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 .
Claim Objections
Claim 6 is objected to because the word “mofetil” is misspelled.
Claims 10 and 11 are objected to because of the following informalities: they recite “any combinations” but should recite “any combination.” Appropriate correction is required.
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 1-5, 13, 14, 16, and 17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a mental step) without significantly more. The claim(s) recite(s) a mental step of measuring the effects of immune suppression in a subject based on the analysis of a number of immune cells and a protein’s expression level.
Analysis of subject-matter eligibility under 35 U.S.C. § 101 requires consideration of three issues: (1) whether the claim is directed to one of the four categories recited in §101; (2A) whether the claim is directed to a judicial exception (i.e., a law of nature, natural phenomenon, or abstract idea that is integrated into a practical application; and (2B) whether the claim as a whole recites additional elements that amount to significantly more than the judicial exception. MPEP 2106(I), (III). See Alice Corp. Pty. Ltd. v. CLS Bank Int'l, 573 U.S. 208, 110 U.S.P.Q.2d 1976 (2014); Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 71, 101 USPQ2d 1961, 1965 (2012).
Applying the Alice/Mayo test to the claims:
Question 1: Yes, the claims are directed to a process. MPEP 2106.03.
Question 2A prong 1: Yes, the claims recite a judicial exception, specifically a mental step of analyzing the number of immune cells and the protein expression level to measure the effects of immune suppression on the subject. This step of correlating the results of the “quantifying” and “determining” step with an effect on the subject is an abstract idea that can be carried out in the mind. MPEP 2106.04(I), (II)(A). In addition, the claim recites a natural phenomenon, namely the subject’s natural response to immune suppression.
Question 2A prong 2: No, the claim does not recite additional elements that integrate the judicial exception into a practical application. The analysis and measurement steps are not followed by, for example, a concrete step of treating the subject based on the outcome of the mental correlation step. Compare Vanda Pharms. Inc. v. West-Ward Pharms., 887 F.3d 1117, 1135-36, 126 U.S.P.Q.2d 1266, 1281 (Fed. Cir. 2018) (particular treatment step applied the natural relationship in a manner that integrated it into a practical application). MPEP 2106.04(d)(2).
Question 2B: No, the claim does not recite additional elements that amount to significantly more than the judicial exception. Claim 1 contains broadly drawn steps of “quantifying a number of [any] immune cells in [any] biological sample of [any] subject” and “determining [any] expression level of [any] protein from the biological sample.” Before the effective filing date of the invention, skilled artisans routinely quantified immune cells in biological samples from subjects, and they routinely determined protein expression levels, specifically in subjects with immune suppression.
Diks et al. (2021, Frontiers in Immunology—B Cell Biology 12:690328 (reference U) teach that immunosuppressive treatment is prescribed for a variety of indications that are themselves immunosuppressive. (Page 11, column 1.) Diks asked whether immunosuppressed patients can still mount normal immune responses to vaccines. (Page 11, columns 1-2.) Diks reviewed nearly thirty studies on the effects of vaccines carried out between 2003 and 2017 on immunosuppressed patients, for example recipients of solid-organ transplants. (Supplemental Table 7 at 18-22.) Diks demonstrates that combining counting immune cells and assaying protein-expression level was routine and conventional in this art. For example, the Hoshina study reviewed by Diks employed flow cytometry (FC) and an opsonophagocytic killing assay (OPK) in conjunction with ELISA to measure protein expression. (Page 18 of supplement, row 4.) The Harrison study likewise employed FC to count cells followed by ELISA for expression measurement. (Page 18 of supplement, row 5.) Many of the studies reviewed by Diks used both flow cytometry (cell counting) and ELISA or ELISpot (gene-expression measurement) to assay the immune response of vaccinated immunosuppressed subjects. Gray-Owen et al. (US 2003/0022292; reference A) teach that immunosuppression can be assessed by quantifying cell proliferation and by measuring cytokine expression, e.g., by ELISA. (Paragraph 76.) Rakhmanov (2009, Proceedings of the National Academy of Sciences USA 106: 13451-13456; reference V) teach that the relative expression of CD21low B cells above 20% of the total B cell count in peripheral blood are indicative of type 1a common variable immunodeficiency (CVID) and generated gene-expression profiles of those cells in CVID patients. (Page 13451, column 2; page 13453, column 2; page 14355, column 1.)
Because the broadest reasonable interpretation of claims 1-5, 13, 14, 16, and 17 includes a mental step and a natural phenomenon and the claims lack elements that amount to significantly more than those judicial exceptions, they fail to claim patent-eligible 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.
Claims 1 and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gray-Owen et al. (US 2003/0022292).
Gray-Owen teaches that immunosuppression can be assessed by quantifying cell proliferation and by measuring cytokine expression, e.g., by ELISA. (Paragraph 76.) Gray-Owen teaches that these measurements are useful in determining whether a given Opa protein can suppress an immune response. (Paragraph 76.)
