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 .
Response to Amendment
The amendment filed 16 January 2026 is acknowledged. Claims 110 and 116 are amended. Claims 113, 114, and 117 are canceled. Claims 130-134 are new.
Claim Status
Claims 110-112, 115-116, 118-134 are pending. Claims 118-129 are withdrawn as drawn to an unelected invention as previously described. Claims 110-112, 115-116, and 130-134 are under examination in the instant office action.
Withdrawal of Rejections
The rejection of claims 114 and 116-117 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of the amendment to the claims.
The rejection of claim 114 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 is moot in view of the cancellation of claim 114.
The rejection of claims 113 and 114 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 for new matter is moot in view of the cancellation of claims 113 and 114.
The rejection of claim 117 under 35 U.S.C. 103 as being unpatentable over Benson et. al. in view of Aiuti et. al. is moot in view of the amendment to the claims.
The rejection of claims 113 and 114 under 35 U.S.C. 103 as being unpatentable over Benson et. al. in view of NCT02982902 is moot in view of the amendment to the claims.
Claim Rejections - 35 USC § 112(b)- New, necessitated by amendment
Claim 132 is 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.
Claim 132 is indefinite for the recitation of “wherein the T cell are at least those selected from the group consisting of:” followed by a list separated by the conjunction “and”. It is unclear what it means for T cells to be “at least those” and which or how many would be required to be selected from the list, and to what degree. For the purposes of expedited prosecution, the claim will be interpreted as “wherein the T cells are T cells selected from the group consisting of: […]”
Claim Rejections - 35 USC § 101- Maintained, changes necessitated by amendment
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 116, 130, 133, and 134 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract idea without significantly more.
The claims recite a method for detecting an increase in the number of Tim-3-positive T cells in a subject, wherein the subject has a chronic viral infection. The claim states that, the method comprising detecting a decrease in copy number, amount, and/or activity of Ptpn2 in immune cells from the subjects. This indicates that, although not explicitly recited, detecting a decrease requires the comparison of the different copy number, amount, or activity values, which is both a mathematical concept and a mental step because it can be performed mentally. Further, it is noted that the relationship between gene expression or activity (e.g. Ptpn2 activity in a T cell) and the expression of a biomarker, Tim3, is a natural phenomenon of gene regulation and activity natively performed by the T cell. For example, although not prior art, Hudson, William H., et al. "Proliferating transitory T cells with an effector-like transcriptional signature emerge from PD-1+ stem-like CD8+ T cells during chronic infection." Immunity 51.6 (2019): 1043-1058 (Of record, PTO-892 dated 10/16/2025) teaches that “Stem-like Tcf-1+ CD8+ T cells initially differentiated into a transitory population of CD101−Tim3+ cells that later converted into CD101+ Tim3+ cells. Recently generated CD101−Tim3+ cells proliferated in vivo, contributed to viral control, and were marked by an effector-like transcriptional signature including expression of the chemokine receptor CX3CR1, pro-inflammatory cytokines, and granzyme B” (Summary), suggesting that the relationship between Tim3 expression and T effector function is a natural phenomenon driven by gene regulation and response to environment by the T cell. (Step 2A Prong 1: yes, recites an abstract idea).
