DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claims dated 2/1/2024 are under consideration.
Priority
The present application claims benefit to US provisional applications: 63/386,411 (filed 12/7/2022); and 63/381,435 (filed 10/28/2022).
Priority is recognized.
Information Disclosure Statement
The listing of references in the specification or the citation of references throughout the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The use of terms, such as in paragraphs 93 and 131, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear 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 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 1, 13, 14, 15, 16, 18, 20, 21 and 39 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions without significantly more.
The claims include a series of steps and thus are methods, one of the four statutory categories.
The claim(s) recite(s):
“determining the likelihood of the response to the cell therapy product in the patient at least in part from the gene expression level in the cell therapy product” (claim 1);
“an increase in the gene expression level of the at least one gene as compared to a control value is indicative of a reduced likelihood of a response as compared to a control likelihood of response rate” (claim 1);
“determining the likelihood of CAR T-cell exhaustion in the cell therapy product at least in part from the gene expression level in the cell therapy product” (claim 13);
“an increase in the gene expression level of the at least one gene as compared to a control value is indicative of an increased likelihood of CAR T-cell exhaustion in the cell therapy product as compared to a control likelihood of CAR T-cell exhaustion in a cell therapy product” (claim 13);
“an increase of at least about 2-fold in the gene expression level of IL-4 as compared to a control value of IL-4 is indicative of an increased likelihood of CAR T-cell exhaustion in the cell therapy product as compared to a control likelihood of CAR T-cell exhaustion in a cell therapy product” (claim 15);
“an increase of at least about 2-fold in the gene expression level of HLA-DQB1 as compared to a control value of HLA-DQB1 is indicative of an increased likelihood of CAR T-cell exhaustion in the cell therapy product as compared to a control likelihood of CAR T-cell exhaustion in a cell therapy product” (claim 16);
“selecting the immunotherapy CAR-T cell product for administration to the patient and a combination therapy at least in part from the measuring of the gene expression level of at least one gene” (claim 39); and
“the immunotherapy CAR-T cell product is selected for administration to the patient if the gene expression level of the at least one gene is at or below a control value for the at least one gene, or wherein the immunotherapy CAR-T cell product and the combination therapy are selected for administration to the patient if the gene expression level of the at least one gene is above the control value for the at least one gene” (claim 39).
The step of “determining the likelihood of the response” of claim 1 broadly encompasses an abstract idea in that it can be performed in a purely mental manner by considering a limited amount of data, e.g., the expression level of one gene as compared to a control value.
The recitation regarding “an increase in the gene expression level of the at least one gene as compared to a control value” in claim 1 sets forth a correlation that is naturally arising in the context of cell therapy product. The recitation sets forth the relationship between IL-4 levels and HLA-DQB1 levels that naturally correlate within a reduced likelihood of a response.
The step of “determining the likelihood of CAR T-cell exhaustion” of claim 13 broadly encompasses an abstract idea in that it can be performed in a purely mental manner by considering a limited amount of data, e.g., the expression level of one gene as compared to a control value.
The recitation regarding “an increase in the gene expression level of the at least one gene as compared to a control value” in claim 13 sets forth a correlation that is naturally arising in the context of cell therapy product. The recitation sets forth the relationship between IL-4 levels and HLA-DQB1 levels that naturally correlate within a reduced likelihood of a response.
The recitation regarding “an increase of at least about 2-fold in the gene expression level of IL-4 as compared to a control value of IL-4” in claim 15 sets forth a correlation that is naturally arising in the context of cell therapy product. The recitation sets forth the relationship between IL-4 levels and HLA-DQB1 levels that naturally correlate within a reduced likelihood of a response.
The recitation regarding “an increase of at least about 2-fold in the gene expression level of HLA-DQB1 as compared to a control value of HLA-DQB1” in claim 16 sets forth a correlation that is naturally arising in the context of cell therapy product. The recitation sets forth the relationship between IL-4 levels and HLA-DQB1 levels that naturally correlate within a reduced likelihood of a response.
The step of “selecting the immunotherapy CAR-T cell product for administration” of claim 39 broadly encompasses an abstract idea in that it can be performed in a purely mental manner by considering a limited amount of data, e.g., the expression level of one gene as compared to a control value.
The judicial exceptions are not integrated into a practical application because the claims do not involve:
improvements to the functioning of a computer or to any other technology or technical field;
applying or using the judicial exceptions to effect a particular treatment or prophylaxis for a disease or medical condition;
applying the judicial exception with, or by use of, a particular machine; or
effecting a transformation or reduction of a particular article to a different state or thing.
