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 .
Priority
This application is a 371 of PCT/EP2022/057450 filed on 03/22/2022.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. EP21164116, filed on 03/22/2022. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The content recited in this instant application is supported in the original disclosure of foreign application EP21164116 filed on 03/22/2021, thus the examined claims in this instant application have an effective filing date of 03/22/2021.
Claim Status
Claims 1-16 are pending and examined herein below.
Information Disclosure Form
One Information Disclosure Statement (IDS), filed 11/02/2023, is acknowledged and considered. One NPL reference in IDS filed on 11/02/2023 is stricken for the reason detailed herein. NPL, cite No. 18, Malehmir et al., is not provided and thus not considered.
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:
Claims 1-2, 4, 6, 9, 11-12 and 14-15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claimed invention is directed to an abstract idea without significantly more.
The claimed invention is directed to a natural phenomenon, a law of nature, and an abstract mental process without significantly more. The claim(s) recite(s) a correlation/natural relationship, a natural reaction, an observation, and a comparison. This judicial exception is not integrated into a practical application because the additional elements amount to insignificant extra-solution steps. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements use routine and conventional techniques and methods/processes.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101
(see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the
claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental
economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)). Only if a claim
(1) recites a judicial exception and
(2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception. See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIALEXCEPTION
Step 2A, Prong 1
Claims 1-2 and 16 recite “assessing a treatment response associated with immunotherapy … based on the presence, absence or abundance of auto-aggressive CD8+ PD-1+ T-cells”; Claim 4 recites “presence of … hepatic auto- aggressive CD8+ PD-1+ T-cells … indicative for an absence of or an adverse treatment response”; Claim 6 recites “absence of hepatic auto-aggressive CD8+ PD-1+ T-cells … indicative for a therapeutically effective treatment response”; and Claim 9 recites “presence of … hepatic auto- aggressive CD8+ PD-1+ T-cells … indicative for an adverse hepatic side effect” which all amount to detecting naturally occurring cells and correlating said measurements to a result, namely a treatment response. Thus, the limitations of instant claims 1-2, 4, 6, 9, and 16 are directed to a natural phenomenon.
Claim 16 further recites “recommending immunotherapy for said subject” who has “no non-treatment response, no adverse treatment response, a therapeutically effective treatment response and/or no adverse hepatic side effect,” which is directed to a law of nature because a side effect or lack thereof after treatment is a natural physiological reaction. Further, recommending treatment based on observation of a natural physiological reaction, which can be done in the human mind, is directed to an abstract mental process.
Claims 11-12 recite “hepatic auto-aggressive CD8+ PD-1+ T cells … exhibit an increased expression compared to control CD8+ T cells” and “exhibit a reduced expression compared to control CD8+ T cells,” respectively, are limitations reciting a comparison, and are thus drawn to an abstract mental process. "The courts consider a mental process (thinking)
that "can be performed in the human mind, or by a human using a pen and paper" to be an
abstract idea. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1372, 99 USPQ2d
1690, 1695 (Fed. Cir. 2011). As the Federal Circuit explained, "methods which can be performed mentally, or which are the equivalent of human mental work, are unpatentable abstract ideas the
'basic tools of scientific and technological work' that are open to all.''' 654 F.3d at 1371, 99
USPQ2d at 1694 (citing Gottschalk V. Benson, 409 U.S. 63, 175 USPQ 673 (1972)). See
also Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. 66, 71, 101 USPQ2d 1961,
1965 (2012) ("[M]ental processes[] and abstract intellectual concepts are not patentable, as they
are the basic tools of scientific and technological work'" (quoting Benson, 409 U.S. at 67, 175
USPQ at 675)); Parker v. Flook, 437 U.S. 584, 589, 198 USPQ 193, 197 (1978) (same).
Accordingly, the "mental processes" abstract idea grouping is defined as concepts performed in
the human mind, and examples of mental processes include observations, evaluations,
judgments, and opinions.' See MPEP 2106.049(a)(2).
