Immunotherapy Response Signature

§101 §103 §112

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 . The amended claims filed 8/13/2026 are under consideration. The amendments and arguments presented in the papers filed 8/13/2026 ("Remarks”) have been thoroughly considered. The issues raised in the Office action dated 3/13/2026 listed below have been reconsidered as indicated. a) The amendments to the specification addressing priority claims and trade name or mark usage are acknowledged. b) The objections of claims 28, 30 and 34 are withdrawn in view of the amendments to the claims. c) The rejection of claim 34 under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions without significantly more has been withdrawn because it requires a step of administering a treatment to the patient in all embodiments, which integrates the judicial exceptions of claim 33. d) The rejections of claims 1, 2, 3, 5, 6, 7, 8, 9, 11, 12, 16, 17, 18, 20, 27, 28, 31 and 33 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn in view of the amendments to the claims. e) The rejections of claims 8, 9, 16 and 17 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, are withdrawn in view of the amendments to the claims. f) The rejections of claim(s) 1-3, 5-9, 11-12, 18, 20, 27, 28, 30-31, 33 and 34 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Hacohen (WO 2016/100975 A1) are withdrawn in view of the amendments to the claims. The Examiner’s responses to the Remarks regarding issues not listed above are detailed below in this Office action. New and modified grounds of rejection necessitated by amendment are detailed below and this action is made FINAL. Election/Restrictions Applicant elected without traverse Group I (claims 1-35) in the reply filed on 12/23/2025. It is noted the claims of non-elected Groups II (methods of preparing a report) and III (system claims) have been cancelled. Priority The present application is a 371 national stage entry of PCT/US2021/058741 (filed 11/10/2020), which claims benefit of: US provisional application 63/112,035 (filed 11/10/2020); and US provisional application 63/112,359 (filed 11/11/2020). Priority to the ‘359 provisional application is not recognized as it was filed after the PCT application. The priority to 11/20/2020 is recognized. Information Disclosure Statement The listing of references in the specification or the citation of references throughout the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or on a submitted IDS, they have not been considered. Claim Interpretation In claim 1, the “performing an assay” step broadly encompasses using or assaying any part of the “biological sample” and/or cell-free materials derived from the cancer in the subject. 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 30, 31 and 33 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions without significantly more. The following are modified rejections. The claims are drawn to a method, one of the four statutory classes. The claim(s) recite(s) “selecting a treatment for the cancer in the subject based on the results of [performing an assay to assess a copy number of JAK2 in a biological sample comprising cells and/or cell-free materials derived from the cancer in the subject]”. The step is an abstract as it may be performed purely in the mind by consideration a limited amount data regarding the copy number of JAK2 nucleic acids in the biological sample. The amended claim also sets forth a natural phenomenon that is the biological relationship between the copy number of JAK2 in the cancer and a patients response to an immunotherapy. In summary, the selecting step represents an abstract idea that is a mental process (MPEP 2106.04.a.2.III.A) because it is the observation and evaluation of information to reach a judgment or conclusion. Where the evaluation of data to reach a conclusion is based in the biological correlation between a biomarker, e.g., JAK2 copy number, and the presence of a phenotype, e.g., likely to benefit from an immunotherapy, such an association is an accepted part of how a biological organism functions, as an element of the claim is a natural phenomenon. MPEP 2106.04.b.I. The judicial exceptions are not integrated into a practical application because the claims do not involve: improvements to the functioning of a computer or to any other technology or technical field; applying or using the judicial exceptions to effect a particular treatment or prophylaxis for a disease or medical condition; applying the judicial exception with, or by use of, a particular machine; or effecting a transformation or reduction of a particular article to a different state or thing. The claimed limitations add insignificant extra-solution activity to the judicial exceptions as performing an assay is a mere data gathering step. MPEP 2106.05.g The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims encompass the use of suitable methods and materials known in the art (p. 3 of the instant specification), including any method capable of determining a DNA copy number can be used and the skilled artisan is aware of and capable of using a number of different platforms for assessing copy number changes (p. 29 of the instant specification). The Examiner’s response to the traversal of the 101 rejections The Remarks argue under the governing framework, claim 30 is patent-eligible