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 .
Introductory Remark
Non-Final rejection dated 10/2/2025 is withdrawn and the instant non-final rejection is
being issued in its place. All paragraph numbers remain the same between the withdrawn and
instant non-final rejection.
New non-final rejection is to correct an inadvertent discrepancy due to inclusion of the concluding paragraph that identified the action as final. This paragraph is removed and the action is, as was, non-final.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/20/2025 has been entered.
Claim 52 is/are newly added. Claims 1, 7, 8, 11-14, 17-19, 24-26, 30, 31, 34-46, 48-52 is/are currently pending with claims 7, 8, 11-13, 19, 24-26, 30, 31, 34-41 is/are withdrawn. Claims 1, 14, 17, 18, 42-46, 48-52 is/are under examination.
Claim Suggestion
Claim 1 is amended to recite “a population of primary immune cells comprising a disrupted TCRa gene”. Although, it is clear that the cells within the population comprise the genetic disruption, yet to improve readability of this claim following language is recommended: “a population of primary immune cells comprising cells with a disrupted TCRa gene”.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 52 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 52 recites “wherein the TCRa gene is the TRAC gene”. However, TCRa and TRAC are synonyms for the same gene. See TRAC gene information on NCBI (in PTO-892) that shows that TRAC is also known as TCRA. Thus claim 52 fails to further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Interpretation
Claim 1 recites a limitation “wherein the population comprises no more than about 0.01% TCR+ cells.” in line 13. This limitation is interpreted as an intended result of the method comprising steps (a), (b) and (c). Regarding wherein/whereby clauses reciting intended results, MPEP 2111.04 guides "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). In the instant case, the method positively recites process steps and the limitation “wherein the population comprises no more than about 0.01% TCR+ cells.” is a result that flows from a method that comprises steps (a), (b) and (c).
The same interpretation is applied to the intended result limitation presented in new claim 50.
Claim Rejections - 35 USC § 102
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.
Rejection of Claim(s) 1, 18, 44-46, 48, 50-51 under 35 U.S.C. 102(a)(1) as being anticipated by Kamiya et al (Blood Advances, Volume 2, Issue 5, March 13, 2018; ref of record) is withdrawn because claim 1 is now amended to recite “primary immune cells comprising a disrupted TCRa gene” thus necessitating a new grounds of rejection.
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.
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.
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.
Rejection of claim 14, 17, 42-43, 49 under 35 U.S.C. 103 as being unpatentable over Kamiya et al (Blood Advances, Volume 2, Issue 5, March 13, 2018; ref of record) as applied to claim 1 above, and further in view of Poirot et al (Cancer Res; 75(18) September 15, 2015; ref of record) is withdrawn because this rejection depended on now withdrawn U.S.C. 102 rejection of claim 1.
Claim(s) 1, 14, 17, 18, 42-46, 48-52 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kamiya et al (Blood Advances, Volume 2, Issue 5, March 13, 2018; ref of record) and Poirot et al (Cancer Res; 75(18) September 15, 2015; ref of record) as evidenced by TRAC gene information on NCBI (August 2025; in PTO-892).
Regarding claim 1, Kamiya teaches an in vitro method of producing a population of primary immune cells depleted of immune cells expressing endogenous TCR (Abstract; Materials and Methods: Cell lines and T cells).
Kamiya’s method comprises labeling a population of primary immune cells that comprises cells with a reduced expression of TCRa the with anti-CD3 and anti-TCRab antibodies (= claimed step a, in part) and separating using LD columns to remove CD3/TCRab-positive T-cells (= claimed step b) (Materials and Methods: PEBL and CAR constructs). Finally, Kamiya collects the CD3/TCRab-negative T-cells (unlabeled) to use in their mouse model experiments (= claimed step c; Figure 6).
Regarding the intended results recited in claim 1 and claim 50, see Claim Interpretation section above. Kamiya’s method for depleting immune cells expressing endogenous TCR using the combination of CD3 and TCRab antibodies results in a population comprising less than 0.01% TCR+ cells on the day of the depletion and less than 1% TCR+ cells up to about 2 months after depletion (encompasses 10 days after depletion recited in claim 50; Figure 1B, S3). Kamiya states “Magnetic removal of residual CD3/TCRab-positive cells yielded virtually pure populations of CD3/TCRab-negative T cells (Figure 2B); in 11 T-cell preparations from 6 donors, T cells expressing normal levels of CD3/TCRab were 0.01% (<0.01% to 0.15%) after only 1 round of CD3/TCRab depletion” (page 520, left column, para 1). Therefore, the day of the depletion, Kamiya’s method achieved a population comprising a median of about 0.01% TCR+ cells. Long-term culture for up to 2 months resulted in persistent downregulation with even at 55 days in culture (significantly longer than the claimed 10 days in claim 50) less than 1% of the cells were TCR+ (page 520, para 2; Figure S3 in Supplementary Materials; in PTO-892). Therefore, Kamiya’s method achieves a population comprising less than 1% TCR+ cells at day 10.