Claim 14 recites “CD8+ T cell precursors exhibit a change in expression over time” and claim 15 recites “a decrease in expression over time … of at least one biomarker” and “an increase in expression over time…of at least one biomarker,” which are assessments made within a time window (instant Specification, pg. 7, lines 5-7), requiring a comparison between an expression level at an initial time point (beginning of the time window) and an expression level at a final time point (end of time window). Thus, the limitations of claims 14 and 15 reciting a comparison are drawn to an abstract mental process.
Step 2A, Prong 2
These judicial exceptions are not integrated into a practical application because the additional elements of determining hepatic auto-aggressive CD8 positive (+) PD-1 positive (+) T cells (claim 1) and determining data indicating the presence, absence or abundance (claim 2) amount to insignificantly extra-solution activities, namely data-gathering steps that do not add a meaningful limitation to the natural phenomenon, law of nature, or abstract mental process recited in the instant claims. Further, the additional element of “recommending immunotherapy (claim 16),” does not integrate the judicial exception into a practical application because the step or act of recommending requires a natural observation (observing a treatment response), which is deemed an abstract mental process.
ELIGIBILITY STEP 2B: WHETHER ADDITIONAL ELEMENTS AMOUNT TO SIGNIFICANTLY MORE THAN THE JUDICIAL EXCEPTION (INVENTIVE CONCEPT)
Step 2B
The additional element of “determining hepatic auto-aggressive CD8 positive (+) PD-1 positive (+) T cells (claim 1),” which the instant Specification clarifies “comprises contacting the sample with a detection agent that specifically binds to the biomarker or a transcript encoding it (instant Specification, pg. 7, lines 32-39),” is not sufficient to amount to significantly more than the judicial exception because this detection and quantification method is routine and conventional in the art. For example, Ma et al. teach molecular signatures of exhaustion for a subset of CD8+ T cells that are associated with poor prognosis in subjects diagnosed with hepatocellular carcinoma (HCC). Ma et al. teach using flow cytometry, which involves using fluorescently labeled antibodies with specific affinity to the surface markers of the target T cells, to detect and assess expression levels of CD8+ PD-1 T cells (see Ma et al., PD1Hi CD8+ T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma, 2019, Journal for ImmunoTherapy of Cancer, 7, 331, 1-15, provided in IDS filed 11/02/2023). Further, Wherry et al. teach molecular signatures of and pathways associated with exhaustion of CD8+ T cells during chronic viral infections. Wherry et al. teach using flow cytometry to detect and assess expression profiles of CD8+ T cells that express CD69 (antigen) on the cell surface (E.J. Wherry et al., Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection, 2007, Immunity, 27, 670–684).
Further, the additional element of “recommending immunotherapy,” a mental process, when combined with the method of assessing treatment response, based on expression levels of a subset of T cells, drawn to a natural phenomenon/natural correlation, does not impart patentability to the judicial exception because the treatment (PD-1/PD-L1 inhibitors) being recommended is routine and conventional in the art (see Lee et al., EP3739338 A2 and Lombardi et al., PD-1/PD-L1 Immuno-Mediated Therapy in NAFLD: Advantages and Obstacles in the Treatment of Advanced Disease, Feb. 2022, Int. J. Mol. Sci., 23, 2707, 1-14).
For reasons discussed herein above, the instant claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exceptions and thus fail to impart patent eligibility to the natural phenomenon, law of nature, and abstract mental process recited in the instant claims 1-2, 4, 6, 9, 11-12, 14-16.
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.
Claim(s) 1-6, 10-11 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al., (Foreign Application No. EP3739338 A2, provided in IDS filed 11/02/2023), in view of Wang et al., (D.Y. Wang et al., Toxicities associated with PD-1/PD-L1 blockade, 2018, Cancer J., 24, 1, 36–40), as evidenced by Ma et al., (Ma et al., PD1Hi CD8+ T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma, 2019, Journal for ImmunoTherapy of Cancer, 7, 331, 1-15, provided in IDS filed 11/02/2023), and Hansel et al., (Hansel et al., The Inhibitory T Cell Receptors PD1 and 2B4 Are Differentially Regulated on CD4andCD8TCells in a Mouse Model of Non-alcoholic Steatohepatitis, 2018, Front. Pharmacol., 10, 244, 1-16).