because, when considered as a whole, it recites a specific laboratory-based cancer treatment-selection method applied to a cancer-derived biological sample that is not directed merely to a mental process and without conceding the merits of any previous rejection, Applicant respectfully submits that the amended claims are directed to patent-eligible subject matter (p. 18). Claim 30 remains rejected for the reason provided above, consistent with the guidance provided in the MPEP. The Remarks argue the Office Action identifies the recitation of selecting a treatment for the cancer in the subject based on the results of the assay in step (a) as an abstract idea allegedly performable in the mind and applicant respectfully disagrees and submits that this characterization improperly isolates one phrase and ignores the remainder of the claim as a whole. The Remarks argue claim 30, as amended, is not directed merely to a mental process because it requires "performing an assay to assess a copy number of JAK2 in a biological sample comprising cells and/or cell-free materials derived from the cancer in the subject... ", with the assay performed on nucleic acids of JAK2 in the sample. The Remarks argue that limitation is not merely a mental process, because it requires a physical cancer-derived biological sample and a laboratory assay performed on that sample. The Remarks argue when considered as a whole, claim 30 is directed to a specific laboratory-based evaluation of a cancer-derived biological sample for use in treatment selection, not to a purely mental process. See p. 19. The arguments have been fully considered but are not persuasive. The Examiner’s conclusion is that the claim is directed to judicial exception without significantly more, not that the claim is directed “purely” to a mental process. The Examiner has considered the claim includes a step of “performing an assay to assess a copy number of JAK2”. This step is an additional element that does not integrate the underlying judicial exceptions for the reason provided above, including that finding that the step is a data gathering step which is not significant following the guidance provided in MPEP 2106.05.g. Additional, the Examiner has considered whether or not the step of “performing an assay” is routine and conventional and found that in view of the instant specification, such a step broadly encompasses routine and conventional techniques known to the ordinary artisan. The Remarks argue that claim as a whole integrates any such exception into a practical application. The Remarks argue that claim 30 requires "performing an assay to assess a copy number ofJAK2 in a biological sample comprising cells and/or cell-free materials derived from the cancer in the subject" and "selecting a treatment for the cancer in the subject based on the results of the assay of step (a), wherein the treatment comprises an immunotherapy when the copy number of JAK2 indicates that the subject is likely to benefit from administration of the immunotherapy". The Remarks argue the specification identifies JAK2 as a gene whose copy number may be assessed for this purpose and it further describes that such copy-number analysis may be used to select checkpoint inhibitor therapy, chemotherapy, or combinations thereof, and that loss of copy number may indicate lack of benefit from checkpoint inhibitor therapy. Likewise, Example 3 describes using profiling of genes, including JAK2, to guide whether an immunotherapy or an alternative therapy is selected for treating a patient. See p. 19. The arguments have been fully considered but are not persuasive. The arguments address how the step of “performing an assay” and the step of “selecting a treatment” are related, but not how the abstract idea of “selecting a treatment” is integrated. There is no evidence of how the step of “selecting a treatment” informs how the step of “performing an assay” is carried out. Thus, the relationship between the two steps does not integrate the judicial exception. It is also noted that a judicial exception may not integrate itself (MPEP 2106.04.II.A.2) and there are no additional elements in the claim that integrate the judicial exception into a practical application. The Remarks argue the specification explains why improved treatment selection matters because checkpoint inhibitor therapy carries a high cost, is not always efficacious, and may lead to serious adverse effects including accelerated tumor growth during treatment. The Remarks argue improved identification of patients that are likely to benefit from a given therapy has clinical value and concludes claim 30 does not merely recite observing a natural relationship, but applies a specific JAK2 assay result to make a patient-specific treatment selection. See p. 20. The arguments have been fully considered but are not persuasive. The argument provide no evidence that the claimed method represents an improvement. It is important to note, the judicial exception alone cannot provide the improvement. The improvement can be provided by one or more additional elements or the improvement can be provided by the additional element(s) in combination with the recited judicial exception. See MPEP 2106.04.d. Here the step of “performing an assay” does not improve the field of evaluating copy numbers in nucleic acids; nor does the step of “selecting