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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 18May2026 has been entered.
Claims Status
Claim(s) 3-22 is/are currently pending and presented for examination on the merits.
Response to Amendment and Arguments
The rejection(s) of claim(s) 7,8,13 under 35 U.S.C. § 112(a) have been withdrawn in view of the recent claim amendment filed on 18May2026.
All other previously presented rejection(s) are maintained in modified form, as necessitated by the recent claim amendment filed on 18May2026, for reasons given in the "Response to Arguments" below. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Rejections Maintained/Modified as Necessitated by Claim Amendments
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.
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.
Claim(s) 3-13 and 20-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Savoldo et al. (Blood, 01October2007, Vol. 110, No. 7; hereinafter “Dotti”), in view of WO 2015/028444 A1 (hereinafter “WO444”).
Regarding claims 3-13 and 20-22, Dotti teaches a method of treating cancer comprising administering EBV-specific cytotoxic T lymphocytes (EBV-CTLs), comprising a CD30-directed (HRS3 scFv) CAR for the treatment of cancer [e.g., abstract; introduction; patients, materials, and methods]. Dotti teaches EBV-CTLs expressing the CD30 directed CAR kill CD30+ allogeneic tumor cells (e.g., likewise, the CD30 directed CAR EBV-CTLs are considered allogeneic to the tumor cells) [e.g., fig. 3]. Dotti further teaches this approach results in effective and sustained immune responses (e.g., effective dose was administered), CARs that are better able to persist and kill tumor targets, and that a number of preclinical studies support the benefits [e.g., pg. 9, column 2, para 2]. Dotti concludes that adoptive cell therapy (ACT) of EBV-CTLs grafted with a CD30-directed CAR may enhance immunotherapy of EBV+ subjects, and suggests anti-cancer effect against CD30+ tumors should be benefited by local and systemic stimulation of the naive receptor by the EBV-infected B cells, without harm to the function of the immune system as a whole [e.g., pg. 10].
Dotti does not expressly teach administration of the allogenic CAR, wherein the comprises (1) a hinge domain, (2) a transmembrane (tm) domain, (3) a CD28 intracellular domain (ICD), (4) a CD3z (comprises ITAMs) intracellular signaling domain, or (5) the sequences of the antigen binding domain (scFv), hinge, tm, CD28, or CD3z domains.
WO444 teaches anti-CD30 CARs and their uses including ACT for treating CD30+ cancer cells in a subject in need thereof [e.g., title and abstract]. WO444 further teaches disclosed CD30-directed CARs are toxic to CD30+ cancer cells and non-toxic to CD30+ noncancerous cells [e.g., abstract]. WO444 teaches the preferred embodiment of anti-HRS3 (CD30) CAR T cell is SEQ ID NO: 3, which has a 98.2% sequence identity match to instant claimed SEQ ID NO: 36 (see alignment below for details), comprising a signal peptide, HRS3 scFv (CD30 antigen binding domain), hinge domains, a CD28 tm, a CD28 ICD, and a CD3z (comprising ITAMs) signaling domain (within instant claimed range(s) of variability) [e.g., figs. 1-3, 5-6; pg. 11, lines 15-34]. It is noted for the record that instant CAR SEQ ID NOs: 35 and 36 differ by a signal peptide sequence, therefore the alignment of instant SEQ ID NO: 36 below is considered to also apply for instant SEQ ID NO: 35.
