DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08 April 2026 has been entered (please see paragraph 4 below regarding the entry of non-compliant claim amendments).
Claims 17, 29, and 48 have been amended, and claims 49-51 have been added. Claims 1-15, 19-28, 30-35, 42-47, and 49 remain/are withdrawn. Applicant’s amendments and arguments have been thoroughly reviewed, and have overcome the rejections of claims 16, 29, and 48 under 35 USC 112 set forth in the prior Office action; accordingly, claims 16, 29, and 48 (as well as new claims 50-51) are now allowed (see also paragraph 10 below). Claims 17-18 remain rejected for the reasons given below (and it is noted that the prior art thus continues to apply against the species presently under consideration). Any rejections and/or objections not reiterated in this action have been withdrawn. This action is non-final.
Non-Compliant Amendment Entered as a Courtesy
It is noted that Applicant’s clam amendments filed 08 April 2026 fail to comply with all requirements of 37 C.F.R. 1.121(c), as new claims 49-51 include markings (specifically, underlining, whereas the new claims should have been presented in “clean” form; see 37 C.F.R. 1.121(c)(3)). While the amendments have been entered as a courtesy, future amendments should comply with all requirements of 37 C.F.R. 1.121.
Election/Restrictions
Applicant’s election of Group I in the reply filed on February 2, 2023 is again acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 19-24, 26-28, and 30-31 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on February 2, 2023.
Applicant’s election of the species of an ALK fusion, and lung adenocarcinoma, in the reply filed on February 2, 2023 is also again acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election was treated as an election without traverse (MPEP § 818.01(a
It is again noted that the claims currently under consideration do not read on the originally elected species, with the Group I claims now encompassing methods involving detection of various groups of genes (the groups including ALK); search and examination was thus extended as previously indicated (see, e.g., paragraph 8 of the Office action mailed September 22, 2023), and the claims remain under consideration as directed to the gene combination of EGFR, ALK, ROS1, KRAS, BRAF, ERBB2, MET, RET, FGFR1, and KIT/PGDFRA (now separately recited as KIT and PGDFRA). The claims presently withdrawn as being directed to non-elected species are claims 1-15, 25, 32-35, and 42-47, as well as new claim 49 (which depends in the alternative from withdrawn claims “1, 9, or 15”). Claims 16-18, 29, 48, and 50-51 read on the elected invention and species.
Applicant’s continued traversal of the withdrawal of claims 1-15, 25, 32-35, and 42-47 (Reply page 14 bridging to page 15) has been reviewed and considered, but is not persuasive. It is noted that the prior art continues to apply against claims 17-18.
Again, the examiner agrees that the result of the practice of the methods claimed may be detection of an ALK fusion alone (as indicated in the Reply on page 15). However, the limitations of the claims under consideration are clearly not met by testing for ALK alone; rather, one must perform a testing that “includes amplification of EGFR, ALK, ROS1, KRAS, BRAF, ERBB2, MET, RET, FGFR1, KIT, and PDGFRA genes” (see text of each of independent claims 16 and 17). Further, given the actual language of the claims, search and examination requires consideration of methods related to this entire group of genes (not ALK alone). Should all claims as directed to the gene grouping presently under consideration be allowed, Applicant may be entitled to rejoinder of claims requiring all limitations of those allowed claims (e.g., claims to methods requiring amplification of a gene grouping of which the above noted group is a subcombination); further, upon allowance of all claims to one species, search and examination may potentially be extended to additional species (in accordance with the guidance set forth in MPEP 803.02). At the present time, however, Applicant’s traversal remains non-persuasive.