Throughout the disclosure, Lee teaches a method for predicting treatment response to PD-1 /PD-L1-targeted immunotherapy of a subject having cancer. Lee teaches different embodiments of the invention, with one embodiment, referenced as experimental 3, comprising subjects having hepatocellular carcinoma. Lee teaches the method for predicting response to PD-1 and/or PD-L1-targeted immunotherapy with method steps comprising obtaining the subject’s peripheral blood sample before or after receiving the immunotherapy. Lee teaches the method further comprises detecting the number of immune cells in the peripheral blood sample of the subject having cancer. Lee teaches the immune cells include immune PD1+CD8+ cells, PD1+CD8+IFNγ+ cells, PD1+CD8+TIM3+ cells, PD1+CD8+LAG3- cells, PD1+CD8+LAG3+ cells, PD1+CD8+IFNγ+LAG3+ cells, PD1+CD8+TIM3+LAG3- cells, PD1+CD8+IFNγ+ TIM3+LAG3+ cells, and PD1+CD8+IFNγ+TIM3+LAG3- cells, but not limited thereto. The number of immune cells detected are compared to a first cut-off value/ or a second cut-off value to indicate whether the subject has benefitted from the immunotherapy. The first cut-off value/or the second cut-off value is determined by statistical analysis of a correlation between the number of immune cells in a group of subjects having cancer and an expected risk of disease progression in the group of subjects having cancer. The statistically significant value obtained is used to define the correlation.
Regarding claims 1-2, the instant Specification defines hepatic “CD8 positive (+) PD-1 positive (+) T cells exhibiting traits of activation and exhaustion” as T cells positive for CD8 and PD-1, expressing biomarkers indicative of activation and exhaustion (instant Spec, pg. 6, lines 1-5). The prior art teaches that biomarkers expressed by CD8 positive (+) PD-1 positive (+) T cells that are indicative of activation and exhaustion include expression of TIM3, CTLA4, 2B4(CD244), LAG3, CD39 and TIGIT (see Ma et al., 2019, Journal for ImmunoTherapy of Cancer, 7, 331, pg. 3, full para 6). Using the broadest reasonable interpretation, in light of the instant Specification, Lee teaches a method for assessing a treatment response associated with immunotherapy in a subject in need thereof comprising the steps of: (a) determining (i) hepatic CD8 positive (+) PD-1 positive (+) T cells exhibiting traits of activation and exhaustion or in a sample of a subject in need of immunotherapy (EP3739338 A2: para 0065). Lee further teaches a method for assessing a treatment response associated with immunotherapy in a subject in need thereof comprising the steps of:(a) determining data indicating the presence, absence or abundance of (i) hepatic CD8 positive (+) PD-1 positive (+) T cells (EP3739338 A2: paras 0055-0065; claims 4 and 11). Lee does not explicitly teach “auto-aggressive” hepatic CD8 positive (+) PD-1 positive (+) T cells exhibiting traits of activation and exhaustion or (ii) CD8+ T cell precursors thereof.
Throughout the review article, Wang teaches that it was known in the art, at the time of filing, that immune checkpoint inhibitors targeting PD-1/PD-L1 interactions produce effective post-treatment responses in a cohort of patients across different cancer types. Wang further teaches these PD-1/PD-L1 targeted immunotherapies can induce a range of autoimmune-like complications that may affect any organ. Wang teaches that treatment for treatment-induced toxicities consists mainly of immune suppression with corticosteroids and other agents. Wang teaches PD-1, expressed on the surface of T cells, binds to PD-L1 to stop T cells from killing cells. However, continuous PD-1/PD-L1 interactions leads to T cell exhaustion, causing progressive loss of T cell function. Wang further discusses the mechanisms of immune-related adverse events (irAEs) induced by the immunotherapy, beginning with the PD-1/PD-L1 inhibitors blocking interactions between PD-1 and its ligands PD-L1 or PD-L2. Blocking these interactions enables recovery of T cell function which can be used to kill cancer cells. However, other cells may get attacked and destroyed, manifesting as an autoimmune or inflammatory response in normal tissue that results in irAEs. Lastly, Wang gives an overview of clinical and pathologic features of toxicities induced by PD-1/PD-L1-targeted treatments and reviews their management.