Alignment of instant claimed CAR (SEQ ID NO: 36) with WO444 (CAR #1138 polypeptide, SEQ: 3):
Sequence Key (instant SEQ ID NO);
Signal peptide (34); HRS3 scFv (14-15,18);hinge region (33); CD28 tm (20); CD28 ICD(26); CD3z (25)
Query Match 98.2%; Score 3623; Length 690;
Best Local Similarity 98.7%;
Matches 681; Conservative 2; Mismatches 5; Indels 2; Gaps 2;
Qy 1 MDFQVQIFSFLLISASVIMSRMAQVQLQQSGAELARPGASVKMSCKASGYTFTTYTIHWV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MDFQVQIFSFLLISASVIMSRMAQVQLQQSGAELARPGASVKMSCKASGYTFTTYTIHWV 60
Qy 61 RRRPGHDLEWIGYINPSSGCSDYNQNFKGKTTLTADKSSNTAYMQLNSLTSEDSAVYYCA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RRRPGHDLEWIGYINPSSGCSDYNQNFKGKTTLTADKSSNTAYMQLNSLTSEDSAVYYCA 120
Qy 121 RRADYGNYEYTWFAYWGQGTTVTVSSSGGGSGGGGSGGGGSVIELTQSPKFMSTSVGDRV 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 RRADYGNYEYTWFAYWGQGTTVTVSSSGGGSGGGGSGGGGSVIELTQSPKFMSTSVGDRV 180
Qy 181 NVTYKASQNVGTNVAWFQQKPGQSPKVLIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQ 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 NVTYKASQNVGTNVAWFQQKPGQSPKVLIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQ 240
Qy 241 SEDLAEYFCQQYHTYPLTFGGGTKLEIKRSDPAEPKSPDKTHTCPPCPAPELLGGPSVFL 300
|||||||||||||||||||||||||||||||||||||||||||||||||| : ||||||
Db 241 SEDLAEYFCQQYHTYPLTFGGGTKLEIKRSDPAEPKSPDKTHTCPPCPAPP-VAGPSVFL 299
Qy 301 FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 360
|||||||||||:||||||||||||||||||||||||||||||||||||||||||||||||
Db 300 FPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 359
Qy 361 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 360 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ 419
Qy 421 VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 420 VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 479
Qy 481 FSCSVMHEALHNHYTQKSLSLSPGKKDPKFWVLVVVGGVLACYSLLVTVAFIIFWVRSKR 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 480 FSCSVMHEALHNHYTQKSLSLSPGKKDPKFWVLVVVGGVLACYSLLVTVAFIIFWVRSKR 539
Qy 541 SRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS-RVKFSRSADAPAYQQGQNQLYN 599
|||||||||||||||||||||||| || |||||||| ||||||||||||||||||||||
Db 540 SRLLHSDYMNMTPRRPGPTRKHYQAYAAARDFAAYRSLRVKFSRSADAPAYQQGQNQLYN 599
Qy 600 ELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRR 659
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 600 ELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRR 659
Qy 660 GKGHDGLYQGLSTATKDTYDALHMQALPPR 689
||||||||||||||||||||||||||||||
Db 660 GKGHDGLYQGLSTATKDTYDALHMQALPPR 689
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the autologous CD30 directed CAR in the method of treating cancer comprising administration of an autologous CD30 directed (HRS3) CAR EBV-CTL as taught by Dotti, with allogeneic CAR T cells as taught by Dotti, and the CD30-directed CAR sequence taught by WO444, to arrive at a method of treating cancer comprising administration of an allogeneic CD30 directed (HRS3) CAR EBV-CTL. A PHOSITA would have been motivated to substitute the autologous anti-CD30 CAR of Dotti with the allogeneic cells of Dotti as well as the anti-CD30 CAR construct as taught by WO444, because Dotti teaches allogeneic tumor killing (e.g., CAR cells from one subject were able to kill cancer from another subject) which an PHOSITA would understand to be a beneficial (e.g., can use one manufactured drug product to treat more than one subject); both Dotti and WO444 teach same and/or overlapping field of CD30 directed CAR T cell therapy to treat cancer(s); and while Dotti teaches a CD30 directed (HRS3) CAR EBV-CTL, it does not expressly disclose the full and specific anti-CD30 CAR domain(s) or the CAR construct sequence(s). WO444 fills this gap by teaching a CD30 directed CAR comprising an HRS3 scFv, a hinge, a tm, a CD28 ICD, and a CD3z domain, as well as the sequences thereof in a method substantially similar and capable of substitution to that of Dotti. There would have been a reasonable expectation of success for a PHOSITA to substitute the allogeneic cell source of Dotti and the anti-CD30 CAR construct of WO444 in place of the autologous source CD30 directed CAR taught by Dotti, because Dotti teaches the general CD30 directed CAR and its efficacy in against allogeneic tumors, and WO444 teaches the specific structure/sequences (with the same HRS3 scFv) of a CD30 directed CAR, which is a predictable use of prior art elements according to their established functions, leading to the predictable result of an allogeneic anti-CD30 CAR. This rationale aligns with the principle of a simple substitution of one known element for another to obtain predictable results (see MPEP 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues:
Dotti teaches away from additional costimulatory endodomains: Dotti expressly recognizes the "primary strategy" of adding costimulatory endodomains to CARs, details its inherent limitations (inability to "precisely mimic the physiologic sequence of costimulatory events," see page 2628, first full paragraph in right column), and deliberately adopts a different, "second strategy" using EBV-CTLs to receive physiologic costimulation from APCs via native TCR engagement. This reasoning directly contradicts the Examiner's proposed modification: grafting WO444's costimulatory endodomains into Dotti's EBV-CTLs.