Regarding claim 18, Kamiya teaches the primary immune cells were engineered to comprise anti-CD19 CAR (Materials and Methods: PEBL and CAR constructs).
Regarding claims 44 and 45, Kamiya teaches magnetic bead-conjugated anti-CD3 and anti-TCRab antibodies and separating using magnetic columns (Materials and Methods: PEBL and CAR constructs).
Regarding claim 46, the term “allogenic” is not a property of an immune cell but indicates a relation between the donor and receiver of a cell. In case of allogenic transplantation, the donor and receiver of a cell belong to the same species but are different subjects. Kamiya teaches deriving immune cells from a human subject. These cells are inherently allogenic when considered in relation to another subject. Of note, the purpose of Kamiya’s disclosure is to generate allogenic T-cells from healthy donors with reduced potential of GvHD (Introduction, para 2, 3, 5). Therefore, Kamiya teaches allogenic primary immune cells.
Regarding claims 48 and 51, Kamiya teaches deriving T-cells from peripheral blood of human donors as the primary immune cells (blood derived T-cells = PBMC as required for claim 51; Materials and Methods: Cell lines and T cells).
Regarding a population of immune cells comprising cells with a disrupted TCRa/TRAC gene as recited in claim 1(a) and claim 52, Kamiya does not teach cells with disrupted TCRa/TRAC gene. Of note, as noted in U.S.C 112d rejection of claim 52, TCRa and TRAC are synonyms (see TRAC gene information from NCBI as evidence).
Regarding claims 14, 17 and 49, Kamiya does not teach immune cells that are further genetically modified to reduce or eliminate the expression of endogenous CD52 (as recited in claim 14) using methods recited in claim 17 and thus further labeling the immune cell population with an anti-CD52 antibody (as recited in claim 49).
Regarding claims 42 and 43, Kamiya does not teach a biotin-based isolation method.
Poirot rectifies these deficiencies.
First, regarding a population of immune cells comprising cells with a disrupted TCRa/TRAC gene as recited in claim 1(a) and claim 52, Kamiya’s method comprises reducing endogenous TCRa expression by genetically modifying the primary immune cells by transducing the cells with MSCV retroviral construct expressing the CD3-targeting PEBL construct (PEBL = protein expression blocker, Abstract – lines 6-7; Materials and Methods: PEBL and CAR constructs). This reduces the expression of endogenous TCR (Figure 2; Results-para 1-line 1; also see section ‘CD3 downregulation with PEBLs suppresses TCRab expression’). Kamiya teaches that their method of reducing endogenous TCRa results in about 75% reduction because they show that about 25% of the cells in the population remain TCRa-positive 5 days after transduction (page 520, col. 1, para 1; Figure 2A).
However, other means to reduce TCRa expression were known in the art. For example, Kamiya references Poirot as teaching an alternate TALEN-based method (see reference to Poirot on page 516, col. 1, para 3).
Poirot teaches a TALEN-based method to disrupt TCRa/TRAC gene in T-cells (= cells recited in claim 1(a) and claim 52; Figure 1; Materials and Methods: Cells, TALENs). This method results in about 20.5% TCRab-positive cells 5 days after transduction (page 3854, col. 2, last para; Figure 1c-third panel)
The combination of prior art cited above under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S., 82 USPQ2d 1385 (2007): Exemplary rationales that may support a conclusion of obviousness are in MPEP 2143.
In the present situation, rationale B (Simple Substitution of One Known Element for Another To Obtain Predictable Results) is applicable. MPEP 2143 guides that for rationale B “Office personnel must articulate the following: (1) a finding that the prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components; (2) a finding that the substituted components and their functions were known in the art; (3) a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable; and (4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness”.