Allowable Subject Matter/Claim Interpretation
Claims 16, 29, 48, and 50-51 are allowed. It is noted that Applicant’s amendments to claims 29 and 48 (removing references to genes not recited in independent claim 16, as well as to squamous cell lung carcinoma) have clarified what is being claimed, and that Applicant’s traversal at pages 16-17 of the Reply was found persuasive with regard to the claim language pertaining to actionability indices and prevalence as now recited in the claims. It is noted that the allowed claims require “treating lung adenocarcinoma”, concluding with a requirement for “determining an actionable treatment recommendation” that requires knowledge of the presence or absence of variants specified in the “determining” of the claim, followed by “generating a report” and “treating the lung adenocarcinoma according to” the recommendation (which encompasses, e.g., choosing to withhold a treatment, but with the claim language requiring that the “determining” [and subsequent “generating a report” and “treating”] follows the “testing” and “detecting” of claim 16).
While dependent claims 29 and 48 are allowable and recite encompassing any “combinations thereof” of different AI + Prevalence categories (none of which is necessarily required based on the wording of the claims), it is noted that the language “AI3 + Prevalence >1% when the variant is a RET translocation, an EGFR copy number gain, an ERBB2 copy number gain, and FGFR1 copy number gain, a KIT amplification, or a PDGFRA amplification” has been interpreted as requiring all of the first three recited variants and one of the last three recited variants (as this is consistent with the present wording/punctuation of the claim).
Claim Rejections - 35 USC § 112(b)/second paragraph
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 17-18 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 17-18 are indefinite because amended claim 17 requires “identifying the patient with lung cancer as either eligible or ineligible for treatment with at least one of said treatments based on the presence or absence of the at least one variant and the actionability index and prevalence categorization”, but – while the claim recites testing a lung tumor same “for at least one variant at least one of” a group eleven genes, all of which must be amplified and sequenced – only provides an AI category and Prevalence for a subset of the genes that may be embraced by the claims (and does not otherwise make clear how the “identifying” and the objective set forth in the claim preamble is to be met). While the claims are sufficiently clear with respect to embodiments of the genes/variants actually recited in the ”determining” an AI and prevalence for the patient recited in the claim (which is not a required AI and prevalence, given the conditional “when” language), it is unclear what the claims actually encompass with regard to the other types of variants embraced by the claims (and some type of further information with regard to each possible gene is required by the amended “identifying” step in order for the boundaries of the claims to be reasonably clear). Accordingly, further clarification is required.
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 17-18 remain rejected under 35 U.S.C. 103 as being unpatentable over Heist and Engelman (Cancer Cell 21:448 [March 2012]; cited in IDS) in view of Krawczyk et al (Mutations in Human Genetic Disease, Chapter 10, InTech [2012]; cited in IDS), and Leamon et al (US 2013/0059762 A1 [07 March 2013; filed 16 Nov 2012]; cited herein).
Initially, it is reiterated that the claims are indefinite for the reasons given above, and that independent claim 17 only recites an AI category and prevalence corresponding to variants of a subset of the genes that must be amplified and sequenced during the performance of the claimed method (such that the requirements of the “identifying” of the claim are not clear with respect to all embodiments of the claim, etc.). Further, it is noted that for the single AI + Prevalence referenced in claim 17, the claim language specifies that this categorization applies “when” the recited conditions are met (i.e., this is a conditional/contingent claim limitation). As discussed in MPEP 2111.04(II): “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met”.