This judicial exception is not integrated into a practical application because the claim's function is to identify the presence of T cells with the particular correlation between decrease in PTPN2 copy number, amount, or activity and the expression of Tim3; there is no application of the detection of Tim-3-positive T cells via the correlation with PTPN2 activity. Also, as in MPEP 2106.04(d), the claim does not use the judicial exception to improve a computer or some other technology, does not apply the judicial exception for a particular treatment, does not perform the data analysis using a particular machine, and does not use the judicial exception to transform one article to another. Instead, the non-mathematical steps of detecting a decrease in copy number, amount, and/or activity of PTPN2 insignificant extra solution activity because it is mere data gathering. MPEP 2106.05(g) states that the courts have found the following to be mere data gathering: performing clinical tests on individuals to obtain input for an equation, In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989); and determining the level of a biomarker in blood, Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. at 79, 101 USPQ2d at 1968. In this claim, as in the prior cases, the non-mathematical steps of the method merely perform laboratory manipulation on samples from the subject. (Step 2A Prong 2: no, not integrated into a practical application)
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because, in addition to the considerations in Step 2A Prong 2, the non-mathematical and non-mental data gathering steps are well-understood, routine, conventional activity in the field. For example, the specification teaches: "For example, biological material may [sic] obtained from a blood sample, such as a peripheral or cord blood sample, or harvested from bone marrow or amniotic fluid. Methods for obtaining such samples are well known to the artisan" (p. 135 lines 5-7); "In a particular embodiment, the mRNA expression level can be determined both by in situ and by in vitro formats in a biological sample using methods known in the art […] Additionally, large numbers of tissue samples can readily be processed using techniques well-known to those of skill in the art, such as, for example, the single-step RNA isolation process of Chomczynski (1989, U.S. Patent No. 4,843,155) […]" (p. 86 line 8-18); "A skilled artisan can readily adapt known mRNA detection methods for use in detecting the level of PTPN2 mRNA expression levels" (p. 86 line 33 - p. 87 line 2) "Methods for detecting the phosphatase function of Ptpn2 are well-known in the art. For example, the phosphorylation of Ptpn2 targets, including receptor tyrosine kinases (e.g., INSR, EGFR, CSF IR PDGFR, etc.), non-receptor tyrosine kinases (e.g., JAK1, JAK.2, JAK3, etc.), Src family kinases (e.g., Fyn, Lek, etc.) and STAT family members (e.g., STAT1, STAT3, STAT5A, STAT5B, STAT6, etc.), can be measured and compared before and after PTPN2 inhibitor treatment” (p. 69 lines 29- p. 70 line 2) (Emphases are the examiner’s). In summary, the instant specification teaches that the sample collection and analysis required to product the data for analysis are well-known in the art. (Step 2B: no, not significantly more). Therefore, claim 116 is rejected as being directed to a judicial exception.
Regarding claim 130, claim 130 recites the detection of the decrease in copy number, amount, and/or activity of Ptpn2 in a subject that has a chronic viral infection. This does not add significantly more to the judicial exception because it amounts to merely reciting an additional naturally occurring relationship which is the relationship between the copy number or activity of PTPN2 and the expression of the biomarker TIM3 in the immune cells of a subject who has a chronic viral infection.
Regarding claims 133 and 134, the claims recites wherein Ptpn2 comprises a nucleic acid sequence with at least 95% identity to SEQ ID NOs: 1, 3, 5, 7, 9, 11, and 13 or encodes an amino acid sequence having at least 95% identity to SEQ ID NOs: 2, 4, 6, 8, 10, 12, and 14; b) Ptpn2 is human or mouse; c) the subject is an animal model of the viral infection; and d) the subject is a mammal (claim 133) and wherein the subject is a mouse or a human (claim 134). This does not add significantly more to the judicial exception because, as described for the subject with the chronic viral infection, applies the comparison of Ptpn2 in the particular context of an animal model of viral infection wherein the Ptpn2 decrease is a decrease in, for example, mouse or human Ptpn2 (e.g. human PTPN2 is 100% identical to SEQ ID NO: 1 as evidenced by PTPN2 protein tyrosine phosphatase, non-receptor type 2 [ Homo sapiens (human) ] dated 26 August 2015, the PTPN2 human gene includes sequence Accession EF445017.1 (Of record, PTO-892 dated 4/24/2025).
Response to Arguments
Applicant argues that claim 116 as amended does not recite a judicial exception because it does not recite a mental step or abstract idea; rather, claim 116 only recites the active process of detecting a biomarker (Remarks p. 1/16/2026). Applicant further argues that the eligibility of amended claim 116 is clear from the current guidelines under Subject Matter Eligibility Examples: Life Sciences (2016) specifically Example 29 which indicates that claim 1 reciting a method of detecting JUL-1 is not directed towards a judicial exception. This is not persuasive because the fact pattern of Example 29 does not match that of the instant claim. Claim 1 of the example recites:
1. A method of detecting JUL-1 in a patient, said method comprising: a. obtaining a plasma sample from a human patient; and b. detecting whether JUL-1 is present in the plasma sample by contacting the plasma sample with an anti-JUL-1 antibody and detecting binding between JUL-1 and the antibody.
