CTNF 18/553,523 CTNF 95756 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Election/Restrictions Applicant's reply to the Restriction Requirement, dated May 9, 2026, has been received. By way of this submission, Applicant has amended claims 16-18, introduced new claim 20, and elected Group I, claims 1-15, drawn to methods of stratifying a subject with neurological or psychiatric disease manifestation, and the species of CD19 as the B cell marker, CD56 as the NKT cell marker, CD19 as the monocyte marker, CD16 as the species of CD56dimC16+ NK cell marker, with detecting intrathecal immunoglobulin synthesis, with determining whether or not type 2 or type 3 oligoclonal bands can be detected, with determining a level of plasma cells, CD138 as the plasma cell marker, and relapsing forms of multiple sclerosis (RMS) as the disease. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). 08-06 AIA Claim s 1-20 are pending. Claims 10-15 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (claim 19) or species (claims 10-15) , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 9, 2026 . Claims 1-9, 16-18, and 20 are therefore under examination before the Office . Claim Rejections - 35 USC § 101 07-04-01 AIA 07-04 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 1-9, 16-18, and 20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception ( i.e ., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claims recite a natural phenomenon, a correlation between immune cell levels and neuro-inflammatory autoimmune disease. This judicial exception is not integrated into a practical application because the claimed data gathering steps do not add a meaningful limitation to the method as they are insignificant extra-solution activity. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because quantifying levels of a biomarker is a well-understood, routine, conventional activity in laboratory technique, and therefore insufficient to amount to an inventive concept. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc ., No. 10-1150 (March 20, 2012). “Laws of nature, natural phenomena, and abstract ideas” are not patentable. Diamond v. Diehr , 450 U.S. 175, 185 (1981); see also Bilski v. Kappos , 561 U.S. 593,604, 95 USPQ2d 1001, 1007 (2010). “Phenomena 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). The Supreme Court does acknowledge that it is possible to transform an unpatentable law of nature, but one must do more than simply state the law of nature while adding the words “apply it.” Essentially, appending conventional steps, specified at a high level of generality, to laws of nature, natural phenomena, and abstract ideas cannot make those laws, phenomena, and ideas patent-eligible. In Prometheus , the Court found that “[i]f a law of nature is not patentable, the neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself.” Additionally, “conventional or obvious [pre]solution activity” is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook , 437 U.S., at 590; see also Bilski , 561 U. S.: “[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’. . . adding ‘insignificant post-solution activity’” (quoting Diehr , at 191-192). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” The first step under this guidance is determining if the claim is directed to one of the four statutory categories (process, machine, manufacture, or composition of matter). In this case, the claims are a method (process). The second step is determining if the claims recite or involve judicial exception(s), such as laws of nature, natural phenomena, natural products, or an abstract idea. In this case, the claims are drawn to methods of stratifying a subject with neurological or psychiatric disease manifestation by determining levels of immune cells in a cerebrospinal fluid sample. This is a natural correlation/observation of a natural phenomenon, the relationship between immune cell levels in said sample and neuro-inflammatory autoimmune disease. Furthermore, the judicial exception is not integrated into a practical application, as the claims do not rely on or use the exception in a further step. See MPEP 2106.04(d). Thus, it must be determined if the claim as a whole recites something significantly more than the judicial exceptions. The methods comprise two steps, a determining step and a stratifying step. The determining step is performed by measuring biomarkers in the cerebrospinal fluid sample. The use of antibodies or immunoassays to determine levels of a biomarker has been characterized by the Court as “mere data gathering” and “insignificant extra-solution activity”. Determining the level of a biomarker in blood by any means has been recognized by the courts as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner ( e.g ., at a high level of generality) or as insignificant extra-solution activity. Mayo , 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC , 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017). MPEP 2106.05 (II). Additionally, determining levels of immune cells in a cerebrospinal fluid sample was well-known in the art to be useful in assessing disease (see, e.g ., Han (J Immunol. 2014 Mar 15;192(6):2551-63, cited in IDS). Using this method to make such a diagnosis would have been a routine, conventional choice, and as such does not offer significantly more than the exception itself. The stratifying step is merely a mental process of evaluation that amounts to only an abstract idea, and can be performed within the mind. MPEP 2106.04(a)(2)(III). As such, this step does not add "significantly more" to the exception. The remaining claims further characterize the exception itself, e.g ., additional details for performing the determining. These specifics are also directed to the data gathering step of the determining, and routine choices when practicing routine and well-known assays for detecting immune cells. Therefore, claims 1-9, 16-18, and 20 are patent ineligible. Conclusion The closest prior art is Han (J Immunol. 2014 Mar 15;192(6):2551-63, cited in IDS). Han teaches that immunophenotyping cerebrospinal fluid (CSF) cells by flow cytometry is useful in diagnosis of relapsing–remitting multiple sclerosis (MS) (page 2551, right column: "Thus, understanding the heterogeneity of intrathecal immune responses and their relationship to disease phenotype is a prerequisite for rational selection of optimal therapy in patients with MS, as well as other neuroimmunological diseases for which pathogenic mechanisms are even less understood." and page 2552, left column, second paragraph: "... RR-MS patients have intrathecal expansion of B cells and plasmablasts, in comparison with noninflammatory neurologic diseases (NIND) controls."). Han further teaches that B cells are increased in CSF of patients with MS when compared to noninflammatory neurologic disease controls (page 2555, "Differences in B cells"). Han further teaches that monocytes are decreased in CSF of patients with MS when compared to noninflammatory neurologic disease controls (page 2556, "Differences in monocytes"). However, Han does not teach that patients with a neuro-inflammatory autoimmune disease have decreased levels of CD56 dim CD16+ NK cells relative to a control sample. No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER JOHANSEN whose telephone number is (571)272-0280. The examiner can normally be reached Monday-Friday, 7:00 to 3:00. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /PETER JOHANSEN/Examiner, Art Unit 1644 Application/Control Number: 18/553,523 Page 2 Art Unit: 1644 Application/Control Number: 18/553,523 Page 3 Art Unit: 1644 Application/Control Number: 18/553,523 Page 4 Art Unit: 1644 Application/Control Number: 18/553,523 Page 5 Art Unit: 1644 Application/Control Number: 18/553,523 Page 6 Art Unit: 1644 Application/Control Number: 18/553,523 Page 7 Art Unit: 1644
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