The instant Specification defines “auto-aggressive” CD8+ PD-1+ T cells as T cells resident in the liver that exhibit traits of activation and exhaustion and upon stimulation, attack liver tissues (instant Spec, pg. 6). The instant Specification further clarifies “stimulation” may include anti-PD-1 antibodies or PD-1L used in immunotherapy (instant Spec, pg. 6). Additionally, the prior art teaches that in non-alcoholic steatohepatitis (NASH), an advanced form of non-alcoholic fatty liver disease (NAFLD), PD1 is upregulated in CD8+ T cells in mouse models (see Hansel et al., 2018, Front. Pharmacol., 10, 244, pg. 9, full paras 7-8). Thus, using the broadest reasonable interpretation, in light of the instant Specification, Wang teaches the limitation(s) in claims 1-2 reciting auto-aggressive PD-1+ T cells exhibiting traits of exhaustion (Wang et al., 2018, Cancer J., 24, 1, pgs. 1-2, Abstract and Introduction).
It would have been prima facie obvious, at the time of filing, to combine the teachings of Lee and Wang to modify the method of predicting immunotherapy response by detecting CD8+ PD-1+ T cells in a subject with cancer pre and post treatment, as taught by Lee, with the teachings of molecular signatures for PD-1+ T cells exhibiting traits of activation and exhaustion post PD-1/PD-L1-targeted treatment, which may lead to treatment-induced adverse autoimmune-like toxic side effects in different organs, as taught by Wang. The prior art teaches that PD-1/PD-L1-targeted treatment can be effective for treating cancer but can also induce organ toxicity or injury, particularly in the presence of CD8+ PD-1+ T cells exhibiting exhaustion and auto-aggressive signatures. A skilled artisan would have been motivated to combine these teachings to modify the treatment response prediction method of Lee to a method of assessing immunotherapy treatment response by detecting the same immune cells with the added trait taught by Wang of auto-aggressive, because it would enable a skilled artisan to determine toxicity or injury incurred post treatment by a subject and determine if a multidisciplinary approach to treatment, comprising several specialists, is needed for effective treatment. A person having ordinary skill in the art would have a reasonable expectation of success because combining these teachings to arrive at the claimed invention amounts to combining prior art elements using known methods to yield expected and predictable results.
Regarding claim 3, Lee and Wang teach all the limitations of claim 1. Wang further teaches wherein said treatment response is the absence of or an adverse treatment response (Wang et al., 2018, Cancer J., 24, 1, pgs. 1-2, Abstract and Introduction, pg. 12, Fig. 1).
It would have been prima facie obvious, at the time of filing, to combine method of predicting immunotherapy response by detecting CD8+ PD-1+ T cells in a subject pre and post treatment, as taught by Lee, with the teachings that PD-1/PD-L1-targeted treatment can induce autoimmune-like complications that may affect any organ system, as taught by Wang. A skilled artisan would have been motivated to combine these teachings to arrive at the claimed invention because it would enable a skilled artisan to recognize when a toxic side effect is presented or induced by the treatment, allowing for the subject’s treatment plan to be adjusted such that injury caused by the adverse side effect is addressed while the immunotherapy is paused (Wang et al., 2018, Cancer J., 24, 1, see pg. 7, full para 1). A person having ordinary skill in the art would have a reasonable expectation of success because combining these teachings to arrive at the claimed invention amounts to combining prior art elements using known methods to yield expected and predictable results.
Regarding claim 4, Lee and Wang teach all the limitations of claim 1and Wang further teaches the limitation(s) of claim 3. Lee further teaches wherein the presence of (i) said hepatic CD8+ PD-i+ T-cells is indicative for an absence of or an adverse treatment response associated with immunotherapy (EP3739338 A2: para 0065)
Regarding claim 5, Lee and Wang teach all the limitations of claim 1. Lee further teaches wherein said treatment response is a therapeutically effective treatment response (EP3739338 A2: paras 0022, lines 7-12 and 0065, col. 16, lines 53-58, and col. 17, lines 1-6).
