FINAL ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is responsive to the Amendment and Response filed 18 August 2025. Claims 16-17 and 29 have been amended and claim 48 has been added. Claims 1-15, 19-28, 30-35, and 42-47 remain withdrawn, while claims 16-18, 29, and 48 are now under consideration. Applicant’s amendments and arguments have been thoroughly reviewed, and have overcome the following objections/rejections set forth in the prior Office action:
The rejections of claims 17-18 under 35 USC 112(b), in view of Applicant’s clarifying amendments;
The rejection of claim 29 under 35 USC 112(d), in view of the amendment of the claim; and
The rejection of claims 17-18 under 35 USC 103 in view of the amendment of the claim to recite the new limitation “wherein the resulting amplicons are attached to adapters using conventional blunt-ended ligation” (although it is noted that the claims remain rejected under 35 USC 103 on the new grounds set forth below).
Claims 16-18, 29, and 48 remain rejected for the reasons given below, which include new grounds of rejection necessitated by Applicant’s amendments. Any rejections and/or objections not reiterated in this action have been withdrawn. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
With regard to the amendment of each of the independent claims to include the new limitation “wherein the resulting amplicons are attached to adapters using conventional blunt-end ligation”, it is noted that support for this amendment may be found in provisional application 61/891,224, filed 15 October 2013.
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Claims 19-24, 26-28, and 30-31 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 has been treated as an election without traverse (MPEP § 818.01(a)).
It is reiterated 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. Claims 16-18, 29, and 48 read on the elected invention and species and remain under consideration herein; it is noted that new claim 48 is under consideration to the extent that it depends from claim 16.
Applicant’s continued traversal of the withdrawal of claims 1-15, 25, 32-35, and 42-47 (Reply page 12 bridging to page 13) has been reviewed and considered, but is not persuasive. 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 13). 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 claims as directed to the gene grouping 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 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 is non-persuasive.
Claim Interpretation
Regarding claims 17-18, it is noted the recitation of the limitation “the identification” in amended independent claim 17 is interpreted as referring back to the patient information obtained as a result of the prior step/activity of “identifying the patient with lung cancer as either eligible or ineligible for treatment….”.
Claim Rejections - 35 USC § 112(b)/second paragraph
THE FOLLOWING ARE NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claims 16, 29, and 48 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 16 and 48 are indefinite because it is unclear whether the claims are limited to methods of treating lung adenocarcinoma in a patient, as appears to be required by the language of independent claim 16 (see both the preamble and the final step of claim 16), or whether the claims may also encompass methods involving treatment of a patient with squamous cell lung carcinoma, as appears to be suggested by the language of new dependent claim 48 (which recites “determining an actionability index (AI) and a prevalence for the patient based on the at least one variant”, and reciting a group of alternatives that include alternatives “for squamous cell lung carcinoma”). While it is noted that claim 48 recites various possible claims from which it may dependent in the alternative, the claim is currently under consideration as it is directed to the method of claim 16 and methods dependent therefrom. In view of the language of claim 48, both claim 16 (as it embraces the subject matter of claim 48) and claim 48 are unclear with regard to what subject matter is embraced by and excluded from the claims; accordingly, further clarification of the actual boundaries of the claims is required. (It is noted that amended claim 29, which also depends from claim 16, is not included in this rejection [despites its dependence from claim 16] because it clear recites only lung cancer adenocarcinoma).
Claims 29 and 48 remain/are indefinite over the recitation of the limitation “AI” and various more specific types thereof (e.g., “AI1”, “AI2”, etc.) because – while it is again noted that Applicant has amended the claim in response to a prior rejection to remove reliance on a Table – the recited terms correspond to categories that are fluid and subject to change over time, rather than fixed and definite (see, e.g., pages 30-31 of the specification). Applicant traverses the prior rejection of claim 29 on the grounds that “the definitions for each of the five AI categories, as disclosed in the specification, are not subject to change over time” (referring to page 30 of the specification), and further because “while claim 29 includes the limitation ‘wherein the AI and prevalence comprises,’ which is open-ended and indicates that additional variants may be included, the variants that are specified in claim 29 associated with a specific AI and prevalence remain as required limitations of the claim” (Reply page 14). This argument has been thoroughly considered but is not persuasive given that the specification provides other sources of information regarding various AIs and variants associated therewith, which again would be expected to change over time (see, e.g., paragraphs 160-163), and because the language employed in the specification at the location relied upon in Applicant’s arguments (page 30) cannot reasonably be considered as a fixed/limiting “definition” (as the specification employs language such as “____ represents a category”, which one of ordinary skill in the art would not consider as a definition; i.e., “represents” is not synonymous with “defined as” or equivalent terminology).
Claim 48 is also indefinite in view of the recitation in that claim of a variety of genes and variants that do not appear among the group of genes required by claim 16, such that it is unclear how claim 48 relates to and further limits claim 16. For example claim 48 refers to PIK3CA, AKT1, HRAS, PTEN, etc., none of which are specified as being among the group of genes amplified and sequenced via the method of claim 16. Again, while claim 48 recites various other claims in the alternative, the claim is under consideration herein as it is directed to the method of claim 16; the present claim language does not make clear how (and whether) claim 48 is further limiting of that claim with respect to genes that are not required to be tested.
Claim Rejections - 35 USC § 112(d)/fourth paragraph
THE FOLLOWING ARE NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claim 48 is 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. As discussed above, claim 29 is indefinite, particularly with regard to how and whether the claim is necessarily dependent from claim 16 (given the recitation in claim 29 of both lung adenocarcinoma and squamous cell lung carcinoma, and of various genes as alternatives that are not among those recited in claim 16). To the extent that the claim is broadening of the methods of claim 16 (from which it depends) – as it appears to be based on at least one possible interpretation of the claim language (e.g., as it refers to drawing conclusions regarding a patient with respect to squamous cell lung carcinoma, and relying of genes/mutations not among those specified in claim 16) – the claim fails to comply with the requirements of 35 U.S.C. 112(d). 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.
Claim Rejections - 35 USC § 103
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.
THE FOLLOWING ARE NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claims 17-18 are 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), Varley and Mitra (Cold Spring Harb Protoc 4(7):1-7 (2009) (doi: 10.1101/pdb.prot5252); previously cited), and Leamon et al (US 2013/0059762 A1 [07 March 2013; filed 16 Nov 2012]; cited herein).
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. 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 all claims for “at least one variant” in an ALK gene (independent claim 16) or that comprises an ALK fusion (independent claim 17). 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 the “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.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DIANA B JOHANNSEN whose telephone number is (571)272-0744. The examiner can normally be reached Monday-Friday, 7:30 am-3:30 pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached at (571) 272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682