In the instant case, (1) The prior art of Kamiya teaches the base method which differs from the claimed method by the substitution of the following components: substituting Kamiya’s T-cells with a reduced TCRa expression produced by the PEBL construct with the cells claimed in claim 1(a) that have a disrupted TCRa/TRAC gene to achieve the same effect. (2) The substituted components were known in the art as taught by Poirot. (3) As established above, an ordinary artisan recognizes both Kamiya and Poirot teach T-cells with reduced expression of the TCRab, albeit using different methods. Furthermore, an ordinary artisan recognizes both methods for reducing TCRab expression result in a population of cells that is similarly TCRab+ (Kamiya’s method results in 25% TCRab+ while Poirot’s method results in 20.5% TCRab+). Thus, an ordinary artisan would substitute Kamiya’s method for reducing TCRab expression with Poirot’s method expecting to yield a predictable result of a population of T cells with similarly reduced TCRab expression due to TCRa/TRAC gene disruption.
Therefore, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR. Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute Kamiya’s T-cells with reduced TCRa expression produced by the PEBL construct with Poirot’s T-cells with reduced TCRa expression produced by TCRa/TRAC gene disruption in Kamiya’s method expecting to yield a predictable result of a method that further depletes TCR+ cells from the population of cells using CD3/TCR dual-antibody based depletion taught by Kamiya.
Second, regarding immune cells that are further genetically modified to reduce or eliminate the expression of endogenous CD52 (as recited in claim 14) using methods recited in claim 17 and thus further labeling the immune cell population with an anti-CD52 antibody (as recited in claim 49), Kamiya and Poirot teach the method of claim 1 (see analysis above).
In addition to teaching T-cells with disrupted TCR gene using a TALEN-based method, Poirot teaches genetically modified CAR-T cells engineered to reduce the expression of endogenous CD52 using transcription activator-like effector nuclease (TALEN; Materials and Methods: Cells, TALENs, CARs; required for claims 14 and 17). Furthermore, Poirot teaches labeling their genetically modified T-cells with anti-CD52 antibody to deplete any remaining CD52+ T-cells (Figure 1C, required for claim 49). Similar to Kamiya, Poirot’s genetically modified CAR-T cells also comprise reduced TCR expression and CD19 CAR (Abstract). Poirot teaches that further reducing expression of targets of chemotherapeutic agents such as CD52 (Alemtuzumab target) from TCR-reduced CD19 CAR-T cells allows for use of these cells for patients that were or need to be administered chemotherapeutic agents such as Alemtuzumab, a chemotherapeutic agent that also mediates lymphodepletion and promotes engraftment (Introduction, para 3).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to include a T-cell with disrupted TRAC gene that is further genetically modified to comprise reduced CD-52, as also taught by Poirot, in Kamiya’s method of depleting TCR+ cells from a population of immune cells using anti-CD3+TCR antibodies. Furthermore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the depletion methods of Kamiya and Poirot by including anti-CD52 antibody, as taught by Poirot, in Kamiya’s method to ensure a population of immune cells with minimal CD52 positive cells. An ordinary artisan would be motivated to include a TRAC and CD52 gene-disrupted T-cells, such as taught by Poirot, in Kamiya and Poirot’s depletion method to deplete any remaining TCR+ and CD52+ T-cells which would allow for use of these modified T-cells in the treatment of patients that were or need to be administered Alemtuzumab that targets CD52. An ordinary artisan would reasonably expect to deplete CD52 from TRAC and CD52 gene-disrupted T-cells because Poirot teaches a method to deplete CD52 from such T-cells.
Third, regarding a biotin-based isolation method to deplete TCR+ cells from the population of immune cells wherein the anti-CD3 and anti-TCR antibody are biotin conjugated as recited in claims 42 and 43, Kamiya teaches a magnetic-bead based isolation to remove CD3 and TCRab positive cells from their population of engineered CAR-T cells. However, Poirot teaches a biotin-based isolation, an equivalent method to Kamiya’s magnetic-bead based isolation method that is also used for separating cells from a population of cells. Poirot removes TCRa positive cells from their population of engineered CAR-T cells using a biotin conjugated antibody (as required for claim 42). The method further includes contacting labeled cells with anti-biotin magnetic microbeads (Supplemental methods: Magnetic enrichment; required for claim 43). Therefore, it would be obvious to an ordinary artisan to substitute Kamiya’s magnetic-bead based isolation method with an equivalent biotin-based isolation method, as taught by Poirot. Such a method would yield a predictable result wherein CD3 and TCRab positive cells are removed from the population of engineered CAR-T cells.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Response to Arguments
Applicant’s arguments with respect to the U.S.C. 102 rejection of claim(s) 1, 18, 44-46, 48, 50 and 51 have been considered but are moot because the new ground of rejection necessitated by claim amendment. The new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant’s arguments with respect to the U.S.C. 103 rejection of claim(s) 14, 17, 42-43, 49 have been considered but are moot because the new ground of rejection necessitated by claim amendment. Arguments pertinent to instant U.S.C. 103 rejection of claim(s) 14, 17, 42-43, 49 are addressed below.