Regarding claim 6, Lee and Wang teach all the limitations of claim 1 and Lee teaches the limitation(s) of claim 5. Lee further teaches that “the subjects having hepatocellular carcinoma who have received the anti-PD-1/ PD-L1 immunotherapy, when the number of immune cells of the subjects having hepatocellular […..] is less than the second cutoff value after treatment (Post), the subjects having hepatocellular carcinoma have good prognosis and the anti-PD-1 / PD-L1 immunotherapy shows better treatment effectiveness on the subjects having hepatocellular carcinoma” (EP3739338 A2: para 0065, col. 16, lines 54-58 and col. 17, lines 1-6). Using the broadest reasonable interpretation, absence of the recited T cell subset post treatment indicating effectiveness of treatment is an extension of the recited T cells detected at an amount lower than a threshold cutoff level post treatment indicating effectiveness of treatment. Thus, a skilled artisan would expect and predict the same or improved effect/result for the absence of the recited T cell subset post treatment as with a detected amount below a threshold cutoff level of the recited T cell subset post treatment, as taught by Lee. Thus, Lee, in view of Wang, teaches the limitation(s) of instant claim 6 reciting wherein the absence of (i) said hepatic auto-aggressive CD8+ PD-1+ T-cells exhibiting traits of activation and exhaustion or (ii) said CD8+ T cell precursors thereof is indicative for a therapeutically effective treatment response associated with immunotherapy (EP3739338 A2: para 0065).
Regarding claim 10, Lee and Wang teach all the limitations of claim 1. Lee further teaches herein said immunotherapy involves PD-1 and/or PD-L1 targeted immunotherapy (EP3739338 A2: para 0021).
Regarding claim 11, Lee and Wang teach all the limitations of claim 1. Lee further teaches wherein said hepatic CD8+ PD-1+ T cells exhibiting traits of activation and exhaustion exhibit an increased expression compared to control CD8+ T cells of at least one biomarker selected from the group consisting of: TOX, CXCR6, TNFa, LAG3, GZMB (Granzyme B) and TIGIT (EP3739338 A2: para 0065).
Regarding claim 16, Lee and Wang teach all the limitations of claim 1. Lee further teaches a method for recommending immunotherapy for a subject comprising assessing the treatment response to immunotherapy for said subject by carrying out the method of claim 1, and, recommending immunotherapy for said subject if the subject is assessed to have no non-treatment response, no adverse treatment response, a therapeutically effective treatment response and/or no adverse hepatic side effect (EP3739338 A2: paras 0023 and 0055-0065).
Claim(s) 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al., (Foreign Application No. EP3739338 A2, provided in IDS filed 11/02/2023), in view of Wang et al., (D.Y. Wang et al., Toxicities associated with PD-1/PD-L1 blockade, 2018, Cancer J., 24, 1, 36–40, provided in IDS filed 11/02/2023), as applied to claim 1, further in view of Lombardi et al., (Lombardi et al., PD-1/PD-L1 Immuno-Mediated Therapy in NAFLD: Advantages and Obstacles in the Treatment of Advanced Disease, Feb. 2022, Int. J. Mol. Sci., 23, 2707, 1-14).
Regarding claims 7-9, Lee and Wang teach all the limitations of claim 1. Lee and Wang do not teach a subject suffering from non-alcoholic fatty liver disease or systemic obesity, an adverse hepatic side effect induced by treatment, or that the immunotherapy-induced adverse hepatic side effect is indicated by the presence of hepatic auto- aggressive CD8+ PD-1+ T-cells exhibiting traits of activation and exhaustion.
Throughout the disclosure, Lombardi teaches that non-alcoholic fatty liver disease NAFLD) involves the enhanced activation of the immune system and can progress to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Lombardi teaches CD4+ effector T cells are activated during the early stages of liver inflammation, accompanied with an increase of natural killer T cells and of CD8+ T cells that contribute to auto-aggressive tissue damage. PD-1/PD-L1 interactions on the surface of liver T cells can be therapeutically targeted to counter T cells activation using specific monoclonal antibodies, including Nivolumab, Pembrolizumab, and Atezolizumab. Lombardi teaches that although PD-1/PD-L1-targeted treatment has been approved to treat HCC, it has not been approved for NAFLD. Lombardi further teaches that these immunotherapy treatments may not improve HCC prognosis and may even worse the disease, leading to an increase of CD8+PD-1+ T cells and effector cytokines which aggravate liver damage. Lombardi describes the main pathogenetic mechanisms that characterize the immune system involvement in NAFLD and further discusses advantages and obstacles of anti PD-1/PDL-1 immunotherapy.