In response, briefly, Dotti’s teachings in context are:
“…In a range of studies, both in vitro and in vivo, the addition of such endodomains improves CAR T-cell function, increasing proliferation, cytokine secretion, and cytotoxic effector activity. While promising, this approach has the limitation that it can never precisely mimic the physiologic sequence of costimulatory events that follow engagement of the native antigen receptor… Moreover, recruitment of each class of effector cells (for example, CD4 helper versus CD8 cytotoxic) has a preferential requirement for a different costimulatory receptor-ligand interaction. Because of these inherent limitations to chimeric receptor manipulation, a second strategy for improving efficacy has been investigated. Instead of expressing the CAR in an undefined population of primary T cells, it is possible to transduce cultured cytotoxic T-lymphocyte lines with specificity for antigens known to be expressed in vivo on professional APCs…By using redirected EBV-CTLs, costimulation will be provided locally by EBC-infected HRS cells in EBV+ HD tumors and systemically by the EBV-infected memory B cells that persist lifelong in lymphoid tissues” [e.g., pg. 2528, ¶ 2-3].
In summary, Dotti is considered to teach (1) that the traditional CAR approach is promising, and the recitations of limitations thereof is not considered teaching away (e.g., Dotti specifically says they are promising), and (2) that the solution to the limitations recited is CAR transduction into CTLs rather than just bulk T cells, because the CTLs receive additional costimulatory signaling from APCs through this method and therefore persist (e.g., good for therapeutic CARs). Remarks regarding “surprising effects” are addressed below. For the reasons provided above, the applicant’s argument(s) is/are not considered persuasive.
Unexpected Results: amended claims require allogeneic administration, which is supported by unexpected results and not taught in Dotti or WO444; (1) elimination of allogeneic T cells and resistance to allo-rejection; (2) absence of fratricide, (3) absence of CRS, and (4) clinical antitumor response in human patients.
In response, Dotti teaches the CD30 direct CAR EBV-CTLs are effective at killing allogeneic tumors (e.g., the CD30 directed CAR EBV-CTLs would by definition be allogeneic to the tumors killed; see rejection above for details), and one of ordinary skill in the art at the time of filing would have understood the potential benefits of allogeneic CAR T cell administration (e.g., a single manufactured CAR T cell drug product could treat more than one single patient). Specifically regarding (1-4) the claims are not commensurate with the scope of the unexpected data as the claims of the instant invention are drawn to a method of treating cancer comprising administering allogeneic CD30 directed CAR EBV T cells, and specifically do not have any (1) alloreactive T cell elimination and resistance to allorejection, (2) CRS-related, (3) fratricide, and/or (4) clinical antitumor response in human patient limitations. Therefore these properties are not considered part of the instant invention and subsequently have not been examined on the merits. In addition, points (1-4) would be considered to flow naturally from the method of treating comprising cancer comprising administration of CD30 direct CAR EBV-CTLs, and Applicant is advised to consult MPEP 2112(I) which provides "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer…", and MPEP 2112(II) which provides: “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003)…”. Therefore, the provided results are not considered unexpected results and the method is considered obvious over Dotti and WO444.
In summary, Applicant arguments regarding claims 3-13 and 20-22 have been thoroughly reviewed but are not persuasive. The rejection(s) of claim(s) 3-13 and 20-22 are maintained in modified form, as necessitated by claim amendment(s).
Claim(s) 14-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Savoldo et al. (Blood, 01October2007, Vol. 110, No. 7; hereinafter “Dotti”) in view of WO 2015/028444 A1 (hereinafter “WO444”).as applied to claim 3 above, and further in view of Chang et al. (Blood (2018) 132, Supplement 1: 225; hereinafter “Chang”).
The teachings of Dotti and WO444 apply as recited above for claim 3.