a treatment” improve how the step of “performing an assay” is done as the claim broadly encompasses using standard techniques to assess the copy number. The Remarks argue the assay limitations that remain in claim 1 are not merely insignificant extra-solution activity. The Remarks argue the recited sample and assay steps are merely insignificant extra-solution activity. The Remarks argue the Office Action does not establish that the assay limitations are well-known. The Remarks argue that although methods for assessing DNA copy number may be known generally, claim 30 does not simply recite performing an assay to assess DNA copy number generally but rather requires performing a specific assay to assess JAK2 copy number in a biological sample comprising cancer-derived material from the subject. See p. 20-21. The arguments have been fully considered but are not persuasive. The technique to identify the biomarker, e.g., JAK2 copy number, is generic and no specific methodology is required and broadly encompasses any method that may determine JAK2 copy number. Instant specification describes using next-generation profiling to identify JAK2 copy numbers, including next-generation sequencing and in situ hybridization (p. 65). The specification also notes that other nucleic acid analysis methods can be used instead of next generation sequencing, such as hybridization and PCR (p. 66). Thus, the specification demonstrates the routine and conventional assays are sufficient to determine the copy number of JAK2. The courts have also found that generic methods to measure a biomarker or DNA are routine and conventional. See MPEP 2106.05.d.II. The Remarks argue the recited assay limitations are significant in the sense that they impose meaningful limits on the claim, rather than being nominal or tangential. See p. 21. The arguments have been fully considered but are not persuasive. The step of “performing an assay” is analogous to performing clinical tests on individuals to obtain input for an equation and determining the level of a biomarker in blood, which has been found to be insignificant extra-solution activity. MPEP 2106.05.g. Here while the assay may not be a “clinical test” is similar in that is gathers data, e.g., JAK2 copy number, which is then used as “input” to select a treatment. Similarly, determining the level of JAK2 by determining its copy number is analogous to determining the level of a biomarker in blood as each measure the amount or level of a molecule in a sample. The Remarks argue assessing JAK2 copy number is not data gathering required for all uses of the alleged judicial exception and claim 30 does not cover all ways of using the alleged judicial exception, but instead is limited to assessing copy number of JAK2. See p. 21. The arguments have been fully considered but are not persuasive. The judicial exceptions are mental processes and natural phenomenon that are based on the copy number of JAK2. While assessing JAK2 copy number may have different uses, the judicial exceptions identified above have no other uses identified uses. For example, it is unclear how selecting an immunotherapy for cancer based on JAK2 copy numbers has any other use. There is no indication that selecting an immunotherapy for a cancer based on JAK2 copy number may be used to identify a patient as having some disease or condition. The Remarks argue the additional limitations include at a minimum, "(a) performing an assay to assess a copy number of JAK2 in a biological sample comprising cells and/or cell-free materials derived from the cancer in the subject, the assay being performed on nucleic acids of JAK2 in the biological sample" and these additional limitations are unconventional. The Remarks argue although methods for determining DNA copy number may have been known generally, that does not establish that the recited additional limitations of claim 30, either individually or as an ordered combination, were well-understood, routine, or conventional. The Remarks argue even if the underlying assay techniques for assessing DNA copy number may have been known, the Office Action has not established that claimed additional limitations directed to assessing JAK2 copy number in the biological sample, on nucleic acids of JAK2 in that sample, were merely well-understood, routine, and conventional. See p. 22. The arguments have been fully considered but are not persuasive. The arguments focus on the use of JAK2 and not whether measuring JAK2 copy numbers were routine and conventional. Also as discussed above, the specification demonstrates the routine and conventional assays are sufficient to determine the copy number of JAK2 and the courts have found generic methods to be routine and conventional. Claim Rejections - 35 USC § 112 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. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: 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 of carrying out his invention. Claims 1, 2, 3, 5, 6, 7, 8, 9, 11, 12, 16, 17, 18, 20, 27, 28, 30, 31, 33 and 34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The following rejections have been modified as necessitated by the amendments to the claims. The claim(s) 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, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claims 1, 2, 3, 5, 6, 7, 8, 9, 11, 12, 16, 17, 18, 20, 27 and 28 broadly encompass “administering a treatment for the cancer in the subject based on the assessment of step (b), wherein the treatment comprises an immunotherapy…or a therapy” based on an indication in view of the JAK2 copy number. The claim broadly encompasses administering any immunotherapy for any cancer or administering any therapy for any cancer based on any assessment of a copy number JAK2. The instant specification only describing administering (claim 1) or selecting (claim 30) a treatment in the context of head and neck tumor samples (p. 75-78, in particular 76). The only treatment evaluated was pembrolizumab or nivolumab (p. 76). The specification reasonably demonstrates possession of treating a head and neck cancer patient with pembrolizumab or nivolumab based on a loss of band 9p24, in particular the loss of genes PD-L1, PD-L2 and/or JAK2 (p. 76). Claims 30, 31, 33 and 34 recite “selecting a treatment for the cancer to the subject based on [performing an assay to assess a copy number of JAKS in a biological sample comprising cells and/or cell-free materials derived from the cancer in the subject]”. The instant specification does not demonstrate possession of the full scope of this step for the reasons outlined above. Based on the guidance in the specification as detailed above, one would not know how to select any and all immunotherapies for all cancer based on the copy number of JAK2. For example, there is no guidance as to when a CTLA-4 inhibitor, LAG-3 inhibitor or CAR T-cell therapy should be selected based on the copy number of JAK2 or when radiation or chemotherapy should be selected based on the copy number of JAK2. The Examiner’s response to the traversal of the written description rejections The Remarks argue claim 1 recites performing an assay on nucleic acids of JAK2 in a cancer-derived biological sample, assessing a copy number of JAK2, and administering a treatment based on that assessment, including immunotherapy when the JAK2 copy number indicates likely benefit from immunotherapy and another or additional therapy when the JAK2 copy number indicates likely lack of benefit and the specification reasonably conveys possession of that subject matter because the specification identifies JAK2 as a gene whose copy number may be assessed in this treatment-selection context. The Remarks argue the specification further describes that such analysis may be used to guide selection of checkpoint inhibitor therapy, chemotherapy, or combinations thereof, including where loss of copy number is associated with lack of benefit from checkpoint inhibitor therapy and the specification presents data showing that JAK2 copy number is significantly correlated with immunotherapy response across multiple cancer types and describes using gene profiling, including JAK2, to guide whether immunotherapy or an alternative therapy is selected for treatment. See p. 23. The Remarks argue claim 30 is likewise supported as it is directed to assessing JAK2 copy number in a biological sample derived from the subject's cancer and selecting treatment based on that assessment. See p. 24. The arguments have been fully considered but are not persuasive. The issue raised by the examiner is that there is no guidance demonstrating possession of the full scope of the claims. The instant specification only describing administering (claim 1) or selecting (claim 30) a treatment in the context of head and neck tumor samples (p. 75-78, in particular 76). The only treatment administered or selected was pembrolizumab or nivolumab (p. 76). The specification reasonably demonstrates possession of treating a head and neck cancer patient with pembrolizumab or nivolumab based on a loss of band 9p24, in particular the loss of genes PD-L1, PD-L2 and/or JAK2 (p. 76). This limited number of species does not demonstrate possession of the full scope of the claims. For examples, there is no guidance as to when a CTLA-4 inhibitor should be administered or selected instead of a PD-1/PDL-1 inhibitor or whether a particular JAK2 copy number results in selecting or administering the same immunotherapy across all types of cancers. While the instant specification generically describes uses of JAK2 copy numbers, the differences between mechanisms of immunotherapies and types of cancers, the species represented in the instant specification does not support the full scope of claimed invention. Claim Rejections - 35 USC § 103 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. 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. Claim(s) 1-3, 5-9, 11-12, 16-18, 20, 27, 28, 30-31, 33-34 and 42-43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hacohen (WO 2016/100975 A1). The following are new rejections necessitated by the amendments to the claims. Regarding claims 1, 3, 5, 6, 7, 18 and 20, Hacohen teaches “performing an assay” by determining genetic alterations associated with cytolytic activity in the tumor (para. 8), where the genetic alteration is the copy number gain of chromosomal band 9p24.2-p23. Hacohen further teaches in paragraph 49, referencing Fig. 6B - “Locus zoom on the 9p24.2-p23 amplification, each bar corresponding to a single gene. PNG media_image1.png 359 375 media_image1.png Greyscale Labeled genes include those with driver potential or those on the locus boundary.” The labeled genes includes JAK2 as depicted in