The examiner notes that this claim recites a method of detecting a biomarker and subsequently recites active method steps comprising detecting by contacting with an antibody. The instant claim 116 recites a method of detecting an increase in the number of Tim-3-positive T cells in a subject comprising detecting a decrease in copy number, amount, and/or activity of Ptpn2 in immune cells from the subject. The instant claim 116, as described above, recites a method for detecting relative changes in one biomarker by detecting a decrease in another. The terms increase and decrease, as described above, recite mathematical concepts and a mental process; and further, the preamble method relates to Tim-3 while the biomarker actually being detected is Ptpn2, which is directed towards the relationship between Ptpn2 gene expression, T cell effector function, and Tim3 expression, as described in the 101 rejection above. Therefore, as described, the judicial exception fails step 2A and 2B and is not integrated into a practical application or incorporating significantly more. The Examiner notes that claim 131, which recites wherein the subject is administered engineered T cells having a decreased copy number of Ptpn2, which is a particular treatment or prophylaxis, is not rejected and is sufficient to resolve the 101 rejection as described.
Claim Rejections - 35 USC § 103- Maintained, changes necessitated by amendment
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.
Claims 110-112 and 115 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20190284529 to Benson et. al., effectively filed 15 March 2018 (PTO-892 dated 4/24/2025) as evidenced by PTPN2 protein tyrosine phosphatase, non-receptor type 2 [ Homo sapiens (human) ] dated 26 August 2015 (PTO-892 dated 4/24/2025) and Yang L, Baltimore D. Long-term in vivo provision of antigen-specific T cell immunity by programming hematopoietic stem cells. Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4518-23. doi: 10.1073/pnas.0500600102. Epub 2005 Mar 9. PMID: 15758071; PMCID: PMC553287 (PTO-892 dated 4/24/2025) as evidenced by Wherry EJ, et. al. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol. 2003 Apr;77(8):4911-27. doi: 10.1128/jvi.77.8.4911-4927.2003. PMID: 12663797; PMCID: PMC152117.
Claim interpretation: Instant claim 110 recites “A method of treating a subject or increasing the number of Tim-3-positive T cell in a subject having a chronic viral infection, comprising administering to the subject a therapeutically effective amount of engineered T cells having a decreased copy number of Ptpn2. MPEP 2111.02 states, “The claim preamble must be read in the context of the entire claim. The determination of whether preamble recitations are structural limitations or mere statements of purpose or use "can be resolved only on review of the entirety of the [record] to gain an understanding of what the inventors actually invented and intended to encompass by the claim" as drafted without importing "‘extraneous’ limitations from the specification." Corning Glass Works, 868 F.2d at 1257, 9 USPQ2d at 1966. If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020)”. The instant preamble recitation “A method of increasing the number of Tim-3-positive T cells” does not further limit the instant claim because it is a recitation of intended purpose or result that does not result in a structural difference to the active steps of administering to a subject having a chronic viral infection a therapeutically effective amount of engineered T cells having a decreased copy number of Ptpn2, wherein the condition is a viral infection. The increase of Tim-3-positive T cells is the intended purpose or result of the invention, and thus does not further limit the scope of the instant method.
Benson et. al. teaches “a method of treating a disease or disorder in a subject in need thereof comprising administering an effective amount of a modified immune effector described herein or a composition thereof. In some embodiments, the disease or disorder is a cell proliferative disorder, an inflammatory disorder, or an infectious disease. In some embodiments, the disease or disorder is a cancer or a viral infection” [0112]. Benson et. al. teaches “In some embodiments, the modified effector cells described herein comprise reduced expression and/or function of the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene. PTPN2 is also a member of the PTP family. Epidermal growth factor receptor and the adaptor protein Shc have been reported to be substrates of PTPN2, which suggested a role for PTPN2 in growth factor mediated cell signaling. In some embodiments, the modified effector cells described herein comprise an inactivating mutation in the PTPN2 gene” [0236-0237]. The inactivating mutation is generated, in some cases, by a gene-regulating systems comprising a gRNA and a Cas endonuclease wherein the gRNA comprises a target domain sequence binding to PTPN2 [0076] (reads on “decreased copy number of Ptpn2). Benson et. al. specifically teaches a method of treating tumor growth in a mouse model of cancer treated with “Ptpn2-edited OT1 T cells compared to unedited OT1 T cells” ([0121], Fig. 7A-Fig. 7E, [0548]) or “Ptpn2-edited PMEL T cells compared to unedited T cells” (Fig. 8A, [0550-0551]). Benson et. al. shows that genetic knockdown of PTPN2 results in increased pSTAT signaling in response to IFNg (Fig. 17, [0615-0616]).
