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 .
Response to Amendment
Claims 6 and 9 have been amended, and claims 10-11 have been newly added as requested in the amendment filed on 7 April 2026. Following the amendment, claims 1-11 are pending in the instant application, and are under examination in the instant office action.
Election/Restrictions
Applicant’s election without traverse of CD19 in the reply filed on 7 April 2026 is acknowledged.
Claims 10-11 are withdrawn as being drawn to non-elected species.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application claims the benefit of Chinese application No. CN202211270320.X filed on 18 October 2022.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claims 1-9 have an effective filing date of 18 October 2022.
Claim Objections
Claim 9 is objected to because of the following informalities: line 2 of the claim states “a the sample”. 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 1-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to without significantly more. The claim(s) recite(s) “calculating”, “subtracting”, “fitting … values into a linear standard curve to create a formula”, and “converting … molar concentration and ΔMFI …into …values”. Additionally, the claim as a whole is directed to detecting anti-chimeric antigen receptor antibodies against humanized CAR T cells. This amounts to mere observation of a natural phenomenon, whereby humans who are administered humanized CAR T cells, have an immune response and produce antibodies against these cells. This is a natural phenomenon judicial exception (see MPEP 2106.04(b)), and is analogous to detection of the existence of cell-free fetal DNA (cffDNA) in maternal blood, Ariosa Diagnostics, Inc. v. Sequenom, 788 F.3d 1371, 1373, 115 USPQ2d 1152, 1153 (Fed. Cir. 2015). These abstract idea judicial exceptions are not integrated into a practical application because the elements recited in addition to the judicially excepted subject matter, do not provide any of the considerations set forth in MPEP 2106.05(a-c), (e) and (h) that provide for integration. Further, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s) because the additional steps/elements were each well-understood, routine, and conventional activities in the art before the effective filing date of the application.
The claim is directed to a method, which is a statutory category of invention. Step 1: YES.
Step 2A, Prong One of the subject matter eligibility analysis requires evaluating whether a claim recites a judicial exception. The instant claims describe at least one of the enumerated abstract idea set forth in MPEP 2106.04(a). Specifically, the claims recite 1) Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations (see MPEP § 2106.04(a)(2), subsection I); and 3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III). Claim 1 recites: “step S6, calculating a concentration of the anti-CAR antibody by detecting average fluorescence intensities of the standards, blank controls, and the samples to be tested using flow cytometry,” which is a mathematical concept. Depending claim 5 further recites additional mathematical concepts: “calculating a protein molar concentration (nM) of each standard using molecular weight of human CD 19 protein and protein concentrations of standards 1 to 5; subtracting an average fluorescence intensity of a blank sample from an average fluorescence intensity of all standards to obtain corresponding AMFI; converting protein molar concentrations and ΔMFI of standards 1 to 5 into a first group of lg values; fitting the first group of lg values into a linear standard curve to create a formula: y = 0.7253x + 3.8192, wherein x is a lg value of protein molar concentration and y is a lg value of ΔMFI; converting all the protein molar concentration and ΔMFI of all samples to be tested into a second group of lg values and substituting the second group of lg values into the formula; and calculating a molar concentration of anti-CAR antibody for each sample. Regarding Mathematical Relationships, MPEP 2106.04(a)(2)(I)(A) states mathematical relationships in claims may be expressed in words or using mathematical symbols. Any claim that recites a numerical formula or equation will be considered as falling within the "mathematical concepts" grouping (MPEP 2106.04(a)(2)(I)(B)). MPEP 2106.04(a)(2)(I)(C) Any claim that recites a mathematical calculation, when the claim is given its broadest reasonable interpretation in light of the specification, will be considered as falling within the "mathematical concepts" grouping. Thus, the claims recite at least one judicial exception as defined by the MPEP.
Next, analysis requires evaluating whether a judicial exception is integrated into a practical application (Step 2A, Prong Two) by reciting additional elements that integrate the judicial exception. The considerations MPEP 2106.05(a-c), (e) and (h), provide the considerations that integrate a judicial exception into a practical application, such that the claim is more than a drafting effort designed to monopolize the judicial exception. The additional elements recited within claim 1 are: transfecting a humanized CAR into Chinese hamster ovary (CHO) cells using lentivirus to generate CHO cells expressing CAR as target cells; collecting samples to be tested; preparing different concentrations of standards using human proteins corresponding to a target of the CAR and establishing a standard curve; incubating the target cells with the different concentrations of standards and the samples to be tested, and capturing an anti-CAR antibody; and, incubating a phycoerythrin (PE)-conjugated anti-human IgG Fe antibody with the CHO cells for labeling. These additional elements do not present any improvement within the technical field. The claims do not recite any particular machine, nor a particular treatment/prophylaxis, or provide a particular transformation of the judicial exception.