Dotti and WO444 do not expressly teach a dual CAR comprising a CD30 directed CAR and a CD19 directed CAR.
Regarding claims 14-19, Chang teaches a Phase I/II trial of multi-target CAR T cells against relapse or refractory (r/r) lymphomas [e.g., title, background]. Chang teaches CD19 CAR T cells have demonstrated improved partial or complete remission response even in very late-stage r/r B cell lymphoma patients (pts), but that many pts experienced relapse or became CD19 CAR T resistant [e.g., background]. Chang teaches that to improve long term efficacy, they developed a new strategy to evaluate the efficiency of multi-target CARs against lymphomas [e.g., background]. Chang further teaches a dual target CAR T cell comprising CD19 and CD30 CARs, and further that overall results demonstrate safety and improved response rates (relative to single CAR T therapy) [e.g., results, conclusions].
Further, it would have been obvious to a PHOSITA to modify the modified methods of treating cancer comprising administration of an allogeneic CD30 directed CAR EBV-CTL as taught by Dotti and WO444 (see above) to include a second CAR construct comprising an anti-CD19 CAR, because Chang teaches a CD19 and CD30 dual CAR T cell as an effective therapy for treating lymphomas that results in improved response rates. There is an expectation of success for a PHOSITA to administer a dual CD19 and CD30 EBV-CTL cell because Dotti and WO444 teach the CD30 CAR EBV-CTL and anti-tumor benefits thereof, and Chang teaches a dual CD19 and CD30 CAR T cell as an effective therapy for treating lymphomas that results in improved response rates. This rationale aligns with the principle of a simple substitution of one known element for another to obtain predictable results (see MPEP 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues Chang does not cure the deficiency of Dotti and WO444 as applied to claim 3 at least because Chang doesn’t teach allogeneic CAR T cells, administration thereof, or any of the ‘unexpected results’ as recited above.
In response, Dotti was relied upon to teach the allogeneic cells are effective in treating cancer, whereas Chang was relied upon to teach a dual CAR T cell comprising CD19 and CD30 CARs (see rejection for details). Regarding the applicant perceived deficiency of Dotti and WO444 for the rejection of claim 3, the responses above are applied here (see response to arguments above for details).
Applicant arguments have been thoroughly reviewed but are not persuasive. The rejection(s) of claim(s) 14-19 are maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim(s) 3-13 and 20-22 is/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 7, 9, 11, 18, 20, 22, 24, 26, 28, 30, 38, and 40 of copending Application No. 17/997,154 (hereinafter “A154”) in view of Savoldo et al. (Blood, 01October2007, Vol. 110, No. 7; hereinafter “Dotti”).
This is a provisional nonstatutory double patenting rejection.
Regarding instant claims 3-13, and 20-22, A154 teaches an Epstein-Barr virus (EBV) specific T cell comprising a CAR (SEQ ID NO: 35 or 36)or nucleic acid encoding a CAR, wherein the CAR comprises: (i) an anti-CD30 antigen binding domain (SEQ ID NOs: 14-15, 18); (ii) a hinge domain (SEQ ID NO: 33); (iii) a CD28 transmembrane domain (SEQ ID NO: 20); (iv) a CD28 intracellular domain (ICD) (SEQ ID NO: 26); and (v) a CD3z (containing ITAMs) domain (SEQ ID NO: 25) [e.g., claims 1, 3, 5, 7, 9, 11, 18, 20, 22, 24, 26, 28, 30, 38, 40]. It is noted for the record that instant CAR SEQ ID NOs: 35 and 36 differ by a signal peptide sequence, therefore the alignment of instant SEQ ID NO: 36 below is considered to also apply for instant SEQ ID NO: 35.