Regarding claim 1, Benson et. al. does not explicitly teach the method comprising administering the genetically engineered T cells having a genomic inactivation of Ptpn2, wherein the condition is a chronic viral infection. Benson et. al. teaches “In some embodiments, the modified immune effector cells and gene-regulating systems described herein may be used in the treatment of a viral infection. In some embodiments, the virus is selected from one of adenoviruses, herpesviruses (including, for example, herpes simplex virus and Epstein Barr virus, and herpes zoster virus), poxviruses, papovaviruses, hepatitis viruses, (including, for example, hepatitis B virus and hepatitis C virus), papilloma viruses, orthomyxoviruses (including, for example, influenza A, influenza B, and influenza C), paramyxoviruses, coronaviruses, picornaviruses, reoviruses, togaviruses, flaviviruses, bunyaviridae, rhabdoviruses, rotavirus, respiratory syncitial virus, human immunodeficiency virus, or retroviruses.” As evidenced by Wherry et. al. HIV, EBV, cytomegalovirus, hepatitis B virus, and hepatitis C virus are all persistent viruses (reads on chronic viral infections) wherein CD8 T cell functional impairment (exhaustion) can accompany ineffective viral control (p. 4911 left column ¶1-right column ¶2).
Regarding claims 111 and 112, Benson et. al. discloses that the gene may be modified in a human or mouse Ptpn2 immune effector cell [0164] (reads on Ptpn2 is human or mouse). Benson et. al. discloses that the gene PTPN2 sequence is NCBI ID 5771. As evidenced by PTPN2 protein tyrosine phosphatase, non-receptor type 2 [ Homo sapiens (human) ] dated 26 August 2015, the PTPN2 human gene includes sequence Accession EF445017.1 which is 100% identical to instant SEQ ID NO: 1. As discussed regarding claim 110 above, Benson et. al. teaches administration of the T-cells to mouse models of cancer (reads on the subject is an animal model of the condition and the subject is a mammal).
Regarding claim 115, Benson et. al. teaches that the cells are mouse T cells [0164] and specifically discloses, for example, OT-1 T cells, which, as evidenced by Yang L, Baltimore D. Long-term in vivo provision of antigen-specific T cell immunity by programming hematopoietic stem cells. Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4518-23. doi: 10.1073/pnas.0500600102. Epub 2005 Mar 9. PMID: 15758071; PMCID: PMC553287 are CD8+ mouse T cells obtained from genetically modified mice (See “Characterization of the Antigen-Specific CD8 and CD4 T Cells Generated by Genetic Programming of WT HSCs” Section).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to administer the T cells comprising a genetic inactivation in the Ptpn2 gene as taught by Benson et. al. in a method of treating a HIV, hepatitis B, hepatitis C, EBV (reads on chronic viral infections as evidenced by Wherry et. al.) as taught by Benson et. al. in order to benefit from the increased T cell effector functions such as cytotoxicity and increased responsiveness to cytokines as taught by Benson et. al. This would have a predictable effect because Benson et. al. teaches that T cells with a Ptpn2 mutation have increased immune function which an artisan would expect to be effective in treating conditions such as cancer and viral infections.
Claims 116 and 130-132 and 134 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20190284529 to Benson et. al., effectively filed 15 March 2018 (PTO-892 dated 4/24/2025) as evidenced by Wherry EJ, et. al. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol. 2003 Apr;77(8):4911-27. doi: 10.1128/jvi.77.8.4911-4927.2003. PMID: 12663797; PMCID: PMC152117, further in view of Aiuti et. al. Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome, Science 341, 6148, published 11 July 2013 (IDS 8/17/2021 NPL No. CA).
Claim interpretation: Instant claim 116 recites “A method for detecting an increase in the number of Tim-3-positive T cells in a subject, comprising detecting a decrease in copy number, amount, and/or activity of Ptpn2 in immune cells from the subject”. MPEP 2111.02 states, “The claim preamble must be read in the context of the entire claim. The determination of whether preamble recitations are structural limitations or mere statements of purpose or use "can be resolved only on review of the entirety of the [record] to gain an understanding of what the inventors actually invented and intended to encompass by the claim" as drafted without importing "‘extraneous’ limitations from the specification." Corning Glass Works, 868 F.2d at 1257, 9 USPQ2d at 1966. If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020)”. The instant preamble recitation “A method for detecting an increase in the number of Tim-3-positive T cell” does not further limit the instant claim because it is a recitation of intended purpose or result that does not result in a structural difference to the active steps of administering to a subject having a condition that would benefit from an increased immune response a therapeutically effective amount of engineered T cells having a decreased copy number of Ptpn2, wherein the condition is a viral infection. The detection of Tim-3-positive T cells is the intended purpose or result of the invention, and thus does not further limit the scope of the instant method beyond the recited active method steps.
