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 .
Claims 1-2, 4-5, 7, 9, 11, 13, 15, 17-18, 21-23, 37, 39, 42-43, 60 and 75 are pending and currently under examination.
Priority
This application 18/289,455 filed on 11/03/2023 is a 371 national phase of PCT/US2022/028371 filed on 05/09/2022, and claims the benefit of provisional U.S. Patent Application No. 63/186,020, filed on 05/07/2021.
The priority date of independent claims 1, 21, 42, 60, and 75 and their dependent claims is determined to be 05/07/2021, the filing date of provisional U.S. Patent Application No. 63/186,020.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (p. 18, 19, 116). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of terms which are trade names or marks used in commerce (including Fluidigm®, BD FACSAria™, and REALease® among others), has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 60 is objected to because of the following informalities: The claim recites “determining the probability of survival or relapse”. “Probability appears to be a typo. Appropriate correction is required.
Claim Interpretation
Claim 2 recites the limitation “wherein the cytokine is ---“. However, claim 1, which claim 2 depends from, does not require a cytokine. Therefore the limitations set forth in claim 2 are not in fact required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1, 2, 4, 5, 7, 9, 11, 13, 15, 17, 18, 21, 22, 23, 37, 39, 42, 43, 60, and 75 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1, 23 and 43 recite “a standard control”. It is unclear what criteria would determine a standard control. For example, it is unclear if the standard control is intended to be a population of NK cells from another individual, a pre-established standard, or a population of NK cells from the same individual.
Claims 2, 4, 5, 7, 9, 11, 13, 15, 17, and 18 are similarly indefinite because they directly or indirectly depend from claim 1.
Claims 21 and 42 recite “a subject in need”. It is unclear what criteria would determine a subject in need or what category a subject in need would comprise.
Claims 22, 23, 37, 39, and 43 are similarly indefinite because they directly or indirectly depend from claim 21 or 42.
Claim 21 is rejected as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP 2172.01. The omitted elements are “50% or more of a population of NK cells obtained from the subject are dysfunctional NK cells”. The claim provides no steps of obtaining a population of NK cells or assaying to determine the claimed percentage of dysfunctional NK cells.
Regarding claim 60, it is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of the claim recites “determining a probability of survival or relapse in a subject having leukemia”. However, the method steps in the claim only require “identifying dysfunctional natural killer (NK) cells in a population of NK cells obtained from the subject”. Thus, it is unclear if applicant intends to cover any method of identifying dysfunctional natural killer (NK) cells, or if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If it is the latter, then it appears that the claims are incomplete, as they fail to provide any active steps that clearly accomplish the goal of “determining a probability of survival or relapse” as set forth by the preamble of the claim. Amending the claim to include an active process step directed towards determining survival may overcome this rejection.
Regarding claim75, it is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of the claim recites “identifying a subject susceptible to leukemia relapse”. However, the method steps in the claim only require “identifying dysfunctional natural killer (NK) cells in a population of NK cells obtained from the subject”. Thus, it is unclear if applicant intends to cover any method of identifying dysfunctional natural killer (NK) cells, or if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If it is the latter, then it appears that the claims are incomplete, as they fail to provide any active steps that clearly accomplish the goal of ““identifying a subject susceptible to leukemia relapse” as set forth by the preamble of the claim. Amending the claim to include an active process step directed towards determining survival may overcome this rejection.
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 60 and 75 is/are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Step 1
The claimed invention is directed to the statutory category of a process.
Step 2A, Prong One
The claim is (claims are) taken to be directed to an abstract idea, a judicial exception.
Claim 60 is directed to a method comprising “identifying dysfunctional natural killer (NK) cells in a population of NK cells obtained from the subject, wherein 50% or more of the population of NK cells are dysfunctional NK cells indicates that the subject has decreased probability of survival or increased probability of relapse relative to a subject wherein less than 50% of the population of NK cells are dysfunctional NK cells”. This limitation is an abstract mental process (see MPEP 2106.04(a)(2)(III)). As written, the identifying step encompasses the mental step of looking at data regarding NK cell types and making mental judgements. The claim is also directed to a law of nature. The claims recite the correlation between a percentage of dysfunctional NK cell types in a NK cell population and probability of survival or relapse. As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
Claim75 is directed to a method comprising “identifying dysfunctional natural killer (NK) cells in a population of NK cells obtained from the subject, wherein 50% or more of the population of NK cells are dysfunctional NK cells indicates that the subject is susceptible to leukemia relapse”. This limitation is an abstract mental process (see MPEP 2106.04(a)(2)(III)). As written, the identifying step encompasses the mental step of looking at data regarding NK cell types and making mental judgements. The claim is also directed to a law of nature. The claims recite the correlation between a percentage of dysfunctional NK cell types in a NK cell population and susceptibility to relapse. As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
Step 2A, Prong Two
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception.
Step 2B
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim does not add any additional specific limitations.
For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1,4, 15,17, 60, and 75 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Chretien et al. (WO2018162404, on IDS dated 11/17/2025).