Alignment of anti-CD30 CAR instant SEQ ID NO: 36 with A154 anti-CD30 CAR SEQ ID NO: 36:
CLUSTAL O(1.2.4) multiple sequence alignment
Signal peptide (34); HRS3 scFv (14-15, 18); hinge region (33), CD28 tm (20); CD28 ICD (26); CD3z (25)
161_SeqID36 MDFQVQIFSFLLISASVIMSRMAQVQLQQSGAELARPGASVKMSCKASGYTFTTYTIHWV 60
A154_SeqID36 MDFQVQIFSFLLISASVIMSRMAQVQLQQSGAELARPGASVKMSCKASGYTFTTYTIHWV 60
************************************************************
161_SeqID36 RRRPGHDLEWIGYINPSSGCSDYNQNFKGKTTLTADKSSNTAYMQLNSLTSEDSAVYYCA 120
A154_SeqID36 RRRPGHDLEWIGYINPSSGCSDYNQNFKGKTTLTADKSSNTAYMQLNSLTSEDSAVYYCA 120
************************************************************
161_SeqID36 RRADYGNYEYTWFAYWGQGTTVTVSSSGGGSGGGGSGGGGSVIELTQSPKFMSTSVGDRV 180
A154_SeqID36 RRADYGNYEYTWFAYWGQGTTVTVSSSGGGSGGGGSGGGGSVIELTQSPKFMSTSVGDRV 180
************************************************************
161_SeqID36 NVTYKASQNVGTNVAWFQQKPGQSPKVLIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQ 240
A154_SeqID36 NVTYKASQNVGTNVAWFQQKPGQSPKVLIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQ 240
************************************************************
161_SeqID36 SEDLAEYFCQQYHTYPLTFGGGTKLEIKRSDPAEPKSPDKTHTCPPCPAPELLGGPSVFL 300
A154_SeqID36 SEDLAEYFCQQYHTYPLTFGGGTKLEIKRSDPAEPKSPDKTHTCPPCPAPELLGGPSVFL 300
************************************************************
161_SeqID36 FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 360
A154_SeqID36 FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 360
************************************************************
161_SeqID36 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ 420
A154_SeqID36 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ 420
************************************************************
161_SeqID36 VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 480
A154_SeqID36 VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 480
************************************************************
161_SeqID36 FSCSVMHEALHNHYTQKSLSLSPGKKDPKFWVLVVVGGVLACYSLLVTVAFIIFWVRSKR 540
A154_SeqID36 FSCSVMHEALHNHYTQKSLSLSPGKKDPKFWVLVVVGGVLACYSLLVTVAFIIFWVRSKR 540
************************************************************
161_SeqID36 SRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNE 600
A154_SeqID36 SRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNE 600
************************************************************
161_SeqID36 LNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRG 660
A154_SeqID36 LNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRG 660
************************************************************
161_SeqID36 KGHDGLYQGLSTATKDTYDALHMQALPPR 689
A154_SeqID36 KGHDGLYQGLSTATKDTYDALHMQALPPR 689
*****************************
A154 does not expressly teach (1) the administration of the CD30 CAR EBV T cell to treat cancer, wherein the cells are allogeneic, or (2) that the cancer is CD30+.
Dotti teaches a method of treating cancer comprising administering EBV-specific cytotoxic T lymphocytes (EBV-CTLs), comprising a CD30-directed (HRS3 scFv) CAR for the treatment of cancer [e.g., abstract; introduction; patients, materials, and methods]. Dotti teaches EBV-CTLs expressing the CD30 CAR kill allogeneic CD30+ tumor cells [e.g., fig. 3]. Dotti further teaches this approach results in effective and sustained immune responses (e.g., effective dose was administered), CARs that are better able to persist and kill tumor targets, and that a number of preclinical studies support the benefits [e.g., pg. 9, column 2, para 2]. Dotti concludes that adoptive cell therapy (ACT) of EBV-CTLs grafted with a CD30-directed CAR may enhance immunotherapy of EBV+ subjects, and suggests anti-cancer effect against CD30+ tumors should be benefited by local and systemic stimulation of the naive receptor by the EBV-infected B cells, without harm to the function of the immune system as a whole [e.g., pg. 10].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to try the CD30 CAR EBV T cell of A154 with the CD30 CAR methods for treating CD30+ cancers, and against allogeneic tumors (e.g., the CARs are therefore allogeneic to the tumor as well) as taught by Dotti, to arrive at the instant invention. A PHOSITA would have been motivated to try CD30 CAR EBV T cell as taught by A154 to treat CD30+ cancers because the CD30 EBV T cell of A154 binds CD30 antigen and Dotti teaches a similar CD30 CAR EBV CTL as an effective anti-CD30+ autologous and allogeneic cancer therapeutic. There would have been a reasonable expectation of success for a PHOSITA to try CD30 CAR EBV T cell as taught by A154 to treat CD30+ cancers using the methods taught by Dotti, because Dotti teaches a similar CD30 CAR EBV CTL as an effective anti-CD30+ autologous and allogeneic cancer therapeutic, and additionally teaches CD30 as a tumor target is beneficial because CD30 directed CARs kill tumors without harm to the function of the immune system as a whole. This rationale aligns with the “obvious to try” principle of choosing from identified, predictable solutions, with a reasonable expectation of success (see MPEP 2143(I)(E)).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant indicated that “if at the time allowable claims are agreed upon the double patenting rejection is proper, a terminal disclaimer may be submitted”.