As described in the 103 rejection above in regards to claims 110-112 and 115, modified Benson et. al. teaches a method of treating a condition that would benefit from an increased immune response in a subject, wherein the subject is administered a therapeutically effective amount of T cells having a genomic inactivation of Ptpn2, wherein the condition is a viral infection. In regards to monitoring the progression of the condition, Benson et. al. teaches that body weight and tumor volume were measured at least twice per week after IV administration of the Pton-2 gene-inactivated T cells [0546]. Benson et. al. teaches detecting the amount of PTPN2 and the activity of PTPN2 (via pSTAT activity/IFNg response) by Western blot in a T cell sample prior to and after gene editing, wherein the unedited sample has a higher amount of PTPN2 than the edited sample (Fig. 17). Regarding claim 117, Benson et. al. teaches the method comprising mouse OT1 T cells ([0121], Fig. 7A-Fig. 7E, [0548]). Benson et. al. does not teach a method for detecting an increase in the number of Tim-3-positive T cells in a subject having a condition that would benefit from an increase immune response, wherein the method comprises detecting copy number, amount, and/or activity in a first sample comprising immune cells from the subject wherein the subject is administered a therapeutically effective amount of engineered T cells having a genomic inactivation of Ptpn2.
Aiuti et. al. resolves this deficiency. Aiuti et. al. teaches a method of treating a patient with Wiskott-Aldrich syndrome (WAS) (a condition that could benefit from an increase in immune function) by administering genetically modified HSCs that increase the function of the WAS gene which is non-functional in these patients (Abstract). Aiuti et. al. teaches monitoring the improvement of immune function over time by monitoring the engraftment of transduced cells (vector copy number, equivalent to copy number) and WASP expression after gene therapy by taking subsequent samples in different hematopoietic stem cell lineages from peripheral blood or bone marrow over time, specifically in CD34+ progenitor cells (Figure 1). Aiuti et. al. also teaches that “Interestingly, the proportion of WASP+ cells was higher in PB-derived platelets as compared with their BM-derived counterparts (fig. S6), suggesting a preferential migration or selective survival advantage of gene-corrected platelets in the periphery”.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to apply the method of measuring the effectiveness of gene therapy in HSCs in Aiuti et. al. to the subjects treated via administering gene-edited T cells of modified Benson et. al. in order to benefit from assessing the effectiveness of the engraftment and gene therapy to enhance the immune system and the effects on immune system cells, such as to detect a survival advantage of PTPN2 modified T-cells as described for the gene-corrected platelets as taught in Aiuti et. al. This combination would result in a method of monitoring the progression of a condition by detecting in a subject sample at a first point in time the copy number, amount, and/or activity of Ptpn2 in T cells; wherein the loss of Ptpn2 in immune cells from the subject would indicate continued survival and engraftment of the T cells. This would have had a predictable effect of allowing monitoring of the efficacy of the treatment or duration of the decrease in Ptpn2 levels in T cells after they were administered because the difference in target genes being detected between Aiuti et. al. and Benson et. al. would not change these routine and conventional methods of detection and monitoring beyond minor changes in antibodies or sequences used to detect the WAS gene and product vs. the Ptpn2 gene and products.
Regarding claim 130, Benson et. al. does not explicitly teach the method comprising administering the genetically engineered T cells having a genomic inactivation of Ptpn2, wherein the condition is a chronic viral infection. Benson et. al. teaches “In some embodiments, the modified immune effector cells and gene-regulating systems described herein may be used in the treatment of a viral infection. In some embodiments, the virus is selected from one of adenoviruses, herpesviruses (including, for example, herpes simplex virus and Epstein Barr virus, and herpes zoster virus), poxviruses, papovaviruses, hepatitis viruses, (including, for example, hepatitis B virus and hepatitis C virus), papilloma viruses, orthomyxoviruses (including, for example, influenza A, influenza B, and influenza C), paramyxoviruses, coronaviruses, picornaviruses, reoviruses, togaviruses, flaviviruses, bunyaviridae, rhabdoviruses, rotavirus, respiratory syncitial virus, human immunodeficiency virus, or retroviruses.” As evidenced by Wherry et. al. HIV, EBV, cytomegalovirus, hepatitis B virus, and hepatitis C virus are all persistent viruses (reads on chronic viral infections) wherein CD8 T cell functional impairment (exhaustion) can accompany ineffective viral control (p. 4911 left column ¶1-right column ¶2).
