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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 4, 2026 has been entered.
Detailed Action
This action is in response to the papers filed March 4, 2026.
Amendments
Applicant's amendments, filed March 4, 2026, is acknowledged. Applicant has cancelled Claims 1-2, 4-24, 28-46, 50, 55-59, and 66-68, and amended Claims 3 and 60, withdrawn Claims 25-27, 47-49, 51-54, 61-63, and 65, and added new Claim 69.
Claims 3, 25-27, 47-49, 51-54, 60-65, and 69 are pending.
Election/Restrictions
Applicant has elected without traverse the invention of Group I, Claims 3 and 60-64, drawn to an iNKT cell, which comprises at least one chimeric antigen receptor (CAR) targeting one or more antigens, and which is deficient in an antigen to which the CAR specifically binds, wherein:
the chimeric antigen receptor specifically binds BCMA, and the iNKT cells are deficient in BCMA;
the chimeric antigen receptor specifically binds CD2, and the iNKT cells are deficient in CD2;
the chimeric antigen receptor specifically binds CD3epsilon, and the iNKT cells are deficient in CD3epsilon;
the chimeric antigen receptor specifically binds CD4, and the iNKT cells are deficient in CD4;
the chimeric antigen receptor specifically binds CD5, and the iNKT cells are deficient in CD5;
the chimeric antigen receptor specifically binds CD7, and the iNKT cells are deficient in CD7;
the chimeric antigen receptor specifically binds TCRalpha (syn. TRAC), and the iNKT cells are deficient in TCRalpha (syn. TRAC); or
the chimeric antigen receptor specifically binds TCRbeta (syn. TRBC), and the iNKT cells are deficient in TCRbeta (syn. TRBC); and
a method of using said iNKT-CAR cell to treat a hematologic malignancy in a patient, the method comprising the step of administering a tandem iNKT-CAR cell to a patient in need thereof, classified in CPC A61K 39/00.
Within Group I, Applicant has elected without traverse the following species, wherein:
i) the alternative Group I first antigen bound by the chimeric antigen receptor and corresponding endogenous gene that is to be rendered deficient is BCMA; and
ii) the alternative hematologic malignancy to be treated is multiple myeloma, as recited in Claim 64.
Claims 3, 25-27, 47-49, 51-54, 60-65, and 69 are pending.
Newly submitted Claims 60 and 69 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: amended Claim 60 and new Claim 69 recite product-by-process steps that belong to non-elected Group III method of making.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, Claims 60, 64, and 69 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
The general policy of the Office is that applicants are not permitted to shift to claim another invention after an election is made and an Office action on the merits is made on the elected invention. See MPEP §819.
The applicant cannot, as a matter of right, file a request for continued examination (RCE) on claims that are independent and distinct from the claims previously claimed and examined (i.e., applicant cannot switch inventions by way of an RCE as a matter of right). See MPEP § 706.07(h), subsection VI.(B).
Claims 25-27, 47-49, 51-54, 60-65, and 69 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claim 3 is under consideration.
Priority
This application is a continuation of application 16/428,789 filed on May 31, 2019, now abandoned. Applicant’s claim for the benefit of a prior-filed application provisional application 62/678,883 filed on May 31, 2018 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Applicant has amended Claim 3, support for which may be found in 62/678,883 filed on May 31, 2018.
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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
1. Claim 3 is rejected under AIA 35 U.S.C. 103 as being unpatentable over Rezvani et al (WO 18/195339; filed April 19, 2018; of record in IDS) in view of MacKenzie et al (1991; of record), Thierry et al (2012; of record), Kuylenstierna (2010; excerpted, 4 pages only; of record), Mamonkin et al (U.S. 2018/0104308; published April 19, 2018, effectively filed April 23, 2015; of record in IDS), Gomes-Silva et al (available online May 24, 2017; previously cited in Applicant’s parent application 16/428,789), and Fleischer et al (December 8, 2017; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Instant specification discloses [0213] activation is synonymous with stimulating the cells to induce proliferation.
With respect to Claim 3, Rezvani et al is considered relevant prior art for having disclosed T, NK, NKT, or iNKT cells expressing at least one chimeric antigen receptor (e.g. Abstract; [0007, 31]) that binds one or more tumor-associated antigens (e.g. [0012]), e.g. BCMA and CD5, or BCMA and CD7 (e.g. [0030]).
Rezvani et al disclosed wherein the genetically modified cells are expanded (syn. activated) (e.g. [00125], “numerically expand CAR+ immune cells”; [00140], “expanded ex vivo”; [00267]).
MacKenzie et al is considered relevant prior art for having taught that those of ordinary skill in the art had long-recognized multiple myeloma cells naturally express CD5.
Thierry et al is considered relevant prior art for having taught that those of ordinary skill in the art had long-recognized iNKT cells naturally express CD5 (e.g. Figure 1, legend, “CD5bright cells in iNKT cells”; pg 277, col. 2; pg 278, col. 1, “iNKT cells exhibit…CD5bright”).
Kuylenstierna is considered relevant prior art for having taught that those of ordinary skill in the art had long-recognized iNKT cells naturally express CD7 (Table 2).
While Rezvani et al disclosed wherein the CAR-expressing immune cell may be further modified to disrupt, alter, or eliminate one or more gene products encoded by the host cell genome (e.g. [0058]), Rezvani et al do not disclose said CAR iNKT cell to be further modified to disrupt, alter, or eliminate at least one endogenous locus encoding the antigen to which the CAR binds.
