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 .
Application Status
This action is written in response to applicant’s correspondence received October 13, 2025. Claims 1, 2, 7-9, 13, 15-17,21-23, 24-34, & 94 are currently pending. Claims 3-6, 10-12, 14, 18-20, 35-93 are cancelled. Claim 94 is new. Any rejection or objection not reiterated herein has been overcome by amendment.
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.
Claims 1, 2, 7-9, 13, 15-17,21-34, 94 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 and 17 are indefinite in the recitation of “Table 1”. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993). See MPEP 2173.5(s).
Here, it is clearly possible for the claims to be complete in themselves. All that is needed from the Table is the gene locations, which can be recited in regular text lines in the claims; recreation of the actual Table in the claim is not necessary.
Claims 2,7-9, 13, 15,16,21-34 and 94 depend from claim 1 and are indefinite for the same reason.
Claim 1 is indefinite in the recitation of measuring methylation in T cells, then step b, “calculating a multipotency score for each of the subject T cells based on a comparison…”, which appears to be a measure per cell. The specification on Pg 18 recites, to isolate a population of T cells with a desired differentiation potential, dividing a starting population of T cells into three or more subpopulations, determining the multipotency score for each subpopulation, c) subsequently identifying and combining the subpopulations with a desired multipotency score, to produce a final population of T cells. It is unclear whether claim 1 is missing a step, or is written in unclear language regarding what is used prior to, or for, a multipotency score calculation, namely in the use of the measurement of individual cells as opposed to groups (subpopulations) of cells, which would result in different mathematical comparisons (score calculations). This also affects the meaning of the subsequent step regarding what subpopulation is being referenced that is separated and collected.
Claims 2,7-9, 13, 15,16,21-34 and 94 depend from claim 1 and are indefinite for the same reason.
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, 2, 7-9, 13, 15-17,21-34, 94 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, and/or abstract ideas), a measure of methylation that is correlated with T-cell differentiation stage, without significantly more. The judicial exception is not integrated into a practical application. The claims incorporate laws of nature (natural cells, natural methylation status), abstract ideas (score calculation), and routine methods recited at broad level (e.g. separate and collect), which rely upon abstract ideas (score).
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.” See, e.g., Benson, at 71-72. 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, then 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.”
Subject Matter Eligibility Analysis (MPEP 2106(III), 2106.04(II)(A)):
Step 1 asks, Are the claims directed to a statutory category? Yes, the claims are directed to a process, more specifically to a method of producing a subpopulation of T cells by measuring methylation status of CpG sites, calculating a score based upon methylation status and separating and collecting the subpopulation of T-cells. It is noted here that “producing” does not mean these cells are produced, as in modified, engineered or manufactured. Rather, a naturally occurring differentiation stage is identified by the process of the method steps, allowing for separation and collection of (i.e. producing) of subpopulation of T cells that exist naturally in the subject’s body, or in nature, akin to their methylation patterns (they exist in nature). and here require abstract ideas: mathematical analysis). The mathematical calculations of scores are abstract ideas, and also ineligible under 35 U.S.C. 101.
Step 2A, Prong I asks, Are the claims directed to (or do they recite, describe, or set forth) a judicial exception (law of nature, natural phenomenon, abstract ideas (i.e. mathematical concepts, mental processes)) (MPEP 2106.04 (a)-(c))? Yes, the claims are directed to a natural phenomenon, a methylation status (which is measured from natural CpG sites in T cells), plus a score(s) calculated based upon methylation status relative to an index, and collecting the T cells of a desired stage, that occur in nature. The methylation status of CpGs in subject T cells, and the correlation between it and the multipotency score of T cells are natural phenomenon or consequence of a natural process. The basic separation and collection of the natural T cells is routine. The claims are also directed to abstract ideas (or mathematical concepts which relate to mental processes), namely calculation of a multipotency score. Since the claims are directed to collection of natural cells it is noted that, while this is a process claim, there is resemblance to process claim examples, e.g. “a method of providing an apple” where, under the broadest reasonable interpretation, the claim is focused on the apple, a nature-based product (MPEP 2106.04(c)), which can be subjected to the markedly different analysis for nature-based products used in a process (MPEP 2106.04(c)). Here the structure and function of the cells remains the same (not markedly different) in nature and in the “collection” of the claims thus, this is not considered a product of nature exception. The appropriate counterpart, the closest natural product, would be the same cells in nature as found in the claims. Recall that primers are considered products of nature because they were deemed to lack markedly different characteristics than natural DNA (Univ of Utah Research Foundation v. Ambry Genetics Corp, 774 F.3d 755,113 USPQ2d 1241 (Fed Cir 2014). Similarly, claims to detecting naturally occurring cell-free fetal (cff) DNA in maternal blood” were held to be directed to the cffDNA, it’s existence and location of cffDNA is a natural phenomenon [and thus] identifying its presence was merely claiming the natural phenomenon itself (Rapid Litig. Mgmt., 827 F3d at1048 USPQ2d at 1374) here the claims are focused on the natural cells (MPEP 2106.04(c)).
Step 2A Prong II: Integration of a Judicial Exception into A Practical Application (2106.04(d)), asks, are there additional elements recited in the claims that integrate the judicial exception into a practical application, which relates.