Regarding claim 131, modified Benson et. al. as described above teaches administering Ptpn2-gene-inactivated T cells (reads on engineered T cells having a decreased copy number).
Regarding claim 132, modified Benson et. al. teaches that the cells are mouse T cells [0164] and specifically discloses, for example, OT-1 T cells, which, as evidenced by Yang L, Baltimore D. Long-term in vivo provision of antigen-specific T cell immunity by programming hematopoietic stem cells. Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4518-23. doi: 10.1073/pnas.0500600102. Epub 2005 Mar 9. PMID: 15758071; PMCID: PMC553287 are CD8+ mouse T cells obtained from genetically modified mice (See “Characterization of the Antigen-Specific CD8 and CD4 T Cells Generated by Genetic Programming of WT HSCs” Section).
Regarding claim 134, modified Benson et. al. discloses that the gene may be modified in a human or mouse Ptpn2 immune effector cell [0164] (reads on Ptpn2 is human or mouse). Benson et. al. discloses that the gene PTPN2 sequence is NCBI ID 5771. As evidenced by PTPN2 protein tyrosine phosphatase, non-receptor type 2 [ Homo sapiens (human) ] dated 26 August 2015, the PTPN2 human gene includes sequence Accession EF445017.1 which is 100% identical to instant SEQ ID NO: 1. Benson et. al. teaches administration of the T-cells to mouse models of cancer and Aiuti et. al. reads on a method of detection in administering HSCs to a human. Therefore, it would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the modified method on Benson et. al. by administering Ptpn2-gene-inactivated T cells to a mouse or a human with a chronic viral infection in order to benefit from the improved method of treating an immune disorder with T cells that have increased cytotoxicity and activation as taught by modified Benson et. al. This would have a predictable effect because Aiuti et. al. suggests monitoring gene-modified adoptive cell therapy in a human and Benson et. al. teaches T-cell adoptive cell therapy in humans and mouse models of human disease; therefore, and artisan would expect this increase in T-cell function to apply to both mouse and human subjects.
Response to Arguments
Applicant’s arguments dated 1/16/2026 have been fully considered but are not persuasive. Applicant argues that “Benson merely describe a wide variety of generic agents for treating a laundry list of generic conditions without reasonable guidance regarding the further selection of the particular agent or the condition recited in the pending claims. Importantly, Benson mentions “viral infection” only two times, and provides no data or information that the agent would even be effective in treating a viral infection. As described in the 103 rejection above, Benson et. al. describes the administration of genetically modified T cells in order to treat a cell proliferative disorder, an inflammatory disorder, or an infectious disease. In some embodiments, the disease or disorder is a cancer or a viral infection. Viral infections are therefore a particular embodiment recited by Benson et. al. Further, as described in the 103 rejection above, Benson et. al. recites a list of types of viral infections that may be treated with the particular treatment. Although Benson et. al. lists multiple genes that may be modified in order to improve T cell function, Benson et. al. teaches the improved efficacy of Ptpn2-gene-inactivated T cells in treating cancer compared to unedited T cells. It is reasonable, then, to enquire what scope of predictability would be understood by a person of ordinary skill in the art by the teachings of Benson et. al. What the art shows is that an artisan would have a reasonable expectation of success in treating the different diseases that can be improved by increased effector T cell function using adoptive T cell therapy with genetically modified T cells with increased effector T cell function. For example, Benson et. al. further identifies CBLB knockout as a modification that improves T cell activity and cytotoxicity against cancer (Fig. 7A). CBLB knockout has also been shown to improve T-cell function in the context of viral infection. Ou, Rong, et al. "Control of virus-specific CD8+ T-cell exhaustion and immune-mediated pathology by E3 ubiquitin ligase Cbl-b during chronic viral infection." Journal of virology 82.7 (2008): 3353-3368 teach that “Here, we have established that in the murine lymphocytic choriomeningitis virus (LCMV) model, induction of the T-cell receptor signaling inhibitor molecule E3 ligase Cbl-b is critically involved in this decision. In particular, our data revealed that Cbl-b controls the program responsible for T-cell tolerance (exhaustion) induction during a chronic viral infection. Thus, Cbl-b−/− mice infected with a low dose of