Fig. 6B, reproduced below: Hacohen teaches determining a genetic alternation in the form of an amplification of a gene selected from PDL-1/CD274 and PDL-2/CD273 (para. 18). Hacohen teaches administering an immunotherapeutic agent to the subject if genetic alterations that are associated with induction or suppression to cytolytic activity are found in the tumor (para. 8). Hacohen further teaches patients that have high cytolytic activity, a plurality of neoantigen mutations, and mutations (esp. amplifications) in genes that function in immunosuppression, while not having mutations that eliminate all alleles required for antigen presentation and cytotoxic T-cell killing, are ideal candidates for the immunotherapy described herein. For instance, treatment with a checkpoint inhibitor may allow the immunosuppression to be reversed allowing the neoantigens to be presented to T-cells that would then kill the tumors (para. 108). It would have been prima facie obvious to have tried to use JAK2 as “gene marker” for determining a copy number representative of 9p24.2-p23, predicting a response to an immunotherapy and administering of the immunotherapeutic agent comprising an immunotherapy is “based on” the results of the determined genetic alteration of the chromosomal band 9p24.2-p23, including JAK2, PDL-1/CD274 or PDL-2/CD273. Regarding claim 2, Hacohen teaches using an array based platform for copy number determinations (para. 411). Regarding claims 7, 8 and 9, Hacohen further teaches predicting a patient will benefit from the immunotherapeutic agent based on a mutation (para. 106), such as copy number amplification (para. 91) within 9p24.2-p23, including JAK2 (Fig. 6B). Hacohen further teaches patients that have high cytolytic activity, a plurality of neoantigen mutations, and mutations (esp. amplifications) in genes that function in immunosuppression, while not having mutations that eliminate all alleles required for antigen presentation and cytotoxic T-cell killing, are ideal candidates for the immunotherapy described herein. For instance, treatment with a checkpoint inhibitor may allow the immunosuppression to be reversed allowing the neoantigens to be presented to T-cells that would then kill the tumors (para. 108). Thus, individuals without those features may be ideal candidates for therapies other than immunotherapies. Regarding claims 11 and 12, Hacohen teaches the immunotherapeutic agent comprises at least one checkpoint inhibitor (para. 26). Hacohen teaches the checkpoint inhibitor may be an anti-PD1 antibody such as nivolumab (para. 26). Regarding claims 16-17, Hacohen teaches “performing an assay” by determining genetic alterations associated with cytolytic activity in the tumor (para. 8), where the genetic alteration is the copy number gain of chromosomal band 9p24.2-p23 (containing PDL1, PDL2) (para. 11). Alternatively, Hacohen teaches determining a genetic alternation in the form of an amplification of a gene selected from PDL-1/CD274 and PDL-2/CD273 (para. 18). Hacohen teaches administering an immunotherapeutic agent to the subject if genetic alterations that are associated with induction or suppression to cytolytic activity are found in the tumor (para. 8), i.e. the administering of the immunotherapeutic agent is “based on” the results of the determined genetic alteration of the chromosomal band 9p24.2-p23, PDL-1/CD274 and/or PDL-2/CD273. Hacohen does not teach the subject has a loss of copy number of JAK2, and administering a treatment that is different from the immunotherapy. Hacohen teaches treating patients with a gain of chromosomal band 9p24.2-p23 as noted above with an immunotherapeutic agent because the patient is likely to benefit (para. 91 and 106). Hacohen further teaches patients that have high cytolytic activity, a plurality of neoantigen mutations, and mutations (esp. amplifications) in genes that function in immunosuppression, while not having mutations that eliminate all alleles required for antigen presentation and cytotoxic T-cell killing, are ideal candidates for the immunotherapy described herein. For instance, treatment with a checkpoint inhibitor may allow the immunosuppression to be reversed allowing the neoantigens to be presented to T-cells that would then kill the tumors (para. 108). However, it would have been prima facie obvious to the ordinary artisan that a patient without a gain of gain of chromosomal band 9p24.2-p23 or a loss of chromosomal band 9p24.2-p23, would not benefit from an immunotherapeutic agent. Hacohen teaches the genetic alteration associated with tumor resistance to cytolytic activity is a mutation in a gene which promotes immune responses or immune-mediated cytotoxicity, and the mutation may be deletion eliminates expression or activity of the encoded polypeptide (para. 93). It would have been prima facie obvious to have treated those patients with a combination , such a combination including a chemotherapeutic agent (para. 64). Regarding claims 27 and 28, Hacohen teaches the cancer is head and neck cancer (para. 11). Regarding claims 30 and 31, Hacohen teaches “performing an assay” by determining genetic alterations associated with cytolytic activity in the tumor (para. 27), where the genetic alteration is the copy number gain of chromosomal band 9p24.2-p23. Hacohen further teaches in paragraph 49, referencing Fig. 6B - “Locus zoom on