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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1, 3-5, 7, 9-10, 13, 15, 17-19, and 21-23 in the reply filed on 2/4/2026 is acknowledged. Claims 24-27 have been canceled.
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, 3-5, 7, 9-10, 13, 15, 17-19, and 21-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
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. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claims recite methods of determining transgene copy number, as well as reciting mathematical formulas to calculate copy number expressed as units of copy number/µL of blood, copy number/mg of tissue, and copy number/µg of gDNA. Additionally, the claims recite normalizing gDNA input and determining genomic DNA recovery rate. These elements and steps are recitations of abstract ideas because they are directed to mathematical concepts including mathematical relationships, mathematical formula and equations, as well as requiring mathematical calculations. In addition to requiring these limitations, claim 22 is directed to the abstract mental process of “determining cellular kinetics” by detecting transgene copy number, which encompasses making additional mathematical calculations as well as drawing conclusions and determinations which can occur within the human mind or with no more than pencil and paper. The same analysis holds for claim 23 which is directed to determining dosing selection and dosing schedule for administration of CAR-T cells by performing the calculations in claim 1 and “adjusting” to achieve a therapeutically effective amount of CAR-T cells. Not only does this encompass making decisions and/or observations, but it also recites the natural correlation between the transgene copy number and dose schedule/dose selection. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of extracting genomic DNA using an automated process and performing ddPCR to amplify a transgene of interest and a reference gene, as well as spiking in a known amount of a control gene. However, these steps are directed to data gathering and do not integrate the recited JE’s into a practical application. Additionally, “adjusting the dosage” in claim 23 itself encompasses the abstract mental concept of making a determination or decision, as well as expressing a mathematical relationship between the copy number and dosage as well as requiring mathematical calculations. Therefore, this element does not integrate the JE’s into a practical application.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, the claims recite steps of extracting genomic DNA using an automated process, performing ddPCR to amplify a transgene of interest and a reference gene, as well as spiking in a known amount of a control gene, however these are recited at a high level of generality and are directed to well understood, routine, and conventional activity. (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, 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." Further "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., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, 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.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112
Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claim 23 is rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement. Although specification is enabling for methods of detecting transgene copy number by the method of claim 1, the specification does not reasonably provide enablement for the method of claim 23, that is determining a dose selection and dosing schedule for CAR-T cell administration to achieve a therapeutically effective amount of CAR-T cells in a subject. The specification does not enable any person skilled in the art to which it pertains or with which it is most nearly connected to make or use the invention commensurate in scope with these claims. There are many factors to be considered when determining whether there is sufficient evidence to support determination that a disclosure does not satisfy the enablement requirements and whether any necessary experimentation is undue. These factors have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The claims require determining dose selection and dose schedule for administration of CAR-T cells in a subject in need thereof by determining the transgene copy number in a biological sample by the method of claim 1, and adjusting the dose selection and/or dose schedule to achieve a therapeutically effective amount of CAR-T cells in the subject.
The invention is in a class of inventions which the CAFC has characterized as 'the unpredictable arts such as chemistry and biology" (Mycolgen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Federal Circuit 2001)).
The specification teaches method of determining transgene copy number in a biological sample of a subject receiving CAR-T cell therapy by extracting genomic DNA, performing ddPCR (digital droplet PCR) to amplify the transgene and a reference gene, and determining transgene copy number in units of copy number per microgram of genomic DNA. However, the specification does not provide any direction or guidance as to how to use this information to adjust the dose selection and/or dose schedule to achieve a therapeutically effective amount of CAR-T cells in the subject. The specification provides no guidance as to any standard that could be used to determine if the dose should be increased, decreased, or unchanged, or if the dosing schedule should be changed based on the results of transgene copy number in a subject receiving CAR-T cell therapy. Additionally, the art is silent as to how to use the transgene copy number of a subject undergoing CAR-T cell therapy to adjust the dosage or dosing schedule to achieve a therapeutically effective amount of CAR-T cells.
Although the level of skill in the art is deemed to be high, the lack of guidance from the specification or the art as to how to adjust dose or dosing schedule of CAR-T cell therapy in subjects to achieve a therapeutically effective amount of CAR-T cells using transgene copy number is higher. Neither the art nor the specification provide any guidance or standard by which the skilled artisan would be informed as to how the dosage or schedule should be adjusted to arrive at the claimed invention. To practice the invention as broadly claimed, an undue amount of unpredictable trial and error experimentation would be required since the skilled artisan would first have to discover the standards by which transgene copy number could be informative of a need for adjusting the dosage or dosing schedule of CAR-T cell therapy. If in fact transgene copy number could be used in this capacity, the skilled artisan would then need to determine how to use the copy number information to then determine how to adjust the dose or dosage schedule to achieve a therapeutically effective amount of CAR-T cells. This experimentation requires an enormous amount of inventive effort with each step providing no guarantee of success or indication of predictable outcome. Thus, given the broad claims in an art whose nature is identified as unpredictable, the large quantity of research required to define these unpredictable variables, the lack of guidance provided in the specification, the absence of a working example, and the lack of any guidance in the art, balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claim as broadly written.
Indefinite
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.
Claims 7, 13, and 15 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 7 recites stability of gDNA extraction as assessed by a quality control concentration of an exogenous gene, selected from “low”, “medium”, and “high” quality. However the terms “low”, “medium” , and “high” are relative terms which renders the claim indefinite. The terms are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 13 and 15 are indefinite because they do not end in a period (.). Accordingly, it is not clear if they require additional elements or steps.