The additional elements do not purport to improve the function of the technical field. Korean application no. KR20190130559A, published 22 November 2019 teaches lentiviral expression vectors were used to generate CHO cells expressing CARs, specifically, CHO cells expressing Axl (CHO-AXL), and CHO cells expressing Ror2 (CHO-ROR2). Collecting samples and preparing different concentrations of standards using human proteins corresponding to a target of the CAR and establishing a standard curve were both well-established practice within the art before filing. Incubating the target cells with the different concentrations of standards and the samples to be tested, and capturing an anti-CAR antibody was routine in the art prior to filing. Japanese application No. JP2019527553A, published 3 October 2019, teaches methods for capturing anti-idiotypic anti-CD19 CAR antibodies from samples. The following prior art teaches US20100151445, published 17 June 2010, teaches anti-human IgG antibodies (paragraph [0032]) and anti-human IgM antibodies (paragraph [0033]) labelled with a fluorescent label (phycoerythrin) (paragraph [0045]). Therefore, none of the additional elements provide any new improvement within the technology or further considerations that demonstrate integration of the judicial exception abstract ideas into any practical application.
Regarding the natural phenomenon judicial exception, in Sequenom (at IV) the Court reiterates the position of the district court wherein it notes: “It is important to note that the ’540 patent does not merely claim uses or applications of cffDNA, it claims methods for detecting the natural phenomenon. Because generally one must be able to find a natural phenomenon to use it and apply it, claims covering the only commercially viable way of detecting that phenomenon do carry a substantial risk of preempting all practical uses of it.” The case law applies to the instant claims, because the claims recite, at a high level of generality, “capturing an anti-CAR antibody” and labeling it, which effectively preempts all practical means for detecting the natural phenomenon itself.
Taken individually or in combination the additional claimed elements recite well-understood, routine, conventional activity in the relevant field (Step 2B: NO Additional elements that amount to significantly more). The crux of the invention seems to be aimed at “creat[ing] a formula: y = 0.7253x + 3.8192, wherein x is a Ig value of protein molar concentration and y is a Ig value of ΔMFI; converting all the protein molar concentration and ΔMFI of all samples to be tested into a second group of lg values and substituting the second group of Ig values into the formula; and calculating a molar concentration of anti-CAR antibody for each sample”. As stated above the claims recite no additional elements beyond what is well-understood, routine and conventional prior to filing. (Section III.A.3. Berkheimer Memorandum).
Thus, the preponderance of evidence suggests that the claims are not eligible subject matter under 35 USC 101.
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.
Claims 1-4 and 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over Valentine et al., Frontiers in Bioscience, 25: 270-282, 2020; taken with, Jensen et al. Biol Blood Marrow Transplant, 16(9): 1245-56, published September 2010; and Portillo et al, STAR protocols, 2: 100956, 17 December 2021.
Regarding claims 1, 4 and 6, Valentine et al. teach using lentiviral vectors to express CD19 in CHO cells (pg. 271, at bullet 3.1). Further the prior art teaches ScFv from murine antihuman CD19 clone FMC63 (3) were synthesized and cloned into a CAR construct with N-terminal GM-CSF signal peptide. This explicitly teaches the humanized CAR comprising CD19 of instant claim 6.
Valentine is silent with respect to collecting samples to be tested; preparing different concentrations of standards using human proteins corresponding to a target of the CAR and establishing a standard curve; incubating the target cells with the different concentrations of standards and the samples to be tested, and capturing an anti-CAR antibody; and incubating a phycoerythrin (PE)-conjugated anti-human IgG Fe antibody with the CHO cells for labeling.
The Jensen et al. prior art overcomes these deficiencies by disclosing methods for analyzing the serological anti-CAR immune responses. Specifically Jensen et al. teach serum was isolated from collected patient blood samples using an established laboratory SOP and a qualified assay to detect CAR-specific serological responses in samples. This teaches the “collecting samples to be tested” of the instant claim. Samples were allowed to clot for 2½ hours at room temperature, centrifuged at 1000 × g at 4°C for 15 minutes and serum was collected, aliquoted and frozen immediately at −80°C. Flow cytometric detection of potential serum antibody responses against the anti-CD19R transgene was performed using parental vs. CD19R-expressing Jurkat cell lines, which teaches using standards comprising human proteins corresponding to a target of the CAR and establishing a standard curve, namely CD19.
