylation at any single locus has not been high enough to provide great clinical sensitivity. Our focus is to increase the repertoire of sensitive DNA hypermethylation markers for lung cancer, and to compose a small panel of molecular markers that could be used to detect lung cancer with high sensitivity and specificity. Given the histopathologic, clinical and molecular differences between lung cancer subtypes, we believe that markers should be developed individually for the major histological subtypes. These markers can later be combined into a lung cancer hypermethylation panel that can be used for detection of all lung cancers.” (i.e. it was recognized in the art that combining well-performing hypermethylated DNA markers for lung cancer would provide for an improved panel comprising a small number of genes with improved sensitivity, specificity, and detection of all stages of lung cancer) (Tsou et al., page 2, column 2, paragraph 1).
Regarding the newly added requirement for performing quantitative multiplex real-time polymerase chain reaction, Dietrich et al. teach quantitative real time PCR detection of SHOX2 DNA methylation (Dietrich et al., Figure 3). Furthermore, Nawaz et al. teach a multiplex methylation specific PCR assay for detection of lung cancer comprising simultaneous amplification and detection of six methylated lung cancer markers comprising HOXA9 (Nawaz et al., page 1145, column 2, paragraph 4-page 1146, column 2).
Regarding the newly added requirement of determining the presence of a hypermethylation result comprising comparing the quantitation result to a predetermined threshold by ROC curve analysis from a population of subjects with lung cancer and a population of subjects with benign lung diseases and establishing a diagnosis if methylation of at least two target genes is elevated compared to a control level, Dietrich et al. teach using a predetermined threshold established by ROC analysis of methylation values in a population of lung cancer cases and a control population with benign lung disease (Dietrich et al., page 830, column 1, paragraph 3- page 831, column 1, paragraph 2 and figure 3, see below)
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Furthermore, Nawaz et al. teach determining a diagnosis when the methylation of at least two markers is elevated as compared to a control population is an optimal choice for multiplex methylation specific PCR for diagnosis of lung cancer (Nawaz et al., page 1142, column 2, paragraph 2).
Regarding the requirements for the use of specific primers and probes for each target sequence:
Zhang et al. teaches primers and probes for SCT hypermethylation that are 100% identical to the claimed primers consisting of SEQ ID NOs: 4-9.
SEQ ID NO:4 vs. “SCT MSP F2”
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SEQ ID NO: 5 vs. “SCT MSP R2”
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SEQ ID NO:7 vs. “SCT MSP F1”
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SEQ ID NO: 8 vs. “SCT MSP R1”
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SEQ ID NO: 6 vs “SCT MSP P2”
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SEQ ID NO: 9 vs “SCT MSP P1”
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Fleishhacker et al. teaches primers and probes for the detection of SHOX2 hypermethylation by methylation specific PCR for the purpose of monitoring response of lung cancer to treatment (i.e. diagnosing/detecting the presence of lung cancer) that are 100% identical to SEQ ID NO: 10-12, recited as primers and probes for SHOX2 by the instant claims (Fleishhacker et al., paragraph 0135, see also alignments below).
Seq ID NO: 10 vs Fleishhacker et al. SEQ ID NO: 31
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Seq ID NO: 11 vs Fleishhacker et al. SEQ ID NO: 33
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Seq ID NO: 12 vs Fleishhacker et al. SEQ ID NO: 34
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Lin et al. teaches primers for the detection of HOXA9 by methylation specific PCR for the purpose of diagnosing cancer that are 100% identical to SEQ ID NO: 13-14, recited as primers for HOXA9 by the instant claims (Lin et al., paragraphs 0028-0029, see also alignments below)
Seq ID NO: 13 vs Lin et al. SEQ ID NO: 5
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Seq ID NO: 14 vs Lin et al. SEQ ID NO: 6
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Finally, regarding SEQ ID NO: 15 (a HOXA9 probe) and SEQ ID NO: 1-3 (primers and a probe for HOXA7), free web-based server tools such as those taught by Tusna̒dy et al., or those referenced by Nawaz et al. (Nawaz et al., page 1145, column 2, paragraph 5) would have allowed the ordinary artisan to input a genomic sequence and readily obtain the full sequence of bisulfite-treated genomic DNA and find a finite number of possible primers and probes within the given sequence. Additionally, Rychlik teaches it is routine and predictable to make primers for DNA amplification wherein primers are designed to a known oligonucleotide sequence. Rychlik teaches criteria to design suitable primers for DNA amplification (see whole document and abstract). Buck expressly provides evidence of the equivalence of primers. Specifically, Buck invited primer submissions from a number of labs (39) (pg. 532, column 3), with 69 different primers being submitted (pg 530, column 1). Buck also tested 95 primers spaced at 3 nucleotide intervals along the entire sequence at issue, thereby testing more than 1/3 of all possible 18-mer primers on the 300 base pair sequence (pg 530, column 1). When Buck tested each of the primers selected by the methods of the different labs, Buck found that every single primer worked (pg 533, column 1). Buck expressly states, “The results of the empirical sequencing analysis were surprising in that nearly all of the primers yielded data of extremely high quality” (Pg. 535, column 2). Therefore, Buck provides direct evidence that all primers would be expected to function, and in particular, all primers designed according to the ordinary criteria. This clearly shows that every primer would have a reasonable expectation of success.