Claims 1, 2, 7, 9, 10, 13, 16, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rakhmanov et al. (2009, Proceedings of the National Academy of Sciences USA 106: 13451-13456, plus Supporting Information).
Rakhmanov teaches quantifying CD21low B cells in circulating blood (which contains plasma) by flow cytometry in common variable immunodeficiency patients. (Page 13451, column 2; Supporting Information page 1.) Rakhmanov observes an increase in CD21low B cells in CVID patients compared to healthy controls. (Page 13451, column 2.) Rakhmanov further teaches comparing gene expression profiles on these CD21low B cells, specifically assaying IgD, IgM, CD19, CD38, CD86, and CXCR5 expression. (Page 13452, column 1; page 13453, column 2, through page 13454, column 1; Table S3 in Supporting Information.) Rakhmanov concludes that the observed CD21low B cells are abnormally expanded in CVID patients. (Page 13455, column 2.)
Claims 1-3, 5, 7, 13, 14, 16, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Struijk et al. (2010, Kidney International 78: 934-940; reference W).
Struijk teaches analyzing patients who have received immunosuppressive therapy after stable kidney transplant. (Abstract; page 938, column 2, through page 939, column 1.) Specifically, Struijk teaches using flow cytometry on blood samples (which contain plasma) to count CD19+ B cells. (Page 939, column 2.) Struijk teaches determining the expression levels of IL-4, IL-2, and IFN-[Symbol font/0x67] using the ELISpot assay. (Page 939, column 2.) Struijk teaches that administering prednisolone (P) and everolimus to kidney-transplant recipients produce a significant rise in response to immunization. (Page 938, column 2.)
Claims 1-3, 5, 7, 9, 10, 13, 14, 16, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Puissant-Lubrano et al. (2010, Experimental and Clinical Transplantation 1: 19-28; reference X).
Puissant-Lubrano teaches analyzing patients who have received rituximab after kidney transplant and are subsequently vaccinated for tetanus. (Abstract.) Specifically, Puissant-Lubrano teaches using flow cytometry on blood samples (which contain plasma) to count CD19+ B cells. (Page 21, column 1.) Puissant-Lubrano teaches determining the expression levels of IgG, IgM, and IgA in serum. (Page 20, column 2, through page 21, column 1.) Puissant-Lubrano observed lower CD19+ B cell counts in the kidney-transplant recipients relative to healthy donors (page 22) and measured the effects of rituximab on the patients’ ability to respond to tetanus toxin. (Pages 24-25.)
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.
Claim 4 is rejected under 35 U.S.C. 102(a)(1) as being unpatentable over Gray-Owen et al. (US 2003/0022292).
Gray-Owen teaches that immunosuppression can be assessed by quantifying cell proliferation and by measuring cytokine expression, e.g., by ELISA. (Paragraph 76.) Gray-Owen teaches that these measurements are useful in determining whether a given Opa protein can suppress an immune response. (Paragraph 76.) Gray-Owen teaches that administration of Opa protein can treat autoimmune disease. (Claim 11.)
It would have been obvious to carry out Gray-Owen’s measurement method on a subject with an autoimmune disease in order to determine whether Gray-Owen’s Opa-administration method is working to treat that autoimmune disease.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over either Struijk et al. (2010, Kidney International 78: 934-940) or Puissant-Lubrano et al. (2010, Experimental and Clinical Transplantation 1: 19-28) taken in view of Strober et al. (US 2014/0243577; reference B).
Struijk teaches analyzing patients who have received immunosuppressive therapy after stable kidney transplant. (Abstract; page 938, column 2, through page 939, column 1.) Specifically, Struijk teaches using flow cytometry on blood samples (which contain plasma) to count CD19+ B cells. (Page 939, column 2.) Struijk teaches determining the expression levels of IL-4, IL-2, and IFN-[Symbol font/0x67] using the ELISpot assay. (Page 939, column 2.) Struijk teaches that administering prednisolone (P) and everolimus to kidney-transplant recipients produce a significant rise in response to immunization. (Page 938, column 2.)
In the alternative, Puissant-Lubrano teaches analyzing patients who have received rituximab after kidney transplant and are subsequently vaccinated for tetanus. (Abstract.) Specifically, Puissant-Lubrano teaches using flow cytometry on blood samples (which contain plasma) to count CD19+ B cells. (Page 21, column 1.) Puissant-Lubrano teaches determining the expression levels of IgG, IgM, and IgA in serum. (Page 20, column 2, through page 21, column 1.) Puissant-Lubrano observed lower CD19+ B cell counts in the kidney-transplant recipients relative to healthy donors (page 22) and measured the effects of rituximab on the patients’ ability to respond to tetanus toxin. (Pages 24-25.)