However, prior to the effective filing date of the instantly claimed invention, Mamonkin et al is considered relevant prior art for having disclosed CD5-CAR T cell or NKT cells (e.g. [0009, 69], wherein said CD5-CAR cells may further express a BCMA-CAR (e.g. [0067]) for the treatment of a CD5-expressing hematological malignancy, including CD5+ B cell malignancies (e.g. [0008, 84]). Mamonkin et al disclosed that the CD5-CAR T cells demonstrated self-killing fratricide, and only acquired fratricide resistance by down-regulating expression of the endogenous CD5 gene (e.g. [0049]).
Mamonkin et al disclosed wherein the genetically modified immune cells are expanded (syn. activated) in culture (e.g. [0100]).
Gomes-Silva et al is considered relevant prior art for having taught that CD7 is naturally expressed by T and NK cells (e.g. pg 285, col. 2), and produced CD7-CAR T cells whose genome is further modified to disrupt the endogenous CD7 locus, thereby minimizing CD7-CAR T cell fratricide, which prevented CD7-CAR T cell expansion (e.g. Figure 1, legend, “T cells expressing CD7 CARs fail to expand”; pg 287, col. 2, Results, “Expression of CD7 CAR precludes T-cell expansion”), and allowing expansion of the CD7-CAR T cells (e.g. pg 288, col. 1, “Genetic disruption of the CD7 gene enables expansion of CD7 CAR T cells”), yet retain robust antitumor activity in vitro and in vivo (e.g. pg 286, col. 1; pg 291, col. 1, “Genetic disruption of CD7 does not impair cytotoxicity of CAR T cells”; col. 2, “CD7KO CD7 CAR T cells eradicate malignant T-cell lines in vitro”; pg 293, col. 1, “CD7KO CD7 CAR T cells are protective in mouse xenograft models of T-ALL”; Figure 7D).
Gomes-Silva et al taught wherein the genetically modified immune cells were expanded (syn. activated) in vitro (e.g. Figure 2, legend, “Total expansion”; pg 288, col. 1, section title, “enables expansion”).
Fleischer et al is considered relevant prior art for having taught, like Gomes-Silva et al, CD5-CAR T cells whose genome is further modified to disrupt the endogenous CD5 locus, thereby minimizing CD5-CAR T cell fratricide, which impaired CD5-CAR T cell expansion, whereby the CD5-CAR, CD5 KO T cells have a substantial reduction in self-activation, achieve greater CD5-CAR expression in the CD5-edited cells than non-edited cells, and achieve a greater degree of activation in the presence of CD5+ target cells than the non-modified CD5-CAR T cells, and thus should lead to more potent and durable therapeutic effects.
Fleisher et al taught wherein the genetically modified CD5-CAR, CD5 knockout T cells are activated in the presence of CD5-positive target cells.
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, immunology, chimeric antigen receptors, and gene editing technologies. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify an iNKT cell expressing at least one chimeric antigen receptor that binds one or more tumor-associated antigens, e.g. BCMA and CD5, or BCMA and CD7, to further comprise a genetic modification to disrupt, disrupt, alter, or eliminate expression of the endogenous CD5 or CD7 gene, as taught/disclosed by Gomes-Silva et al and Fleischer et al, with a reasonable expectation of success because:
i) Rezvani et al disclosed wherein the CAR-expressing immune cell may be further modified to disrupt, alter, or eliminate one or more gene products encoded by the host cell genome;
ii) Mamonkin et al disclosed that the CD5-CAR T cells demonstrated self-killing fratricide, and only acquired fratricide resistance by down-regulating expression of the endogenous CD5; and
iii) both Gomes-Silva et al and Fleischer et al successfully demonstrated the ability to edit the host cell’s genome to disrupt, disrupt, alter, or eliminate expression of the endogenous CD5 gene in CD5-CAR expressing immune cells (Fleischer et al) or the endogenous CD7 gene in CD7-CAR expressing immune cells (Gomes-Silva et al),
being motivated to do so because Gomes-Silva et al and Fleischer et al taught that by performing such gene edits, such reduces CAR cell fratricide, allowing expansion in culture, achieving substantial reduction in self-activation, achieves greater CAR expression than non-edited cells, a greater degree of activation in the presence of CAR antigen-target cells, retain robust antitumor activity in vitro and in vivo, and thus should lead to more potent and durable therapeutic effects.
Those of ordinary skill in the art have long-recognized the successful reduction to practice of activating the artisan’s immune cells in culture, thereby expanding the desired population (Rezvani et al, Mamonkin et al, Gomes-Silva et al, Fleischer et al).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that the cited prior art do not teach or suggest activated iNKT cells.
Applicant’s argument(s) has been fully considered, but is not persuasive.
Instant specification discloses [0213] activation is synonymous with stimulating the cells to induce proliferation.
Rezvani et al disclosed wherein the genetically modified cells are expanded (syn. activated) (e.g. [00125], “numerically expand CAR+ immune cells”; [00140], “expanded ex vivo”; [00267]).
Mamonkin et al disclosed wherein the genetically modified immune cells are expanded (syn. activated) in culture (e.g. [0100]).
Gomes-Silva et al taught wherein the genetically modified immune cells were expanded (syn. activated) in vitro (e.g. Figure 2, legend, “Total expansion”; pg 288, col. 1, section title, “enables expansion”).
Fleisher et al taught wherein the genetically modified CD5-CAR, CD5 knockout T cells are activated in the presence of CD5-positive target cells.
Those of ordinary skill in the art have long-recognized the successful reduction to practice of activating the artisan’s immune cells in culture, thereby expanding the desired population (Rezvani et al, Mamonkin et al, Gomes-Silva et al, Fleischer et al).
Conclusion
2. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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