In response, the double patenting rejection(s) have been maintained.
Claim(s) 14-19 is/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 7, 9, 11-12, 14, 18, 20, 22, 24, 26, 28, 30-31, 33-34, 38, and 40 of copending Application No. 17/997,154 (hereinafter “A154”) and Savoldo et al. (Blood, 01October2007, Vol. 110, No. 7; hereinafter “Dotti”) as applied to claim 3 above, and further in view of Chang et al. (Blood (2018) 132, Supplement 1: 225; hereinafter “Chang”).
This is a provisional nonstatutory double patenting rejection.
The teachings of A154 and Dotti as recited above apply for claim 3.
Regarding instant claims 14-19, A154 further teaches an EBV T cell comprising the anti-CD30 CAR construct described above and further comprising a second CAR construct that binds CD19 [e.g., claims 12, 14, 31, 33-34].
Modified claims of A154 with Dotti do not expressly teach the rationale for selecting CD19 as the second CAR construct, or the administration of the dual CD30/CD19 CAR to treat cancer.
Chang teaches a Phase I/II trial of multi-target CAR T cells against relapse or refractory (r/r) lymphomas [e.g., title, background]. Chang teaches CD19 CAR T cells have demonstrated improved partial or complete remission response even in very late-stage r/r B cell lymphoma patients (pts), but that many pts experienced relapse or became CD19 CAR T resistant [e.g., background]. Chang teaches that to improve long term efficacy, they developed a new strategy to evaluate the efficiency of multi-target CARs against lymphomas [e.g., background]. Chang further teaches a dual target CAR T cell comprising CD19 and CD30 CARs, and further that overall results demonstrate safety and improved response rates (relative to single CAR T therapy) [e.g., results, conclusions].
Further, it would have been obvious to a PHOSITA to modify the modified methods of anti-CD30 CAR administration to treat cancer as taught by A154 and Dotti (see above) to include a second CAR construct comprising an anti-CD19 CAR (as taught by A154, Dotti, and Chang), because Chang teaches a CD19 and CD30 dual CAR T cell as an effective therapy for treating lymphomas that results in improved response rates. There is an expectation of success for a PHOSITA to administer a dual CD19 and CD30 EBV-CTL cell because A154 and Dotti teach the CD30 CAR EBV-CTL administration, anti-tumor benefits thereof and a CD30/CD19 CAR, and Chang teaches a dual CD19 and CD30 CAR T cell as an effective therapy for treating lymphomas that results in improved response rates. This rationale aligns with the principle of a simple substitution of one known element for another to obtain predictable results (see MPEP 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant indicated that “if at the time allowable claims are agreed upon the double patenting rejection is proper, a terminal disclaimer may be submitted”.
In response, the double patenting rejection(s) have been maintained.
Claim(s) 3-13 and 20-22 is/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12, 17, 37-38, and 40 of copending Application No. 17/997,171 (hereinafter “A171”) in view of Savoldo et al. (Blood, 01October2007, Vol. 110, No. 7; hereinafter “Dotti”).
This is a provisional nonstatutory double patenting rejection.
Regarding instant claims 3-13, and 20-22, A171 teaches a method of treating a disease (e.g., cancer) comprising administration of a therapeutically or prophylactically effective quantity of an Epstein-Barr virus (EBV) specific T cell comprising a CAR (SEQ ID NO: 35 or 36)or nucleic acid encoding a CAR, wherein the CAR comprises: (i) an anti-CD30 antigen binding domain (SEQ ID NOs: 14-15, 18); (ii) a hinge domain (SEQ ID NO: 33); (iii) a CD28 transmembrane domain (SEQ ID NO: 20); (iv) a CD28 intracellular domain (ICD) (SEQ ID NO: 26); and (v) a CD3z (containing ITAMs) domain (SEQ ID NO: 25) [e.g., claims 12, 17, 37-38, 40]. It is noted for the record that instant CAR SEQ ID NOs: 35 and 36 differ by a signal peptide sequence, therefore the alignment of instant SEQ ID NO: 36 below is considered to also apply for instant SEQ ID NO: 35.