LCMV Docile mount a strong CD8+ T-cell response that rapidly clears the infection, and the animals remain healthy” (Abstract). Ou et. al. and Benson et. al. also describe the problems faced by wildtype T cells in clearing cancer or a viral infection in as similar scientific problems. MPEP §2144.02 states “The rationale to support a rejection under 35 U.S.C. 103 may rely on logic and sound scientific principle. In re Soli, 317 F.2d 941, 137 USPQ 797 (CCPA 1963). However, when an examiner relies on a scientific theory, evidentiary support for the existence and meaning of that theory must be provided. In re Grose, 592 F.2d 1161, 201 USPQ 57 (CCPA 1979)”. Ou et. al. state “Persistent viral infections in human and animal models are associated with a failure of the host immune response to generate and sustain functional CD8+ and CD4+ T-cell populations as well as antibodies to neutralize infectivity (for reviews, see references 10, 12, 22, 26, 42, 60, and 62). From an evolutionary viewpoint, down-regulation of the immune response represents an adaptive mechanism that limits the damage caused by overaggressive T cells and influences antiviral immunity and the outcome of a viral infection” (p. 3353 left column ¶1) whereas Benson et. al. teaches “Factors limiting the efficacy of genetically modified immune cells as cancer therapeutics include (1) cell proliferation, e.g., limited proliferation of T cells following adoptive transfer; (2) cell survival, e.g., induction of T cell apoptosis by factors in the tumor environment; and (3) cell function, e.g., inhibition of cytotoxic T cell function by inhibitory factors secreted by host immune cells and cancer cells and exhaustion of immune cells during manufacturing processes and/or after transfer […] The present disclosure provides immune cells comprising decreased expression and/or function of one or more endogenous target genes wherein the modified immune cells demonstrate an enhancement of one or more effector functions including increased proliferation, increased infiltration into tumors, persistence of the immune cells in a subject, and/or increased resistance to immune cell exhaustion” [0006-0007]. Therefore, the state of the art and Benson et. al. suggest there is a reasonable expectation of success that genetically modified T cells with improved effector functions would have improved efficacy against a chronic viral infection if they also have improved efficacy against cancer.
Applicant further argues that the claims as instantly amended overcome the teachings of Benson et. al. because Benson et. al. does not teach a chronic viral infection (Remarks 1/16/2026 p. 11-12). This is not persuasive in view of the maintained 103 above because as described and as evidenced by Wherry et. al., Benson lists embodiments for viral infections among which several are understood in the art to be embodiments of chronic viral infections, such as HIV.
Lastly, Applicant argues that neither Benson et. al. nor the other cited documents teach or suggest the “surprising therapeutic benefits of the methods of the present invention in treating a chronic viral infection”. MPEP §2145 states that “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979)” and MPEP §716.02(a) teaches “"A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue” and “Evidence of unobvious or unexpected advantageous properties, such as superiority in a property the claimed compound shares with the prior art, can rebut prima facie obviousness. "Evidence that a compound is unexpectedly superior in one of a spectrum of common properties . . . can be enough to rebut a prima facie case of obviousness”. Applicant describes a series of results in the instant specification demonstrating 1) Ptpn2 regulates proliferation and enhances CD8+ T cell exhaustion in response to a mouse model of chronic viral infection and 2) the mechanism by which Ptpn2 deletion acts is by promoting Tim3+ Granzyme B+ T cells. As described in the 103 rejection and response to arguments above, Benson et. al. makes obvious a method of treating chronic viral infection comprising administering Ptpn2-gene-inactivated T cells for improved T cell effector function and that there is a reasonable expectation of success in improved effector T-cell function compared to wildtype T-cells, and there is a further reasonable expectation of success that the improved effector T-cell function would apply to both cancer and chronic viral infections. After careful consideration of Applicant’s data and the prior art, Benson et. al. makes obvious the instant claims because the benefit shown in treating a chronic infection is within the scope of improvement that an artisan would have a reasonable expectation of success of achieving from the teachings of Benson et. al.