The claimed limitations add insignificant extra-solution activity to the judicial exceptions. The “measuring” of gene expression broadly encompasses mere data gathering.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims encompass the use of methods, such as RNA sequencing and ATAC sequencing (para. 279), that are well-known and used in a conventional manner.
Claim Rejections - 35 USC § 112
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.
Claims 14, 18, 21, 32 and 36 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.
Regarding claim 14, the claim recites “the patient” in the last line, and the phrase lacks proper antecedent basis.
Regarding claim 18, the claim recites “preferably” in line 2. The term separates a broad range or limitation from a narrow range or limitation that falls within the broad range or limitation (in the same claim). This is considered indefinite because the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 18 recites the broad recitation “a tumor antigen”, and the claim also recites a series of particular “tumor antigens”, which are narrower statements of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claim 18, the phrase "such as", which is used multiple times, renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 21, the phrase “e.g.”, which is equivalent to "for example", renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 32, the claim recites “preferably” in line 32. The term separates a broad range or limitation from a narrow range or limitation that falls within the broad range or limitation (in the same claim). This is considered indefinite because the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 32 recites the broad recitation “a tumor antigen”, and the claim also recites a series of particular “tumor antigens”, which are narrower statements of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claim 32, the phrase "such as", which is used multiple times, renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 36, the phrase “e.g.”, which is equivalent to "for example", renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 13, 14, 15, 16, 18, 20, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 36 and 39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu (Nature Communications. 2020. 11:5902, 14 pages) in view of Bell (Frontiers in Immunology. 2021. 12:Article 684642, 16 pages).
Regarding claim 1, Liu teaches measuring gene expression of IL-4 in the “cell therapy products”, T9 CAR-T cells and T1 CAR-T cells (Fig. 1e).
Liu teaches that T9 CAR-T cells secrete fewer IL4 than T1 CAR-T cells (p. 2 of 14, right column; and Fig. 1e). Liu further teaches that T9 CAR-T cells have decreased apoptosis with hyperproliferative capacity (p. 2 of 14, right column), demonstrate less exhaustion (p. 4 of 14, left column; and p. 6 of 14, left column) and have strong antitumor activity in vivo (p. 4 of 14, right column).
Bell teaches that IL-4 in the context of cancer and CAR T cells is largely immunosuppressive (p. 3 of 16, left column). Bell further describes is it known that IL-4 producing T cells are less effective in controlling tumor growth (p. 3 of 16, left column).
It would have been prima facie obvious at the time of filing to have determined that T9 CAR-T cells, which express less IL-4 as compared to a control, have an increased likelihood of producing a response after transfer to a subject. This determination is supported by Bell, which demonstrates that IL-4 expressing T cells are less likely to produce an antitumor response.
Regarding claim 13, Liu teaches measuring gene expression of IL-4 in the “cell therapy products”, T9 CAR-T cells and T1 CAR-T cells (Fig. 1e).
Liu teaches that T9 CAR-T cells secrete fewer IL4 than T1 CAR-T cells (p. 2 of 14, right column; and Fig. 1e). Liu further teaches that T9 CAR-T cells have decreased apoptosis with hyperproliferative capacity (p. 2 of 14, right column), demonstrate less exhaustion (p. 4 of 14, left column; and p. 6 of 14, left column) and have strong antitumor activity in vivo (p. 4 of 14, right column).
Bell teaches that IL-4 in the context of cancer and CAR T cells is largely immunosuppressive (p. 3 of 16, left column). Bell further describes is it known that IL-4 producing T cells are less effective in controlling tumor growth (p. 3 of 16, left column).
It would have been prima facie obvious at the time of filing to have determined that T9 CAR-T cells, which express less IL-4 as compared to a control, have a decreased likelihood of exhaustion after transfer to a subject. This determination is supported by Bell, which demonstrates that IL-4 expressing T cells are less likely to produce an antitumor response.
Regarding claim 14, Liu teaches measuring the expression of IL4 prior to administration (p. 2 of 14, right column; Fig. 1e; p. 2 of 14, right column; p. 6 of 14, left column; and p. 4 of 14, right column).
Regarding claims 15 and 16, the claims do not recite any active methods steps that further limit claim 13. The claims merely set forth information about how the determined levels of gene expression may be used.
Regarding claim 18, Liu co-cultures the T9 CAR-T cells with tumor cells to activate the T9 CAR-T cells (p. 12 of 14, right column), demonstrating the CAR-T cells recognize a tumor antigen.
Regarding claim 20, Bell demonstrates that cell products expressing a chimeric antigen receptor comprising a CD28 co-stimulatory domain are known and are an obvious variant to those with a 4-1BB domain (Figure 1; and p. 2 of 16, left column).