Alignment of anti-CD30 CAR instant SEQ ID NO: 36 with A171 anti-CD30 CAR SEQ ID NO: 36:
CLUSTAL O(1.2.4) multiple sequence alignment
Signal peptide (34); HRS3 scFv (14-15, 18); hinge region (33), CD28 tm (20); CD28 ICD (26); CD3z (25)
161_SeqID36 MDFQVQIFSFLLISASVIMSRMAQVQLQQSGAELARPGASVKMSCKASGYTFTTYTIHWV 60
A171_SeqID36 MDFQVQIFSFLLISASVIMSRMAQVQLQQSGAELARPGASVKMSCKASGYTFTTYTIHWV 60
************************************************************
161_SeqID36 RRRPGHDLEWIGYINPSSGCSDYNQNFKGKTTLTADKSSNTAYMQLNSLTSEDSAVYYCA 120
A171_SeqID36 RRRPGHDLEWIGYINPSSGCSDYNQNFKGKTTLTADKSSNTAYMQLNSLTSEDSAVYYCA 120
************************************************************
161_SeqID36 RRADYGNYEYTWFAYWGQGTTVTVSSSGGGSGGGGSGGGGSVIELTQSPKFMSTSVGDRV 180
A171_SeqID36 RRADYGNYEYTWFAYWGQGTTVTVSSSGGGSGGGGSGGGGSVIELTQSPKFMSTSVGDRV 180
************************************************************
161_SeqID36 NVTYKASQNVGTNVAWFQQKPGQSPKVLIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQ 240
A171_SeqID36 NVTYKASQNVGTNVAWFQQKPGQSPKVLIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQ 240
************************************************************
161_SeqID36 SEDLAEYFCQQYHTYPLTFGGGTKLEIKRSDPAEPKSPDKTHTCPPCPAPELLGGPSVFL 300
A171_SeqID36 SEDLAEYFCQQYHTYPLTFGGGTKLEIKRSDPAEPKSPDKTHTCPPCPAPELLGGPSVFL 300
************************************************************
161_SeqID36 FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 360
A171_SeqID36 FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 360
************************************************************
161_SeqID36 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ 420
A171_SeqID36 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ 420
************************************************************
161_SeqID36 VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 480
A171_SeqID36 VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 480
************************************************************
161_SeqID36 FSCSVMHEALHNHYTQKSLSLSPGKKDPKFWVLVVVGGVLACYSLLVTVAFIIFWVRSKR 540
A171_SeqID36 FSCSVMHEALHNHYTQKSLSLSPGKKDPKFWVLVVVGGVLACYSLLVTVAFIIFWVRSKR 540
************************************************************
161_SeqID36 SRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNE 600
A171_SeqID36 SRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNE 600
************************************************************
161_SeqID36 LNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRG 660
A171_SeqID36 LNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRG 660
************************************************************
161_SeqID36 KGHDGLYQGLSTATKDTYDALHMQALPPR 689
A171_SeqID36 KGHDGLYQGLSTATKDTYDALHMQALPPR 689
*****************************
A171 does not expressly teach that the CAR is allogeneic or that the cancer is CD30+.