Regarding claim 1, Chretien teaches determining in a sample from a patient suffering from leukemia, the proportion of NK cells expressing CD56 (Abstract), i.e. dysfunctional cells, where the level of CD56 is relative to a negative control (i.e. standard) control (p. 17, lines 16-17).
Regarding claim 4, Chretien teaches determining NK cells expressing CD57 (Abstract) and further determining NK cells that are CD57- (p. 3, lines 23-24), which reads on the absence of CD57.
Regarding claim 15, Chretien teaches detecting by flow cytometry (p. 18, lines 21-22).
Regarding claim 17, Chretien teaches a population of cells that is majority (i.e. 50% or more) CD56bright and/or CD56dim/KIR-/CD57- (p. 3, lines 27-28).
Regarding claim 60, Chretien teaches predicting the survival of a patient with leukemia, the method comprising determining NK cells expressing CD56bright, CD56dim or CD57 ; identifying patients with a majority CD56bright and/or CD56dim/KIR-/CD57- (i.e., 50% or more are dysfunctional cells) as bad prognosis and identifying patients with a majority CD56dim/KIR+/CD57-, CD56dim/KIR-/CD57+ and/or CD56dim/KIR + /CD57+ (i.e. less than 50% of the population of NK cells are dysfunctional NK cells) as a good prognosis (p. 4, lines 29-34 through p. 4, lines 1-4); where a "Good Prognosis" denotes a patient with significantly enhanced probability of survival after treatment (p. 7, lines 12-13).
Regarding claim 75, Chretien teaches predicting the relapse-free
survival (RPS) of a patient with leukemia, which reads on identifying susceptibility to leukemia relapse. Chretien teaches predicting comprises determining in a sample from a patient suffering from leukemia, the proportion of NK cells expressing CD56 (Abstract), i.e. dysfunctional NK cells, where the level of CD56 is relative to a negative control (i.e. standard) control (p. 17, lines 16-17). Chretien further teaches that patients with a majority CD56bright and/or CD56dim/KIR-/CD57- (i.e., 50% or more are dysfunctional cells) have a bad prognosis, i.e. are susceptible to relapse.
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.
Claims 1, 2, and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Chretien et al. (WO2018162404, on IDS dated 11/17/2025) in view of Fantl et al. (WO2021050200).
The teachings of Chretien as they relate to claim 1 are stated in the 102 rejection above in this office action.
Regarding claim 2, Chretien does not teach detecting the presence of any of the claimed cytokines.
Fantl is directed to methods for diagnosing and treating cancer, the method comprising measuring TNF, GSM-CSF and IFNg (para 22). Fantl states that infiltrating NK cells express cytokines selected from this group (para 22).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Chretien and Fantl to arrive at the instantly claimed invention. The modification would have entailed adding the cytokines of Fantl to the list of detected molecules of Chretien. One of skill in the art would have been motivated by the fact that the cytokines were known markers of infiltrating NK cells, with established methods for detecting expression in KN cells. Detecting the cytokines would have added insight into characterization of dysfunctional NK cells in patients with leukemia. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 5, Chretien does not teach detecting the presence of cytotoxic granules in said population of NK cells.
Fantl teaches measuring levels of perforin and granzyme B (cytotoxic granule markers) as indicators of poor prognosis (para 23).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Chretien and Fantl to arrive at the instantly claimed invention. The modification would have entailed additionally detecting perforin and granzyme B to detect cytotoxic granules in the patient. One would have been motivated by the fact that these markers are known indicators of poor prognosis. Adding the markers of Fantl would have provided further insight into outcomes for patients, a focus of Chretien. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Claims 9 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Chretien et al. (WO2018162404, on IDS dated 11/17/2025) in view of Davicioni et al. (WO2019028285A2).
Regarding claims 9 and 11, Chretien does not teach detecting the presence of one or more checkpoint markers in said population of NK cells (claim 9), or detecting the presence of C-X-C chemokine receptor type 4 (CXCR4) in said population of NK cells (claim 11).
Davicioni is directed to methods for diagnosing and prognosing cancer progression in a patient (including leukemia, para 38), the method comprising obtaining cancer cells, including NK cells, from a patient and determining levels of cell-specific gene expression (para 10). Davicioni teaches measuring the levels of immune cell specific genes LAG3 (a checkpoint marker), and CXCR4 (para 10).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Chretien and Davicioni to arrive at the instantly claimed invention. The modification would have entailed selecting genes from Davicioni for the method of Chretien. Davicioni states the importance of immune cells in determining prognosis in prostate cancer (para 7), and further that their methods and lists can be applied to other cancers (para 38). One would have been motivated to select genes from the list of Davicioni for measurement in the method of Chretien by the fact that the genes were widely known to be associated with cancer diagnosis and prognosis. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Claims 7,13, 18, 21-23, 37, 39, 42, 43 are rejected under 35 U.S.C. 103 as being unpatentable over Chretien et al. (WO2018162404, on IDS dated 11/17/2025) in view of Jongen et al. (US 20200016198, on IDS dated 11/17/2025).