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have combined the well-performing lung cancer biomarkers SHOX2, SCT, HOXA9, and HOXA7, taught by Dietrich et al. (SHOX2), Hulbert et al. (HOXA7 and HOXA9), and Zhang et al. (SCT, HOXA9, and SHOX2) in any combination into a panel comprising a small number of hypermethylation markers for lung cancer because of the teachings of Hulbert et al. and/or Tsou et al. that combining well performing methylation biomarkers or small panels of biomarkers for individual subtypes of lung cancer would yield an improved panel with high sensitivity and specificity for a greater range of lung cancers than the individual markers or small panels for individual subtypes of lung cancer. Furthermore, it would have been obvious to the ordinary artisan to select the previously published primers and probes taught by Zhang et al., Fleishhacker et al., and Lin et al. that are identical to the recited primers and probes (SEQ ID NO: 4-14) for use in detecting hypermethylation of their corresponding genes in cancer diagnosis assays comprising methylation specific PCR because they are used in similar MSP cancer diagnostic assays in the art. It would likewise have been obvious to the ordinary artisan to derive such primers and probes (i.e. SEQ ID NO: 1-3 and 15) by the well-known, ordinary, and routine methods of methylation-specific primer and probe design taught by Tusna̒dy et al., Rychlik, and Buck, given the known complete nucleotide sequences of the target genes suggested by Dietrich et al., Zhang et al., Fleishhacker et al. and Lin et al., which are all readily available to the public from Genbank (see accessions above). Furthermore, it would have been obvious to the ordinary artisan to combine said known primers and probes into a multiplex methylation specific PCR assay because of the teachings of Nawaz et al. that multiplex panels of methylation markers comprising HOXA9 are diagnostic for non-small cell lung cancer and the teachings of Dietrich et al. that quantitative PCR allows for determination of quantitative cutoffs (i.e. thresholds) for detection of methylation markers that are diagnostic for lung cancer.
The ordinary artisan would have been motivated to combine the known hypermethylation biomarkers for lung cancer HOXA9, SHOX2, SCT, and HOXA7 into a panel because of the teachings of Hulbert et al. and Tsou et al. that combining single hypermethylation biomarkers for lung cancer with varying performance across different subtypes or stages of lung cancer would have been expected to improve the clinical sensitivity and specificity of the assay and allow for detection of lung cancer at a broader range of stages (Hulbert et al., table 2 and abstract and Tsou et al., page 2, column 2, paragraph 1). The ordinary artisan would therefore have been reasonably confident that combining the well-established biomarkers taught by Dietrich et al., Hulbert et al., and Zhang et al. would have resulted in improved clinical lung cancer detection compared to single-marker assays. Furthermore, the ordinary artisan would have been reasonably confident that the combination of said methylation biomarkers into a multiplex PCR assay would have “successfully address[ed] the limitations of various (single-plex) methylation detection assays” (Nawaz et al., page 1139-1140 bridging paragraph) because of the teaching of Nawaz et al. that multiplex methylation specific PCR simultaneously amplifies and detects as many as six methylation marker genes in lung cancer and control samples.
Regarding claim 15, Zhang et al. teaches the presence of SCT hypermethylation is indicative of the presence of lung cancer (Zhang, figure 3 and page 358, column 2, paragraph 3).
Regarding claims 16-17, Zhang et al. teaches performing real-time PCR to amplify SCT using primers consisting of the nucleotide sequences of SEQ ID NOs 4 and 5 or SEQ ID NOs 7 and 8 (see alignments below)
SEQ ID NO:4 vs. “SCT MSP F2”
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SEQ ID NO: 5 vs. “SCT MSP R2”
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SEQ ID NO:7 vs. “SCT MSP F1”
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SEQ ID NO: 8 vs. “SCT MSP R1”
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SEQ ID NO: 6 vs “SCT MSP P2”
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SEQ ID NO: 9 vs “SCT MSP P1”
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Regarding claims 21 and 22, Zhang et al. teach using a probe for SCT consisting of the nucleotide sequence of SEQ ID NO 6 or SEQ ID NO 9 (see alignments above).