Applicant allege that “The final preparations of Poirot comprise 20.5% - 25% of residual TCR-expressing cells (Poirot, Figures 1C and 5C)” and “Kamiya's preparations comprise 200-fold less, <0.01% to 0.15% of residual TCR-expressing cells (Kamiya, p. 320, bottom left)”. Finally, arguing that “Poirot provides no motivation to drop the retrovirus-based protein blocking step.” (page 9, para 3).
In response, the allegation regarding Poirot and Kamiya are a mischaracterization of their results. Poirot teaches that their TALEN-based method results in “20.5% - 25% of residual TCR-expressing cells” as noted by the Applicant. This should be compared with results from Kamiya’s PEBL-construct based method (i.e. “retrovirus-based protein blocking step” recited by the Applicant). Kamiya shows that their PEBL-construct based method results in “25.0% (range, 3.5% to 55.2%; Figure 2A)” TCR-expressing cells (page 520, col.1, para 1). Thus, as noted in the instant rejection, an ordinary artisan recognizes both methods for reducing TCRab expression result in a population of cells that is similarly TCRab+ and thus these methods could be substituted.
It must also be noted that Poirot used a single antibody-based depletion method (TCR antibody only) on their population of immune cells that comprised about 20.5% TCR+cells after the TALEN-based gene disruption. They achieved about 99.9% TCRab-negative cells i.e. about 0.1% TCRab-positive cells (Figure legend on page 3857). In comparison, Kamiya’s dual antibody-based depletion method (CD3+TCR antibody) achieved about “<0.01% to 0.15% of residual TCR-expressing cells (Kamiya, p. 320, bottom left)”, as noted by the Applicant. Thus, an ordinary artisan could recognize that although Kamiya’s and Poirot’s genetic methods for producing cells with reduced TCR expression (i.e. PEBL vs TALEN) resulted in similar results, Kamiya’s dual antibody based depletion method was better at reducing any remaining TCR+ cells as compared to Poirot’s single antibody based method.
Applicant point to MPEP 2144.01(II)(B) citing that “"the omission of an element and retention of its function is an indicium of nonobviousness," (emphasis in the original).” (page 9, para 3) and argue that “The applicant achieves better results than Kamiya while omitting the retrovirus-based protein blocking step practiced in Kamiya. (Compare Kamiya, supra:<0.01% to 0.15% TCR+ cells; instant application Figs. 2A, 2B, 3B, 9A, 9D: consistently <0.001% TCR* cells).” (page 9, last para).
In response, the instant claim does no omit use of immune cells with reduced TCR expression. The claim only recites an alternative to Kamiya’s PEBL-construct based method for reducing TCR expression in T cells. This alternative is taught by Poirot. Same as the instant specification (see Example 1), Poirot also uses a TALEN-based approach and achieves results similar to Kamiya. Thus, the applicability of the cited MPEP section in the instant case is not established.
Regarding the alleged superiority of results, these flow from the claimed active method steps. Regarding wherein/whereby clauses reciting intended results, MPEP 2111.04 guides "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). In the instant case, the combination of Kamiya and Poirot render obvious the positively recited method steps in the claimed method. Furthermore, Kamiya teaches their dual-antibody approach results in the intended results recited in claims 1 and 51.
Applicant point to MPEP 2145 for guidance pertaining to “teaching away” and allege that owing to teachings in Kamiya regarding “necessity of eliminating the TCR+ cells to prevent GvHD”, the results in Poirot which Applicant alleges “yields >20% of TCR+ cells” teach away from instantly claimed method that “yields <0.001% of TCR+ cells” (page 10, para 1).
In response, the allegation regarding Poirot results are mischaracterization of their results. Poirot teaches that their TALEN-based method results in 20.5% TCRab+ cells (Figure 1C). However, neither the claimed method, nor the prior art of either Kamiya or Poirot are limited to only reducing the expression of TCR in T-cells. The claimed method and the prior arts further include the antibody based depletion steps. Thus, Poirot’s teachings regarding efficacy of their TALEN-based method do not teach away from a method that further includes antibody-based depletion steps.
Furthermore, Poirot’s TALEN-based method is similarly efficacious as Kamiya’s PEBL-construct based method (i.e. “retrovirus-based protein blocking step” recited by the Applicant).
Conclusion
No claim is allowed.
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/MATASHA DHAR/Examiner, Art Unit 1632