Regarding claim 7, Chretien does not teach detecting the presence of one or more activation markers in said population of NK cells.
Jongen teaches detecting the presence of CD107a (para 172, Fig. 14) in immune effector cells. Jongen teaches that CD107a shows high activity against leukemia (para 172).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Chretien and Jongen to arrive at the instantly claimed invention. The modification would have entailed additionally detecting CD107a as taught by Jongen. One would have been motivated by the known high activity of CD107a in leukemia, and by the added benefit of expanding the characterization of NK cells in the population. As acknowledged in both Chretien and Jongen, multiple subsets of NK cells were known at the time of filing, There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 13, Chretien teaches the leukemia is AML not ALL.
Jongen teaches the leukemia can be AML or ALL (para 140). Jongen teaches studies in AML (paras 9-13) and teaches the importance of importance of NK cells in leukemia (para 3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Chretien and Jongen to arrive at the instantly claimed invention. One of skill in the art would have been motivated to extend the method of Chretien to additional leukemias such as ALL and substitute ALL for AML to increase the patient benefits to an additional population. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 18, Chretien teaches administering to said subject in need
allogeneic stem cell transplant when the patient has a bad prognosis (p.22, lines 1-6).
However, Chretien does not teach the allogeneic cells are allogeneic NK cells.
Jongen teaches allogeneic haploidentical NK cell reactivity can induce clinical remission in AML patients (para 10) and further states that allogeneic NK cells unlike T cells do not induce graft versus host disease (GVHD), thereby considerably reducing treatment related toxicities (para 24).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Chretien and Jongen to arrive at the instantly claimed invention. The modification would have entailed selecting allogeneic NK cells as the allogeneic cells for treatment. One would have been motivated by the recognized health benefits of using NK cells for the treatment. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claims 21 and 22, Chretien teaches treating leukemia in a patient with a bad prognosis (p.22, lines 1-6), described as majority (i.e. 50% or more) CD56bright and/or CD56dim/KIR-/CD57- (p. 3, lines 27-28), which satisfies the requirements of claim 21. Chretien further teaches determining in a sample from a patient suffering from leukemia, the proportion of NK cells expressing CD56 (Abstract) and treating the patient with allogeneic stem cells after a bad prognosis (p. 22, lines 1-6). However, Chretien does not teach the allogeneic cells are allogeneic NK cells.
Jongen teaches allogeneic haploidentical NK cell reactivity can induce clinical remission in AML patients (para 10) and further states that allogeneic NK cells unlike T cells do not induce graft versus host disease (GVHD), thereby considerably reducing treatment related toxicities (para 24).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Chretien and Jongen to arrive at the instantly claimed invention. The modification would have entailed selecting allogeneic NK cells as the allogeneic cells for treatment. One would have been motivated by the recognized health benefits of using NK cells for the treatment. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 23, Chretien teaches determining in a sample from a patient suffering from leukemia, the proportion of NK cells expressing CD56 (Abstract), where the level of CD56 is relative to a negative control (i.e. standard) control (p. 17, lines 16-17).
Regarding claims 37 and 39, Chretien does not teach the subject previously received treatment for leukemia (claim 37) or the subject has relapsed (claim 39).
Jongen teaches drug resistance and relapse remain major problems and allogeneic hematopoietic stem cell transplantation (HSCT) is often the final treatment (para 3) , i.e. after the previous treatment and relapse. Jongen further teaches subjects who had received immunosuppression (para 225) and patients who were treated with remission reduction chemotherapy were eligible to participate in the immunotherapy study (para 147), which teaches elements of claim 37.
Jongen further teaches immune effector cell therapy can be used for patients relapsing shortly after induction therapy (para 80).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Chretien and Jongen to arrive at the instantly claimed invention. The modification would have entailed selecting subjects who had previously received treatment and relapse. Given the interest of both Chretien and Jongen in survivability and relapse one would have been motivated to include subjects from these groups. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claims 42 and 43, Chretien teaches treating leukemia in a patient with a bad prognosis (p.22, lines 1-6), determining in a sample from a patient suffering from leukemia, the proportion of NK cells expressing CD56 (Abstract), where the level of CD56 is relative to a negative control (i.e. standard) control (p. 17, lines 16-17) and a bad prognosis is described as majority (i.e. 50% or more) CD56bright and/or CD56dim/KIR-/CD57- (p. 3, lines 27-28).
However, Chretien does not teach the allogeneic cells are allogeneic NK cells.
Jongen teaches allogeneic haploidentical NK cell reactivity can induce clinical remission in AML patients (para 10) and further states that allogeneic NK cells unlike T cells do not induce graft versus host disease (GVHD), thereby considerably reducing treatment related toxicities (para 24).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Chretien and Jongen to arrive at the instantly claimed invention. The modification would have entailed selecting allogeneic NK cells as the allogeneic cells for treatment. One would have been motivated by the recognized health benefits of using NK cells for the treatment. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Conclusion
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/JESSICA GRAY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682