Heist and Engelman disclose that mutations in several genes, including EGFR, ALK, ROS1, KRAS, BRAF, HER2 (ERBB2), RET, FGFR1, and PDGFRA (i.e., nine of the eleven genes of the group set forth in independent claim 17), have known associations non-small cell lung cancer (NSCLC) (see entire reference, particularly the illustrations at page 448, as well as the more detailed information regarding each gene on page 448.e1). Heist and Engelman provide guidance with respect to what therapies are appropriate for subjects with NSCLC known to have mutations in particular genes (see the Table at bottom right of page 448 and the guidance on page 448.e1), and teach that the “treatment and diagnosis of’ NSCLC “has been revolutionized by the development of targeted agents for cancers harboring specific genetic mutations", and that routine genetic testing for such mutations “from lung cancer biopsies is becoming the standard for providing optimal patient care” (page 448.e1 at top). Heist and Engelman summarize how the identification of the relevant mutations in a subject’s tumor “can direct patients and physicians” to appropriate therapies, clinical trials, etc., and note that their provided Table lists which therapies and trials are appropriate for subject’s with various types of mutations (page 448.e1 at top), which meets the requirement of “identifying” treatment eligibility as recited in claim 17 (as the claims simply recite “identifying….based on the presence or absence of the at least one variant and the actionability index and prevalence categorization”, which (in addition to being indefinite) broadly encompasses forming a conclusion corresponding to an “identification” that is in any way “based on” the recited information (which again is presently unclear). With regard to testing for specific variants, and in particular the originally elected variant of an ALK fusion, Heist and Engelman disclose the preferred EML4-ALK fusion as set forth in dependent claim 18 (see page 448.e1 under the heading “ALK”); this meets the requirements of the claims for “at least one variant” in an ALK gene, as well as an ALK fusion. Further, Heist and Engelman teach that crizotinib is an approved treatment for cancers harboring ALK fusions (see again page 448.e1, and the Table at the bottom right of page 448); this meets the requirement of an “identifying” of treatment eligibility of independent claim 17 (even to the extent that the claims are directed to embodiments that actually require detection of an ALK variant or fusion, and a corresponding appropriate treatment, including with crizotinib).
Heist and Engelman do not teach the relevance of the additional gene MET, or of the alternative or additional gene KIT, of the group specified in the claims (or appropriate therapies for subject’s with variants in these genes, although such a further teaching is not a requirement of the claims). Additionally, Heist and Engelman do not disclose a method comprising a testing for “at least one variant” that includes amplification/exponential amplification of all genes of the claims “in a single assay” (as is required by independent claim 17).
Like Heist and Engelman, Krawczyk et al disclose the use of genetic testing of lung cancer samples for the presence of relevant mutations to allow for the identification of targeted therapies (see entire reference). Krawczyk et al provide guidance with regard to targeted therapies for those genes not referenced by Heist and Engelman (as well as most of the others of the elected group); see, e.g., Table 2 at pages 212-213, which recites MET at page 212 and c-Kit at page 213). Krawczyk et al also summarize various different methods available to perform the genetic testing of mutations relevant to NSCLC, including, e.g., direct and next generation sequencing, microarrays "containing oligonucleotide mutation probes", multiplex SNaPshot PCR (minisequencing), real time PCR, and FISH (page 206) and (like Heist and Engelman) teach that routine genetic testing of lung cancer biopsies “is becoming the standard to providing optimal patient care” (page 207). Krawczyk et al thus suggest that a variety of different known methods may be used successfully to perform genetic testing of mutations associated with NSCLC in lung tumor samples, teach the testing of numerous relevant genes together, and further teach that the purposes of such methods are for both research and “to determine patients who might benefit from molecularly targeted therapies” (page 211-212). Krawczyk et al also teach the creation of databases that provide information regarding NSCLC-associated mutations, treatment options, and outcomes (page 212).
Leamon et al teach methods “useful for multiplex PCR”, including methods in which “target specific primers” are employed in selective amplification of sequences associated with cancer, with such amplification products also being “used in various downstream processes including nucleic acid sequencing and to detect the presence of genetic variants” (see entire reference, particularly the Abstract); it is noted that target genes taught by Leamon et al include EGFR, ALK, ROS1, KRAS, BRAF, ERBB2, MET, RET, FGFR1, KIT, and PDGFRA (see, e.g., paragraphs 96-97). Leamon et al disclose methods in which – following multiplex amplification of targets of interest – amplicons are pooled, primer sequences are removed, and universal adapters are attached via ligation (see, e.g., Figure 2 and the description thereof, as well as the Summary at paragraphs 56-79). In preferred embodiments, such methods are achieved via the use of target specific primers including cleavable groups (such as uracil, uridine, or inosine), with amplification being followed by cleavage (via use of the resulting cleavable groups in amplification products) and ligation of adapters to the cleaved products via blunt ended ligation (including of a standard/conventional type) (see again paragraphs 56-79, in particularly paragraph 62 and 70-71, as well as paragraph 136, and claims 1-15).