the 9p24.2-p23 amplification, each bar corresponding to a single gene. Labeled genes include those with driver potential or those on the locus boundary.” The labeled genes includes JAK2 as depicted in Fig. 6B, reproduced below: PNG media_image1.png 359 375 media_image1.png Greyscale Hacohen teaches “selecting a treatment for the cancer” of a subject by selecting the subject for immunotherapy if the genetic alteration associated with induction of cytolytic activity, tumor resistance to cytolytic activity and/or suppression of cytolytic activity is detected in the tumor (para. 27). Hacohen further teaches patients that have high cytolytic activity, a plurality of neoantigen mutations, and mutations (esp. amplifications) in genes that function in immunosuppression, while not having mutations that eliminate all alleles required for antigen presentation and cytotoxic T-cell killing, are ideal candidates for the immunotherapy described herein. For instance, treatment with a checkpoint inhibitor may allow the immunosuppression to be reversed allowing the neoantigens to be presented to T-cells that would then kill the tumors (para. 108). Regarding claim 33, Hacohen teaches the immunotherapy comprises administration of a checkpoint inhibitor (para. 28). Regarding claim 34, Hacohen teaches administering the selected immunotherapy (para. 8). Regarding claim 42, the claim broadly encompasses a cancer comprising breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, Hodgkin lymphoma, liver cancer, lung cancer, renal cell cancer, melanoma, stomach cancer, rectal cancer, or any solid tumor that exhibits DNA replication errors comprising comprise one or more of mutations, insertions, deletions, mismatch repair deficiency (MMRd),microsatellite instability (MSI-H), high tumor mutational burden (TMB), or copy number variations (CNV). Hacohen teaches the cancer is head and neck cancer (para. 11). Regarding claim 43, Hacohen teaches the checkpoint inhibitor is a PD-1 pathway inhibitor (para. 26). Examiner’s Response the Remarks regarding the Hacohen reference The Remarks argue Hacohen is silent regarding JAK2 copy number (p. 26-27). While a review of the Hacohen reference in concert with the interview held 6/30/226 found the Hacohen did not mention JAK2 in the text, a more thorough review on the entire reference, including the figures, found that Hacohen does identify JAK2 as a potential gene of interest in chromosome 9. The claims are rendered obvious for the reasons provided above in the new 103 rejections as necessitated by the amendments to the claims. The Remarks argues Hacohen teaches does not teach loss of the relevant copy number or administering a different treatment on that basis and the rejection instead reasons that, because a gain may indicate benefit, absence of gain, or the presence of loss, would indicate lack of benefit. The Remarks argue teaching that gain may correlate with benefit does not teach or suggest that loss of copy number of JAK2 is a negative predictive biomarker and Hacohen also does not equate absence of amplification with loss, or otherwise identify loss as a reason to withhold immunotherapy. The Remarks argue a disclosure of copy number gain or amplification in the 9p24.2-p23 region does not, without more, provide a reason to select JAK2 specifically and then infer the opposite therapeutic conclusion from loss of JAK2 copy number. The Remarks argue paragraph 64 also does not cure this deficiency because paragraph 64 merely states that a combination therapy may include additional agents, including chemotherapeutic agents and it does not teach selecting chemotherapy, or any treatment different from immunotherapy, for a patient identified by loss of copy number of JAK2, and it does not provide a reason to do so with a reasonable expectation of success. The Remarks argue the rejection therefore relies on hindsight rather than on a teaching or suggestion in the prior art and the rejection also fails to identify any articulated reason, grounded in the prior art, why a skilled artisan would have specifically selected loss of JAK2 copy number as the basis for directing a patient away from immunotherapy and toward chemotherapy or combination treatment. See p. 27. The arguments have been fully considered but are not persuasive. Hacohen teaches the genetic alteration associated with tumor resistance to cytolytic activity is a mutation in a gene which promotes immune responses or immune-mediated cytotoxicity, and the mutation may be deletion eliminates expression or activity of the encoded polypeptide (para. 93). In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, based on the teachings of Hacohen and the knowledge available to one of ordinary skill, that a lack of JAK2 is linked to a tumor resistance to cytolytic activity and as such, to have treated the patient with a therapy other than an immunotherapy. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Conclusion No claims 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. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH G DAUNER whose telephone number is (571)270-3574. The examiner can normally be reached 7 am EST to 4:30 EST with second Fridays Off. 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 5712723157. 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. /JOSEPH G. DAUNER/ Primary Examiner, Art Unit 1682