Regarding claim 24, Fleishhacker et al. teach using a probe for SCT consisting of the nucleotide sequence of SEQ ID NO 12 (see alignment below).
Seq ID NO: 12 vs Fleishhacker et al. SEQ ID NO: 34
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Regarding claims 23 and 25 requiring the use of specific nucleotide sequences for use as probes to detect HOXA7 and HOXA9, respectively, Genbank AF032095.2, AC112502.7, and AC004080.2 teach the complete nucleotide sequences of the recited genes. As was discussed above, the method taught by Dietrich et al. in view of Zhang et al., Hulbert et al., Tsou et al., Fleishhacker et al., Lin et al., Nawaz et al., Tusna̒dy et al., Rychlik, Buck, and Genbank teaches methods of diagnosing lung cancer in a human subject comprising: isolating genomic DNA from bronchial aspirates (i.e. a bronchial washing sample), converting unmethylated cytosine to uracil by treating the genomic DNA with sodium bisulfite, and performing multiplex real time, methyl-specific PCR using methyl-specific primers and probes designed by well-known and routine methods in the art (see Tusna̒dy et al, Nawaz et al., Rychlik, Buck, and Genbank) to amplify and detect the presence of methylated biomarkers that are diagnostic for lung cancer. The complete nucleotide sequence of each of the recited genes HOXA7, SHOX2, and HOXA9, are taught by Genbank AF032095.2, AC112502.7, and AC004080.2, respectively and would have been readily converted to the corresponding bisulfite-treated sequences in the program of Tusna̒dy et al. These complete sequences would have presented the ordinary artisan with a finite number of possible primers and probes for amplification of the methylated region. Then, since Buck taught that a large number of primers designed to detect the same target amplicon functioned reasonably well, an ordinary artisan would have expected predictable results, and thus would have had a reasonable expectation of success when testing the finite number of possible amplification primers and probes. Absent unexpected results, the ordinary artisan would have been reasonably confident that any primer combination designed to amplify the known sequences of bisulfite-converted AF032095.2, AC112502.7, or AC004080.2 would have successfully amplified a target methylated amplicon of AF032095.2, AC112502.7, or AC004080.2 because of the teachings of Rychlik and Buck that design of primers to known sequences is routine and predictable.
Regarding claim 26, the presence of a CpG island or islands that can be methylated is an inherent property of the recited genes. The claim does not recite any active method steps. The claim recites that the method of claim 14 (which requires the use of specific primers) “targets at least one CpG island within each of the… genes”. This limitation recites the natural consequence of the active method steps required by claim 14. Furthermore, CpG islands, defined by the frequency of adjacent CG dinucleotides in genomic DNA are readily identifiable from the complete nucleotide sequences of the genes in question. Said complete nucleotide sequences are taught by Genbank AF244355.1, AF032095.2, AC112502.7, and AC004080.2.
Regarding claims 27-30, the sequence of the genes in question is a known property of the recited genes. In this regard, the complete sequence of HOXA7, SCT, SHOX2, and HOXA9 are taught by Genbank AF032095.2, AF244355.1, and AC004080.2, respectively.
Response to arguments
The response asserts that claim 14 defines the use of fifteen distinct oligonucleotide sequences (SEQ ID NOs 1-15) that must operate simultaneously with equivalent properties when reacting against bisulfite-converted DNA templates.
The response asserts that “the assertion that designing the 15 required primers and probes is routine is inaccurate in the context of MSP… particularly within a multiplex assay”, and further asserts “the successful development of 15 distinct oligonucleotide reagents that function accurately and simultaneously in [said] assay, overcoming… extreme technical hurdles is demonstrably non-routine and non-obvious.”
This argument has been thoroughly considered and is not persuasive for the following reasons.
First, the argument is not commensurate in scope with the claims. Claim 14 recites using primers SEQ ID NO 4 and 5 or SEQ ID NO 7 and 8 for SCT, and none of the claims recite using all four of these primers together. Furthermore, the claims recite performing RT-PCR using primers SEQ ID NO 4 and 5 with probe SEQ ID NO 6 (claim 21) or SEQ ID NO 7 and 8 with probe SEQ ID NO 9 (claim 22). In addition, the claims as written do not require combining all of the recited probes (SEQ ID NOs 3, 6, 9, 12, 15) into a single reaction (claims 22-25 only recite using one probe each). Finally, as was described in the 112(b) rejection above, it is unclear whether claim 14 requires the broader embodiment simultaneously amplifying and detecting a combination of at least any two target genes (i.e. using primers for two of the target genes) or the narrower embodiment requiring amplifying and detecting all four of the target genes.