Dotti teaches a method of treating cancer comprising administering EBV-specific cytotoxic T lymphocytes (EBV-CTLs), comprising a CD30-directed (HRS3 scFv) CAR for the treatment of cancer [e.g., abstract; introduction; patients, materials, and methods]. Dotti teaches EBV-CTLs expressing the CD30 CAR kill CD30+ allogeneic tumor cells [e.g., figs. 3]. Dotti further teaches this approach results in effective and sustained immune responses (e.g., effective dose was administered), CARs that are better able to persist and kill tumor targets, and that a number of preclinical studies support the benefits [e.g., pg. 9, column 2, para 2]. Dotti concludes that adoptive cell therapy (ACT) of EBV-CTLs grafted with a CD30-directed CAR may enhance immunotherapy of EBV+ subjects, and suggests anti-cancer effect against CD30+ tumors should be benefited by local and systemic stimulation of the naive receptor by the EBV-infected B cells, without harm to the function of the immune system as a whole [e.g., pg. 10].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention substitute the cell source and the disease (e.g., cancer) treated by the administration of the CD30 CAR EBV T cell of A171 with the allogeneic CD30+ cancers treated by CD30 CAR EBV T cells as taught by Dotti, to arrive at the instant invention. A PHOSITA would have been motivated to substitute the cell source and the disease (e.g., cancer) treated with CD30 CAR EBV T cell as taught by A171 with the allogeneic CAR cells and the CD30+ cancer treated by CD30 CAR EBV T cells as taught by Dotti because the CD30 EBV T cell of A171 binds CD30 antigen and an embodiment wherein the disease treated cancer is disclosed, and Dotti teaches a similar CD30 CAR EBV T cell as an effective anti-CD30+ allogeneic cancer therapeutic. There would have been a reasonable expectation of success for a PHOSITA to substitute the cell source and the disease (e.g., cancer) treated by administration of a CD30 CAR EBV T cell as taught by A171 with the methods to treat allogeneic CD30+ cancers as taught by Dotti, because Dotti teaches a similar CD30 CAR EBV T cell as an effective anti-CD30+ allogeneic cancer therapeutic, and additionally teaches CD30 as a tumor target is beneficial because CD30 directed CARs kill tumors without harm to the function of the immune system as a whole. This rationale aligns with the principle of a simple substitution of one known element for another to obtain predictable results (see MPEP 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant indicated that “if at the time allowable claims are agreed upon the double patenting rejection is proper, a terminal disclaimer may be submitted”.
In response, the double patenting rejection(s) have been maintained.
Claim(s) 14-19 is/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12, 17, , and 37-40 of copending Application No. 17/997,171 (hereinafter “A171”) and Savoldo et al. (Blood, 01October2007, Vol. 110, No. 7; hereinafter “Dotti”) as applied to claim 3 above, and further in view of Chang et al. (Blood (2018) 132, Supplement 1: 225; hereinafter “Chang”).
This is a provisional nonstatutory double patenting rejection.
The teachings of A171 and Dotti as recited above apply for claim 3.
Regarding instant claims 14-19, A171 further teaches an EBV T cell comprising the anti-CD30 CAR construct as described above and further comprising a second CAR construct that binds CD19 [e.g., claims 29, 39, 43].
A171 and Dotti do not expressly teach the rationale for selecting CD19 as the second CAR construct.
Chang teaches a Phase I/II trial of multi-target CAR T cells against relapse or refractory (r/r) lymphomas [e.g., title, background]. Chang teaches CD19 CAR T cells have demonstrated improved partial or complete remission response even in very late-stage r/r B cell lymphoma patients (pts), but that many pts experienced relapse or became CD19 CAR T resistant [e.g., background]. Chang teaches that to improve long term efficacy, they developed a new strategy to evaluate the efficiency of multi-target CARs against lymphomas [e.g., background]. Chang further teaches a dual target CAR T cell comprising CD19 and CD30 CARs, and further that overall results demonstrate safety and improved response rates (relative to single CAR T therapy) [e.g., results, conclusions].
Further, it would have been obvious to a PHOSITA to modify the modified methods of A171 and Dotti (see above) to include a second CAR construct comprising an anti-CD19 CAR, because Chang teaches a CD19 and CD30 dual CAR T cell as an effective therapy for treating lymphomas that results in improved response rates. There is an expectation of success for a PHOSITA to administer a dual CD19 and CD30 EBV-CTL cell because A171 and Dotti teach the CD30 CAR EBV T cells and anti-tumor benefits thereof, and Chang teaches a dual CD19 and CD30 CAR T cell as an effective therapy for treating lymphomas that results in improved response rates. This rationale aligns with the principle of a simple substitution of one known element for another to obtain predictable results (see MPEP 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant indicated that “if at the time allowable claims are agreed upon the double patenting rejection is proper, a terminal disclaimer may be submitted”.
In response, the double patenting rejection(s) have been maintained.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M CHATTIN whose telephone number is (571)270-0646. The examiner can normally be reached T-F 0600-1600 PST.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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