Lombardi teaches (claim 7) wherein said subject suffers or is suspected to suffer from non-alcoholic fatty liver disease (NAFLD) or systemic obesity (metabolic syndrome) [Lombardi et al., 2022, Int. J. Mol. Sci., 23, 2707, pgs. 1-2, Abstract and Introduction] ; (claim 8) wherein said treatment response is an adverse hepatic side effect (Lombardi et al., 2022, Int. J. Mol. Sci., 23, 2707, pg. 10, section 5.3); and (claim 9) wherein the presence of (i) said hepatic auto- aggressive CD8+ PD-1+ T-cells exhibiting traits of activation and exhaustion or (ii) said CD8+ T cell precursors thereof is indicative for an adverse hepatic side effect associated with immunotherapy (Lombardi et al., 2022, Int. J. Mol. Sci., 23, 2707, pg. 10, sections 5.3).
It would have been prima facie obvious, at the time of filing, to combine the teachings of Lee, in view of Wang, and Lombardi in order to modify the method of predicting immunotherapy response by detecting CD8+ PD-1+ T cells with traits of activation and exhaustion in a subject with cancer pre and post treatment, as taught by Lee, in view of Wang’s teachings of auto-aggressive exhausted T cells involved in post-treatment adverse side effects, to the method of assessing immunotherapy response using the teachings of experimental models showing an increase in CD8+PD-1+ T cells exhibiting traits of exhaustion indicating an adverse hepatic side effect post PD-1/PD-L1-targeted therapy in subjects with NAFLD, as taught by Lombardi. A skilled artisan would have been motivated to combine these teachings to modify the method of Lee to arrive at the claimed invention because this method modification would enable the appropriate treatment recommendation for said subject in need of immunotherapy such that progression of NAFLD to NASH, an advanced and aggressive subtype, is prevented. A person having ordinary skill in the art would have a reasonable expectation of success because combining these teachings to arrive at the claimed invention amounts to combining prior art elements using known methods to yield expected and predictable results.
Claim(s) 12-15 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al., (Foreign Application No. EP3739338 A2, provided in IDS filed 11/02/2023), in view of Wang et al., (D.Y. Wang et al., 2018, Cancer J., 24, 1, 36–40), as applied to claim 1 above, and further in view of Wherry et al., (E.J. Wherry et al., Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection, 2007, Immunity, 27, 670–684), and as evidenced by Ma et al., (Ma et al.,PD1Hi CD8+ T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma, 2019, Journal for ImmunoTherapy of Cancer, 7, 331, 1-15).
Regarding claims 12-15, the teachings of Lee and Wang are discussed herein above. Lee and Wang teach all the limitations of claim 1. Lee and Wang do not teach biomarkers that characterize CD8+ T cell precursors; detecting changes, reduced, or increased expression levels of biomarkers for CD8+ PD-1+ T cells exhibiting traits of activation and exhaustion; or detecting these expression level changes occurring over time for CD8+ T cell.
Throughout the disclosure, Wherry teaches prolonged viral infections normally result in T cell exhaustion. Wherry teaches determining molecular signatures of exhaustion by comparing gene-expression profiles of dysfunctional lymphocytic choriomeningitis virus (LCMV)-specific CD8+ T cells from chronic infection to functional LCMV-specific effector and memory CD8+ T cells generated after acute infection. Wherry teaches results show that exhausted CD8+ T cells overexpress certain inhibitory receptors, including PD-1 and express a distinct set of transcription factors . Wherry further teaches T cell receptor and cytokine signaling pathways undergo significant changes. Wherry further teaches results show exhausted CD8+ T cells alter the expression of genes chemotaxis, adhesion, and migration. Wherry teaches T cell exhaustion develops or worsens over time and gene-expression profiling indicates that T cell exhaustion and T cell state of unresponsiveness are different processes. Wherry further teaches functional exhaustion is likely the result of active suppression and passive defects in signaling and metabolism.