Assuming the claims are amended to incorporate the narrower embodiment argued by the response, as is described in the 103 rejections of record, in the updated 103 rejections set forth in this office action, and reiterated here, the primers and probes of SEQ ID NOs 4-14 are not novel over the cited prior art. The primers and probes for MSP detection of SCT in the context of lung cancer diagnosis consisting of SEQ ID NOs 4-9 are 100% identical to primers and probes for MSP detection of SCT in the context of lung cancer diagnosis taught by Zhang et al. The primers and probes for MSP detection of SHOX2 in the context of lung cancer diagnosis consisting of SEQ ID NOs 10-12 are 100% identical to primers and probes for MSP detection of SHOX2 in the context of lung cancer diagnosis taught by Fleishhacker et al. The primers for MSP detection of HOXA9 in the context of lung cancer diagnosis consisting of SEQ ID NOs 13 and 14 are 100% identical to primers and probes for MSP detection of HOXA9 in the context of lung cancer diagnosis taught by Lin et al. Of the 15 recited primers and probes, only the primers of SEQ ID NOs 1 and 2 and the probes of SEQ ID NOs 3 and 15 appear to be novel over the art. However, as described in the 103 rejection above, the selection of primers and probes for a particular known template sequence is routine and predictable in the art.
The response further asserts that the specific combination of markers HOXA7 + SCT + SHOX2 yields unexpectedly superior results, however the evidence presented is not persuasive for the following reasons.
First, the evidence provided is not commensurate in scope with the claims. MPEP 716.02 (d): “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)” In the present case, the data presented in the response presents sensitivity, specificity, and AUC values for each of the target genes HOXA7, SCT, SHOX2, and HOXA9 individually and only one combination of three target genes (HOXA7 + SCT + SHOX2) in bronchial brushing samples. The claims, as presently written, broadly encompass embodiments wherein at least any two, at least any three (excluding the combination HOXA7+SHOX2+HOXA9), or all of the four recited target genes are detected as hypermethylated in bronchial washing or bronchial brush samples. Furthermore, the evidence provided in the response is not persuasive for the following reasons.
MPEP 716.02(b)(I-II): “I. Burden on applicant to establish results are unexpected and significant. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c). II. Applicants have burden of explaining proffered data "[A]ppellants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness." Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992).
In the present case, the presented data comprise data that is not present in the specification and is not presented as a declaration. Furthermore, the data presented herein does not include any support commensurate in scope with the present claims (only presented for bronchial brush samples, and no data are presented for any of the two-gene panels or any three-gene panel other than HOXA7+SCT+SHOX2) (table 2, reproduced here for convenience).
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Even more, the specification teaches entirely different values for bronchial brushing samples (Table 4) than those presented in the response, both reproduced here for convenience:
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It is unclear how the data presented herein asserting an unexpected increase in sensitivity and specificity relate to the data presented in the original disclosure, whether these data are part of the original disclosure, or would constitute new matter.
Finally, the data presented in the specification for the narrow preferred embodiment argued in the response (bronchial brush sample; HOXA7+SCT+SHOX2) does not support the asserted unexpected result of increased sensitivity of the three gene combination without a trade-off for impaired specificity relative to the best performing single marker. The combination of well-performing single markers predictably results in increased sensitivity (best single marker: 81.1 % Sensitivity compared to the asserted three gene combination 86.1 % Sensitivity). The specificity asserted for the three gene combination by the response is 93.1%. The single markers in the data presented by the specification have specificities of 100 % (SHOX2), 95.8 % (SCT), and 87.5 % (HOXA7). The three gene combination has a specificity (93.1%) that is lower than the two highest performing single genes in the combination.
There is no explanation in the response as to how the single gene data differs from those presented in the specification and the data are not presented in a declaration or affidavit sworn to by the inventor(s).
MPEP 716.01(c)(II) Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
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 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/872,833 (herein referred to as ‘833). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘833 are coextensive in scope to the present claims.
Namely, claim 1 of ‘833 recites a method of diagnosing lung cancer comprising generic steps of measuring the methylation level (i.e. detecting hypermethylation) of at least two genes selected from a list comprising HOXA9 and SHOX2 (‘833, claim 1). Instant claim 1 recites a method for diagnosing lung cancer comprising specific, well-known steps for detecting hypermethylation of at least one gene (i.e. encompassing combinations of two or more) selected from a list comprising HOXA9 and SHOX2.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art to “measure the methylation level” (i.e. detect hypermethylation) of “at least one gene” (comprising HOXA9 and SHOX2) by the well-known method of methyl specific qPCR.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to arguments:
The response asserts that “because the provisional double patenting rejection will be the only remaining rejection following obviation of the above rejections, the examiner should withdraw [this rejection]”. The present application is/remains rejected under USC 101, 112(a), 112(b), 112(d), and 103. Therefore, the rejection is maintained.
Conclusion
No claim is allowed.
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.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682