Although Benson et. al. does not particularly address Tim3+ Granzyme B+ cells, as set forth in MPEP § 2145 (II), “[m]ere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention”. Furthermore, MPEP § 716.02(e) states that “[a]n affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. See also MPEP § 2112.01. In response, it is noted that while new and non-obvious uses of old compositions may be patentable, MPEP § 2112.02(II) states that “when the claim recites using an old composition or structure and the ‘use’ is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978)”. Products of identical composition cannot have mutually exclusive properties. See MPEP § 2112.01. As evidenced by the instant specification, Ptpn2 knockout increases the proportion of Tim3+ differentiated CD8+ T cells in response to IL-2 alone or a combination of IL-2 and IFN-ɑ (Fig. 15E-G); therefore, it is a natural property of the Ptpn2 knockout T cells to differentiate into Tim3+ cells in response to these cytokines and this feature would be present in the method of treating HIV (a chronic viral infection) made obvious by Benson et. al.
Thus, the preponderance of evidence suggests that rather than being surprising, the results present by applicant are either explicitly suggested by the prior art (e.g. improved effector T-cell function) or are inherently present in the method of treating a chronic viral infection by administering Ptpn2-knockout T cells as suggested by Benson et. al.
Claim Rejections - 35 USC § 103- New, necessitated by amendment
Claims 133 is rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20190284529 to Benson et. al., effectively filed 15 March 2018 (PTO-892 dated 4/24/2025), further in view of Aiuti et. al. Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome, Science 341, 6148, published 11 July 2013 (IDS 8/17/2021 NPL No. CA) as applied to claim 116 above, and further in view of Wherry EJ, et. al. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol. 2003 Apr;77(8):4911-27. doi: 10.1128/jvi.77.8.4911-4927.2003. PMID: 12663797; PMCID: PMC152117.
The teachings of Benson et. al. as evidenced by Wherry et. al. in view of Aiuti et. al. as applied to claim 116 are in the 103 rejection above and are incorporated by reference herein.
Benson et. al. does explicitly teach a method of detecting an increase in the number of Tim-3-positive T cells in a subject comprising detecting a decrease in copy number, amount, and/or activity of Ptpn2 wherein Ptpn2 comprises a nucleic acid having at least 95% identity to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1, 3, 5, 7, 9, 11, and 13; wherein Ptpn2 is human or mouse; wherein the subject is an animal model of a viral infection; and the subject is a mammal.
This deficiency is resolved by Wherry et. al.
As described above, Benson et. al. in view of Aiuti et. al. teaches a method of administering Ptpn2-gene-inactivated T cells to a human or mouse with an immune disorder and monitoring the gene-modified cells by detecting the levels of Ptpn2; Benson et. al. teaches mouse models of cancer and makes obvious methods of treating the chronic viral infections HIV, hepatitis B and C, and EBV.
Wherry et. al. teaches “Evidence also suggests that CD8 T cells are important for the acute phase as well as long-term control of other persistent viruses, such as Epstein-Barr virus (EBV), cytomegalovirus, hepatitis B virus (HBV), and hepatitis C virus (HCV) (18, 24, 63, 83). However, in many patients CD8 T cells fail to contain viral replication, particularly during HIV, HBV, and HCV infections. Recent studies suggest that functional impairment (exhaustion) and/or physical deletion of CD8 T cells can accompany ineffective viral control (44, 85). However, the impact of chronic viral infection on the induction and maintenance of epitope-specific CD8 T-cell responses and the impact of persisting antigen on distinct T-cell effector functions are not well understood […] Infection of mice with lymphocytic choriomeningitis virus (LCMV)4 offers an excellent model with which to investigate the effect of chronic infection on CD8 T-cell function. CD8 T cells are critical for the control of LCMV infection, and the adoptive transfer of memory CD8 T cells into persistently infected mice can lead to viral elimination (37)”.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform a method of detecting Ptpn2 levels of gene-modified T cells administered to a subject with a chronic viral infection as taught by modified Benson et. al. in view of Aiuti et. al. in the mouse model of LCMV to benefit from modeling the treatment of a chronic viral infection such as HIV as taught by Benson et. al. in a model that mimics deficient CD8 T cell responses similar to HIV as taught by Wherry et. al. and to benefit from detecting the adoptive transferred gene-edited cells as taught by Aiuti et. al. Regarding the recitation in the preamble of “A method of detecting an increase in TIM3+ T cells”, this method of detecting would inherently meet the method because, as evidenced by the instant specification. This would have a predictable effect because modified Benson et. al. and Wherry et. al. both teach adoptive transfer of cells for the treatment of HIV or a mouse model of HIV, and an artisan would understand that the methods of Aiuti et. al. could be used to monitor gene-modified cells in either humans or mouse models.
Conclusion
No claims are 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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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678