Wherry teaches the limitation(s) of claim 12 reciting wherein said hepatic CD8+ PD-1+ T cells exhibiting traits of activation and exhaustion exhibit a reduced expression compared to control CD8+ T cells of at least one biomarker selected from the group consisting of: KLF2, IL-7R, TCF7, Foxo1 and SELL (Wherry et al., 2007, Immunity, 27, pgs. 670-684 and pg. 674, Table 1). Wherry further teaches the limitation(s) of claim 13 reciting wherein said CD8+ T cell precursors are characterized by at least one biomarker selected from the group consisting of: TCF7, SELL, and IL-7R (Wherry et al., 2007, Immunity, 27, pgs. 670-684 and pg. 674, Table 1). Wherry further teaches the limitation(s) of claim 14 reciting wherein said CD8+ T cell precursors exhibit a change in expression over time of at least one biomarker selected from the group consisting of: TOX, CXCR6, TNFa, LAG3, GZMB (Granzyme B) TIGIT , KLF2,IL-7R, TCF7, Foxo1 and SELL (Wherry et al., 2007, Immunity, 27, pgs. 670-684 and pg. 674 Table 1). Wherry further teaches the limitation(s) of claim 15 reciting wherein (i) said change is a decrease in expression over time if said at least one biomarker is selected from the group consisting of KLF2, IL-7R, TCF7, Foxol and SELL (Wherry et al., 2007, Immunity, 27, pgs. 670-684 and pg. 674 Table 1); and said change is an increase in expression over time if said at least one biomarker is selected from the group consisting of TOX, CXCR6, TNFa, LAG3, GZMB (Granzyme B) and TIGIT (Wherry et al., 2007, Immunity, 27, pgs. 670-684 and pg. 674 Table 1).
It would have been prima facie obvious, at the time of filing, to combine the teachings of Lee and Wang to modify the method of predicting immunotherapy response by detecting CD8+ PD-1+ T cells exhibiting traits of activation and exhaustion in a subject with cancer pre and post treatment, as taught by Lee, in view of the teachings of auto-aggressive exhausted T cells involved in post-treatment adverse side effects taught by Wang, with the teachings of progressive changes to expression levels of biomarkers for CD8+ T cell precursors exhibiting traits of exhaustion during chronic infections, as taught by Wherry. A skilled artisan would have been motivated to combine these teachings to modify the method of predicting treatment response taught by Lee to arrive at the claimed invention because detecting CD8+ T cells or their precursors with the biomarkers taught by Lee and Wherry and the expression levels taught by Wherry would enable a personalized treatment plan that would stem progression of further tissue injury in a subject (see Ma et al., 2019, Journal for ImmunoTherapy of Cancer, 7, 331, pg. 1, Abstract and Wherry et al., 2007, Immunity, 27, 670–684). A person having ordinary skill in the art would have a reasonable expectation of success because combining these teachings to arrive at the claimed invention amounts to combining prior art elements using known methods to yield expected and predictable results.
At the time of filing, it would have been further prima facie obvious to try one or more of the biomarkers with known expression levels for CD8+ PD-1 T cells or their precursors, as taught by Wherry, to modify the method of predicting treatment response by detecting CD8+ PD-1+ T cells with traits of exhaustion, as taught by Lee, to arrive at a method for assessing treatment response by detecting the same subset of T cells exhibiting traits of exhaustion and comprising certain biomarkers with changes in expression levels because a skilled artisan would have a finite number of known solutions with predictable results. A person having ordinary skill in the art would have a reasonable expectation of success because the expression levels of a finite number of known biomarkers, and that are associated with a similar condition as the one recited in the claimed invention, is known and thus a skilled artisan would expect and predict the outcome of measuring said expression levels without undue experimentation.
Conclusion
All examined claims (1-16) are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MELISSA L LIRIANO whose telephone number is (571)272-0085. The examiner can normally be reached Monday-Friday, 7:30 am-3:30 pm (EST).
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/MELISSA LIZETTE LIRIANO/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/ Supervisory Patent Examiner, Art Unit 1677 April 29, 2026
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