Neither Struijk nor Puissant-Lubrano teaches that the immunosuppressant is mycophenolate mofetil.
Strober teaches that mycophenolate mofetil in kidney transplant recipients has assumed an important role in immunosuppression. (Paragraph 35.)
It would have been obvious to substitute Strober’s mycophenolate mofetil for the prednisolone and everolimus of Struijk or the rituximab of Puissant-Lubrano because the references all establish that these agents are known immunosuppressants that prevent rejection of transplanted kidneys. Substituting known equivalents for the same purpose is prima facie obvious. See MPEP 2144.06(II).
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over either Struijk et al. (2010, Kidney International 78: 934-940) or Puissant-Lubrano et al. (2010, Experimental and Clinical Transplantation 1: 19-28) taken in view of Kute et al. (2021, Indian Journal of Nephrology 31: 89-91; reference U2).
Struijk teaches analyzing patients who have received immunosuppressive therapy after stable kidney transplant. (Abstract; page 938, column 2, through page 939, column 1.) Specifically, Struijk teaches using flow cytometry on blood samples (which contain plasma) to count CD19+ B cells. (Page 939, column 2.) Struijk teaches determining the expression levels of IL-4, IL-2, and IFN-[Symbol font/0x67] using the ELISpot assay. (Page 939, column 2.) Struijk teaches that administering prednisolone (P) and everolimus to kidney-transplant recipients produce a significant rise in response to immunization. (Page 938, column 2.)
In the alternative, Puissant-Lubrano teaches analyzing patients who have received rituximab after kidney transplant and are subsequently vaccinated for tetanus. (Abstract.) Specifically, Puissant-Lubrano teaches using flow cytometry on blood samples (which contain plasma) to count CD19+ B cells. (Page 21, column 1.) Puissant-Lubrano teaches determining the expression levels of IgG, IgM, and IgA in serum. (Page 20, column 2, through page 21, column 1.) Puissant-Lubrano observed lower CD19+ B cell counts in the kidney-transplant recipients relative to healthy donors (page 22) and measured the effects of rituximab on the patients’ ability to respond to tetanus toxin. (Pages 24-25.)
Neither Struijk nor Puissant-Lubrano teaches determining the subject’s ability to respond to a COVID-19 vaccination.
Kute teaches that organ-transplant recipients are a high-risk group for COVID-19 infection and recommends vaccination to help build protection. (Page 89, column 1.)
It would have been obvious to provide Kute’s COVID-19 vaccine to a transplant recipient, then use the method of Struijk or Puissant-Lubrano to assess that subject’s response to the vaccine. The skilled artisan would have wished to assay the vaccine’s effectiveness because Kute teaches that organ-transplant recipients are at high risk for COVID-19.
Allowable Subject Matter
Claims 8, 11, and 12 are objected to as being dependent upon a rejected base claim, but they would be allowable if rewritten in independent form including all limitations of the base claim and any intervening claims.
On 8/24/26, the examiner attempted to contact applicants’ representative regarding potential amendments to bring the application into allowance. The attorney who signed the most recent document (a power of attorney on 4/2/25) is no longer employed by the representing firm. The telephone numbers listed in the correspondence information were incorrect. A call to the Minneapolis office of the firm leaving a message for the attorney assigned to the case to call the examiner was not timely returned. This Office action followed.
The examiner has determined that the following claims would be allowable if submitted in response to this Office action.
1. A method of measuring effects of immune suppression in an immunocompromised subject, the method comprising:
(a) quantifying a number of B cells in a biological sample of the subject;
(b) determining an expression level of a protein from the biological sample,
wherein the protein is selected from the group consisting of CPT1a, hexokinase II (HK2), CD11c, FcRL5, and CD39, or any combination thereof;
and
(c) analyzing the number of B cells and the expression level of the protein,
thereby measuring the effects of immune suppression in the subject.
Cancel claim 2.
Cancel claim 4.
6. The method of claim 5, wherein the immunosuppressive agent is mycophenolate mofetil (MMF).
Cancel claim 7.
8. The method of claim 1, wherein the B cell is a CD11c+ B cell.
Cancel claims 9 and 10.
12. The method of claim 1, wherein the immunometabolic marker is CPT1a.
13. The method of claim 1, wherein the analyzing step (c) comprises identifying the number of B cells and the expression level of the protein, and using the number of B cells and the expression level of the protein in combination to determine an immune response in the subject.
Conclusion
Claims 1-7, 9, 10, and 13-17 are rejected. Claims 8, 11, and 12 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lora E Barnhart Driscoll, whose telephone number is (571)272-1928. The examiner can normally be reached M-F 7:00-4:00 p.m. ET.
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/Lora E Barnhart Driscoll/Primary Examiner, Art Unit 3991
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