Jensen et al. detect the presence of antibodies in patient serum that specifically bound to CD19R by a subsequent incubation with FITC-conjugated goat anti-human IgG, Fcγ; however, -the Portillo et al. prior art is relied upon as evidence that a PE-conjugated Mouse Anti-Human IgG Fc, as required by instant claims 1 and 4, was commercially available before the effective filing date of the application. (Portillo pg. 4, Key Resources Table , first antibody listed, BioLegend, Cat#409304; Clone HP6017; RRID:AB_10895907). Since both are anti-human IgG Fc secondary antibodies, the only difference is the labelling conjugate, these can be used interchangeably with predictable success. The method of Jensen calculates the concentration of the anti-CAR antibody by flow cytometry. Specifically, Jensen et al. teach spectratyping analysis of the standards (the parental Jurkat cells of the reference), blank controls (non-reactive serum of the reference), and the patient samples to be tested using flow cytometry (see Figure 5 and legend), this teaches steps S3 through S6 of the instant claim.
It would have been obvious to a person having ordinary skill in the art, before the effective filing date of the application, to use the method of Jensen to assess for anti-CAR antibodies subsequent to the generation and administration of anti-CD19 CAR T cells, as disclosed in Valentine et al. Explicit motivation to do so is provided within the Jensen et al. prior art wherein it teaches: “the lack of T cell persistence observed in these two trials was due to immune rejection responses that are mounted by the patients’ endogenous T cells” (pg. 8, last sentence of first paragraph). Since each of the disclosed elements are merely performing the same function that they did in the separate references, a person having ordinary skill would have been able to combine the elements, according to known methods, in order to predictably detect anti-chimeric antigen receptor (CAR) antibodies against humanized CAR T cells.
Regarding claim 2, Jensen et al. teach collecting 1 ml of venous blood from at least one group of normal people (i.e. known non-reactive serum) and patients using a blood collection tube containing EDTA anticoagulant; conducting centrifugation of the venous blood to obtain plasma; and freezing the plasma at -80°C until use, without repeated freezing and thawing (See pg. 5, section titled Serologic Anti-CAR Immune Response Analysis).
Regarding claim 3, Jensen et al. teach serum collected at the time of patientenrollment (Pre-Trtmt) and at day 50 (UPN035) or day 42 (UPN037) after initiation of treatment was examined for immunoreactivity against Jurkat cells expressing the CD19R. Contact was made for 30 minutes at room temperature in the dark (pg. 5, second to last paragraph).
This does not teach contact with CAR-CHO cells, as recited by the instant claims because Jensen et al. use human T-lymphocytes (Jurkat cells) for their expression rather than expressing the chimeric antigen receptor in CHO cells. But CAR-CHO cells could have been utilized in the ex vivo antibody assays as disclosed by Jensen. Only the expression of the CD19 target antigen on the surface of the cell is required for antibody binding, the type of cell expression said antigen is irrelevant.
While the instant claims recite incubating at 4°C for 30 minutes, and the Jensen prior art teaches 30 minutes at room temperature, the courts have stated that, generally, such differences in temperature or any other parameter that may be changed through routine experimentation, amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421. See MPEP 2144.
Regarding claim 7, the methods for assessing antibodies against the CAR come from a subject who has been infused with CAR T cells; or a normal person who has not been treated with CAR T cells (“known non-responsive serum” of the reference. See Figure 5 and legend.
Regarding claim 8, the methods of Jensen et al. comprise a human protein corresponding to the target of the CAR comprises – specifically the protein CD19 protein expressed on Jurkat cells that are used in ex vivo studies to assess the binding of serum antibodies to CD19. See Figure 5.
Regarding claim 9, Jensen do not disclose “a number of 105 or more of CAR- expressing” cells are required for each of a standard, a blank control, the sample to be tested is collected. However, as with temperature, the Court has stated that such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. MPEP 2144 sets forth Applicant' s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount. In the instant case, the prior art does not even disclose the number of cells utilized in the assays, thus, there is no explicit teaching away. Additionally, the specification as filed provides no evidence that the particular amount is critical since, throughout, it merely states a number of 105 or more CAR-expressing cells is “an embodiment” and not critical.
For all these reasons, the invention of the instant claims is obvious in view of what was disclosed in the art before the effective filing date of the application.
Conclusion
No claim is allowed.
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/STACEY N MACFARLANE/Examiner, Art Unit 1675
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