Regarding claim 21, it would have been prima obvious to the ordinary artisan that CAR-T cells, which are a therapy for cancer, would be administered to subjects diagnosed as having cancer. In particular the CAR-T cells of Liu are specific for Acute Lymphoblastic Leukemia (ALL) cells, i.e., NALM6 tumor cells.
Regarding claim 24, Liu teaches measuring gene expression of IL-4 in the “cell therapy products”, T9 CAR-T cells and T1 CAR-T cells (Fig. 1e).
Liu teaches that T9 CAR-T cells secrete fewer IL4 than T1 CAR-T cells (p. 2 of 14, right column; and Fig. 1e). Liu further teaches that T9 CAR-T cells have decreased apoptosis with hyperproliferative capacity (p. 2 of 14, right column), demonstrate less exhaustion (p. 4 of 14, left column; and p. 6 of 14, left column) and have strong antitumor activity in vivo (p. 4 of 14, right column).
Bell teaches that IL-4 in the context of cancer and CAR T cells is largely immunosuppressive (p. 3 of 16, left column). Bell further describes is it known that IL-4 producing T cells are less effective in controlling tumor growth (p. 3 of 16, left column).
It would have been prima facie obvious at the time of filing to have determined that T9 CAR-T cells, which express less IL-4 as compared to a control, have a decreased likelihood of exhaustion and an higher likelihood of producing a response in a subject after transfer to a subject. This determination is supported by Bell, which demonstrates that IL-4 expressing T cells are less likely to produce an antitumor response.
It would have been prima facie obvious to have administered the T9 CAR-T cells to patients because they produce a better antitumor response, in part based on their reduced expression of IL-4.
Regarding claim 25, Liu teaches measuring the expression of IL4 prior to administration (p. 2 of 14, right column; Fig. 1e; p. 2 of 14, right column; p. 6 of 14, left column; and p. 4 of 14, right column).
Regarding claims 26 and 27, the claims further describe an embodiment when a cell therapy product and combination therapy are administered. The claims broadly encompasses administering only the cell therapy product. Thus, claims 26 and 27 are rendered obvious for the same reason as claim 24.
Regarding claims 28 and 29, the claim further limits the combination therapy but does not require it be administered. Thus, claims 28 and 29 are rendered obvious for the same reason as claim 24.
Regarding claims 30 and 31, the claims further describe when a cell therapy product and combination therapy are administered. The claim broadly encompasses administering only the cell therapy product. Thus, claims 30 and 31 are rendered obvious for the same reason as claim 24.
Regarding claim 32, Liu co-cultures the T9 CAR-T cells with tumor cells to activate the T9 CAR-T cells (p. 12 of 14, right column), demonstrating the CAR-T cells recognize a tumor antigen.
Regarding claim 36, it would have been prima obvious to the ordinary artisan that CAR-T cells, which a therapy for cancer, would be administered to subjects diagnosed as having cancer. In particular the CAR-T cells of Liu are specific for Acute Lymphoblastic Leukemia (ALL) cells, i.e., NALM6 tumor cells.
Regarding claim 39, Liu teaches measuring gene expression of IL-4 in the “cell therapy products”, T9 CAR-T cells and T1 CAR-T cells (Fig. 1e).
Liu teaches that T9 CAR-T cells secrete fewer IL4 than T1 CAR-T cells (p. 2 of 14, right column; and Fig. 1e). Liu further teaches that T9 CAR-T cells have decreased apoptosis with hyperproliferative capacity (p. 2 of 14, right column), demonstrate less exhaustion (p. 4 of 14, left column; and p. 6 of 14, left column) and have strong antitumor activity in vivo (p. 4 of 14, right column).
Bell teaches that IL-4 in the context of cancer and CAR T cells is largely immunosuppressive (p. 3 of 16, left column). Bell further describes is it known that IL-4 producing T cells are less effective in controlling tumor growth (p. 3 of 16, left column).
It would have been prima facie obvious at the time of filing to have determined that T9 CAR-T cells, which express less IL-4 as compared to a control, have a decreased likelihood of exhaustion and an higher likelihood of producing a response in a subject after transfer to a subject. This determination is supported by Bell, which demonstrates that IL-4 expressing T cells are less likely to produce an antitumor response.
It would have been prima facie obvious to have selected the T9 CAR-T cells for administration to patients because the produce a better antitumor response, in part based on their reduced expression of IL-4.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH G DAUNER whose telephone number is (571)270-3574. The examiner can normally be reached 7 am EST to 4:30 EST with second Fridays Off.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached at 5712723157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JOSEPH G. DAUNER/ Primary Examiner, Art Unit 1682