Leamon et al teach that their multiplex PCR methodology produces amplicons that may be employed “in many downstream analysis of assays with, or without, further purification or manipulation” – with such downstream analyses being taught as including mutation analysis and nucleic acid sequencing/resequencing (see paragraph 6) – and further teach that there method provides advantages as compared to prior art methods in allowing for “the simultaneous amplification of thousands of target-specific nucleic acid molecules in a single reaction, which can be used in any applicable downstream assay or analysis”, while avoiding formation of amplification artifacts (see, e.g., paragraph 9). Leamon et al also teach providing/generating reports containing information obtained via their methods (see, e.g., Figures 12, 17, and 18 and the descriptions thereof, and paragraphs 231 and 301).
In view of the teachings of Heist and Engelman, Krawczyk et al, and Leamon et al, it would have been prima facie obvious to one of ordinary skill in the art before the effective date of the claimed invention to have testing lung tumor samples (and particularly samples from a subject with NSCLC) for variants in each of the genes of the claims - via a single assay comprising exponential multiplex amplification with respect to each of the genes and variants taught by the Heist and Engelman and Krawczyk et al references, using the methodology taught by Leamon et al to achieve detection of the presence or absence of variants via amplification and sequencing of amplicons – and to have thereby identified treatment eligibility or ineligibility of a tested subject as indicated by the testing results, and further to have generated a report comprising such results (as taught and suggested by Leamon et al), thereby having performed a method meeting all requirements of the amended claims. First, as discussed above, the combined teachings of the Heist and Engelman and Krawczyk et al references make clear that each of the genes of the recited group contains mutation(s) that may aid in the selection of appropriate therapy for NSCLC; thus, an ordinary artisan would have been motivated to have tested this panel of genes for the benefit of selecting an appropriate targeted therapy and/or clinical trial for a subject, as is suggested by both references. Second, Krawczyk et al further teach a variety of different testing methods may be successfully employed in such testing, and Leamon et al provide particular motivation to practice the detection of multiple cancer-associated mutations via their multiplex PCR amplification and sequencing methodology, for the benefits of allowing for successful, simultaneous testing of numerous target sequences while reducing amplification artefacts. With regard to the limitation of claim 17 reciting “generating a report” comprising the “identification” of a patient for treatment, given Leamon et al’s teach of generating reports providing/presenting testing results – particularly in view of the presentation of information by Heist and Engelman regarding targets/drugs in Table form, which constitutes a type of “report” illustrating treatment eligibility information - an ordinary artisan would also have been further motivated to have generated a report identification of a subject as treatment eligibility/ineligibility for the benefit of communicating this information as taught by Leamon et al (for use by, e.g., a healthcare provider treating the patient). Furthermore, given the specific guidance provided in each of the references, an ordinary artisan would also have had a reasonable expectation of success in performing such methods. (Additionally, to the extent that the claims may be intended to require production of a report including particular data/information, it is noted that as there is no required functional relationship between any such report/information and the claimed method, this type of limitation constitutes nonfunctional descriptive material that is not given patentable weight when comparing the claimed invention to the prior art [see MPEP 2111.05]).
With further regard to dependent claim 18, the disclosure of an EML4-ALK fusion by Heist and Engelman is discussed above.
The Reply of 08 April 2026 traverses the prior rejection of claims under 35 USC 103 on the following grounds.
Applicant summarizes the rejection (Reply page 19), and argues that the none of the cited art teaches the new claim 17 limitation “of determining an actionability index (AI) and a prevalence for the patient based on the at least one variant, wherein the AI and prevalence comprises AI1 + Prevalence >1% for the at least one variant of the specific variants required by the claim and identifying the patient with lung cancer as either eligible or ineligible for treated….based on the presence or absence of the at least one variant and actionability index and prevalence categorization” (Reply page 20).
This argument has been thoroughly considered but is not persuasive because the limitation upon which Applicant’s argument relies is conditional/contingent in nature, and because the present claim language does not clearly require the feature upon which this argument relies (as is discussed in the revised rejection itself). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Conclusion
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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/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682
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