Claim Rejections - 35 USC § 103
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.
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.
Claims 1, 3, 17, 18, 21 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Kebriaei (Kebriaei et al; The Journal of Clinical Investigation, vol 126, pages 3363-3376, 2016).
Kebriaei teaches a method of assessing T cell permanence in patients receiving CAR-T cell therapy (see whole document). With regard to step a of claim 1, Kebriaei teaches extracting genomic DNA using a commercially available kit (see supplemental methods “Quantitative PCR (Q-PCR) and droplet digital PCR (ddPCR) to measure T-cell persistence”). With regard to step b of claim 1, Kebriaei teaches performing ddPCR on the isolated genomic DNA using primers and TaqMan probe sets to detect the CAR transgene as well as the human EIF2C1 house-keeping gene (reference gene) to normalize the genomic DNA. With regard to step c of claim 1 and claim 22, Kebriaei teaches determining transgene copy number in units of copy number/cell as well as units of copy number/µg of gDNA (see figure 4). Claim 22 does not provide any additional steps other than determining transgene copy number “in accordance with claim 1”. Although Kebriaei does not teach if the commercially available kit for genomic DNA extraction was automated or manual, automating a manual activity is considered prima facie obvious. As set forth in the MPEP 2144.04 III “Automating a Manual Activity”:
In re Venner, 262 F.2d 91, 95, 120 USPQ 193, 194 (CCPA 1958) (Appellant argued that claims to a permanent mold casting apparatus for molding trunk pistons were allowable over the prior art because the claimed invention combined "old permanent-mold structures together with a timer and solenoid which automatically actuates the known pressure valve system to release the inner core after a predetermined time has elapsed." The court held that broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art.)
With regard to claim 3, although Kebriaei does not teach the formula used to calculate transgene copy number in units of copy number per ug of genomic DNA, the formula recited in the claims is considered prima facie obvious in view of the prior art cited. The values directed to transgene copy and reference gene copy simply recites the mathematical relationship of the ratio of transgene to reference gene, which is taught by Kebriaei. The value of 3.3 pg/copy is directed to the known mass of the human genome while 1,000,000 is directed to an obvious scaling factor which does not distinguish the claims from the prior art cited.
With regard to claim 17, Kebriaei teaches detecting infused T cells in cerebrospinal fluid and bone marrow at 49 copies/ug of genomic DNA (less than 50 copies) (see page 3370, col 1, first para).
With regard to claim 18, Kebriaei teaches the reference gene used was EIF2C1.
With regard to claim 21, Kebriaei teaches using negative control “no DNA” autologous control T cells.
Claims 4, 5, 7, 9, 10, 13, 15 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Kebriaei as applied to claims 1, 3, 17, 18, 21, and 22 above, and further in view of O’Connell (O’Connell et al; Laboratory Medicine, 2018, vol 48, pages 332-338), Mika (Mika et al; Frontiers in Molecular Biosciences, vol 7, pages 1-9, May 2020), and Heczey (Heczey et al; Molecular Therapy, vol 25, 2017; pages 2214-2224 and Supplemental information pages 1-8).
The teachings of Kebriaei are set forth above and incorporated herein. Kebriaei does not teach measuring genomic DNA extraction recovery or spiking in a known amount of control gene before and after genomic DNA extraction. Kebriaei does not teach using the RNase P gene as a reference gene.
However O’Connell teaches that methods of quantitative PCR, which require DNA extraction from a sample, suffer from inter-specimen variability (see abstract). O’Connell teaches measuring DNA extraction efficiency (page 335, col 1). O’Connell teaches that the use of exogenous spike in control nucleic acid, prior to DNA extraction, allowed for accurate quantification of DNA levels using quantitative PCR despite substantial inter-specimen variability in DNA extraction efficiency (see whole document). Additionally, Mika teaches methods of quantification of CAR T Cells using digital droplet PCR (see whole document). Mika teaches use of RNase P gene (claim 19) as the reference gene in the method (see page 3, col 1). Mika teaches that reproduceable CAR-T cell quantification was achieved in methods that employed the use of spike in control DNA after DNA extraction from blood samples (see materials and methods). Therefore, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date, to have measured DNA extraction efficiency, as taught by O’Connell, in the method involving extraction of genomic DNA taught by Kebriaei, using spike in DNA control sequences, as taught by O’Connell for the obvious benefit of accurately quantifying transgene copy number in the method of Kebriaei. The ordinary artisan would have also been motivated to use spike in nucleic acids after DNA extraction, as taught by Mika, because Mika teaches that doing so provides for reproduceable CAR-T cell quantification. It is additionally noted that Mika also exemplifies the use of different reference genes in the method of determining transgene copy number using ddPCR. Therefore, the substitution of the RNase P gene of Mika for the reference gene taught by Kebriaei is considered the substitution of one known element for another with predictable results.
Kebriaei in view of O’Connell and Mika do not teach expressing copy number in units of copy number per microliter of blood or copy number per milligram of tissue, however Heczey teaches quantification of CAR-T transgene copy number in units of copy number per milliliter of blood. Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing that transgene copy number could be expressed in a number of different units, depending on the sample type obtained, as exemplified by the prior art cited. Absent secondary considerations, the units recited in the instant claims are considered prima facie obvious over the teachings of the prior art.
Conclusion
No claims are allowed.
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/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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