The T-cells remain natural cells throughout the method, and isolation or purification of cells is not sufficient to overcome ineligibility since these T cells exist naturally in the body and there is no functional modification of them taking place (Association for Molecular Pathology v. Myriad Genetics, 569 U.S. 7576(2013)). Merely, selecting a subset of them is considered selecting a naturally occurring population of cells (natural phenomenon) since the selected cells do not have markedly different characteristics than they did prior to selection, and mere purification or enrichment without new functional traits is still considered a product of nature (Association for Molecular Pathology v. Myriad Genetics, 569 U.S. 7576(2013); Mayo v. Prometheus (566 U.S. 66, 2012). Notably, the Specification points out that DNA methylation is a marker for assessing T cell differentiation and differentiation stage is identified by DNA methylation status (a natural correlation) (Pg 1).
Beyond the natural phenomenon (T cell populations’ differentiation by methylation status) and abstract ideas or mathematical steps (score calculation), there is only Insignificant extra solution activity (MPEP2106.05(g)), since “separating and collecting” of cells, does not constitute grounds for integration of the exception, because its breadth is insufficient to be considered particularly narrowing, or to actually integrate the exception as used in this context (MPEP 2106.04(d)). The breadth of “separate and collect” is akin to “apply it”, and here this action simply uses the result of the natural correlation, without a particular, technical application (lacking essential detail), and as such is considered merely the downstream use of a decision (score), and a logical subsequent next step for any method of application (MPEP2106.05(f)).
Step 2B Do additional elements amount to significantly more than the judicial exception, or if these elements are present are they merely well understood routine, conventional activity? (MPEP 2106.05)
Collecting T cells at a differentiation stage, and cell processing methods generally such as collection and sorting, are not a new manufacturing process since collection is routine. Sallusto (Sallusto, F et al., Two subsets of memory T lymphocytes with distinct homing potentials and effector functions, 1999,Nature 401, pages708–712) separated, for example, a differentiation stage, or varied subsets of CD4+ cells (e.g. Fig 6, CD45RA+, CCR7+ sorted from peripheral blood, CCR7+ and CCR7- were sorted from one another (Fig 6c) and subsets of CD34+ cells were sorted by expression of CD45RA, CD45R0 and CCR7 (Table 1); FACS cell sorting (Pg. 712, left col, third full para) inherently collects since the cells are collected into different tubes.
Guan (Guan, L.., et al. Antigen-specific CD8+ memory stem T cells generated from human peripheral blood effectively eradicate allogeneic targets in mice 2018, Stem Cell Research & Therapy 9:337) sorted and collected T cells (Abstract, Pg 2 left col, final para, Pg 3, left col, third and fourth full para, Pg 3 right col fourth para).
Measuring methylation status is conventional and considered mere data gathering and insignificant extra-solution activity, particularly where the recitation is at a high level of generality and methylation studies on T cells are found in the art: Youngblood et al (Nature, 2017; cited on IDS) investigated changes in methylation in T cells during viral infection and measured methylation and determined methylation status (Pg 404, left col para 1; Pg 409, left col, first full para, line 6).
The calculation of a score based upon methylation status of one or more genes is a mental process that amounts to an abstract idea since the calculation relies upon the application of a mathematical formula and can be “performed within the mind.” MPEP 2106.04(a)(2)(III). Notably, the courts do not distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer MPEP 2106.04(a)III., Mental Processes.
The additional claims further characterize the exception of claim 1 and do not integrate the claim or concept into a practical application (see MPEP 2106.04(d)(2)). Thus, claims 1, 2, 7-9 13, 15-17,21-34, 94 are patent ineligible.
Remarks:
Remarks are largely drawn to withdrawn rejections.
The Rationale re: 101 presented by Applicant addresses the two-step framework, then comments upon portions of CellzDirect hepatocyte freezing, where the examiner finds of note, producing is used in a context that differs from the use of “producing” in the amended claims. The CellzDirect invention involved a novel method of preparation of cryopreservation of cells (freezing, thawing and selecting surviving cells from that process, then refreezing those cells), was not at all routine or conventional and claims were directed to that preparation production – they identified a new technique for hepatocyte preservation. The use of “producing” therefore differs here, relative to the amended claims, where in the latter, the cells are the same as found in nature and merely partitioned. As applicant points out, additional detail of the method, e.g., density gradient fractionationation to sort out nonviable hepatocytes, and cryopreserving recovered viable hepatocytes after thawing a second time, where more than 70% of hepatocytes are viable thus is novel and as well, provides more than extra solution activity. As applicant indicates, a process of preserving hepatocytes by repetition of cryopreservation steps was not conventional. Applicant is using cells that are not changed from their natural state and sorting them, combined with abstract ideas and high level (lacking detail) disclosure of that which does not amount to significantly more, plus insignificant extra solution activity. Detailed analysis, inclusive of relevant sections from MPEP, is provided and articulates at each step why Applicant’s claims are rejected.
With ccfDNA, as applicant indicates, the method of preparation was novel, ccfDNA had not been separated/enriched as such previously and the entirety of what is relevant to that case differs from Applicant’s amended claims, which are here thoroughly evaluated with reference to relevant MPEP sections in the included rejection.
Conclusion
All claims rejected. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
/LISA HORTH/Examiner, Art Unit 1681
/GARY BENZION/Supervisory Patent Examiner, Art Unit 1681