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 .
Claims Status
Claim(s) 3-22 is/are currently pending and presented for examination on the merits.
Response to Amendment
The objection(s) to the specification have been withdrawn in view of the Amendment filed on 22Oct2025.
The rejection(s) of claim(s) 22 under 35 U.S.C. § 112(b), and of claim(s) 3-22 under 35 U.S.C. § 112(a) enablement has/have been withdrawn in view of the recent claim amendment filed on 22Oct2025.
All other previously presented rejection(s) and objection(s) are maintained 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
Claim Rejections - 35 USC § 112(a) – written description
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 7-8 and 13 is/are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claimed Invention
Claim(s) 7-8 and 13, are drawn to a chimeric antigen receptor (CAR) that binds CD30.
Breadth of Claims
The invention as disclosed in claim(s) 7-8 and 13 recite(s) “…an amino acid sequence having at least 80% amino acid sequence identity to SEQ ID NO: (respective number)”. The claim(s) encompass a genus of heavy and/or light chain variable regions comprising variability (e.g., 80% identical) in both the heavy and/or light chain variable regions which are claimed as having the function of specifically binding to CD30. This means that the variability in sequence identity can also occur in the CDRs, the domains that are critical for the antibody binding to its target, which one of ordinary skill in the art would understand to result in unpredictable binding characteristics with no reasonable expectation of maintaining CD30 antigen binding. Additionally, the instant disclosure does not provide an adequate number of species of the claimed genus nor does the disclosure provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision what variation can occur to the light and heavy chains, particularly in the CDR regions, such that the obtained structure would result in the claimed functions.
Scope of Disclosed Species
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The anti-CD30 CARs in the Applicant disclosure (see summary table above for details) with 100% sequence identity in the CDR regions of the heavy and light chain variable regions represents the anti-CD30 CARs that the applicant was in possession of at the time of filing. It is noted that there would be support for 100% identity of the full complement of the six CDRs together with some percentages of identity in the framework region that would have been predictable.
State of the Prior Art
At the time of filing, Savoldo et al. (BMC Cancer (2019) 19:203; hereinafter “Savoldo”) taught anti-CD30 CARs were recognized in the art as a promising therapeutic for a Hodgkin Lymphomas, anaplastic large cell lymphomas, cutaneous T cell lymphomas and diffuse large B cell lymphomas [e.g., abstract]. Savoldo taught that two CD30-directed CAR T cell clinical trials were completed and that published results show different patient responses and durability of response [e.g., table 1, pgs. 3-4, “Clinical trials of CD30-directed CAR T cells”]. Savoldo further taught various species of CD30-directed CARs currently in clinical trials as cancer therapies [e.g., table 2]. Therefore, the prior art demonstrates that the binding of CD30 is possible by various CD30 directed CARs with different patient outcomes. The prior art does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 in a CD30-directed CAR that would allow prediction of CDR residues that specifically bind to CD30.
Further, at the time of filing, antibody and CAR functionality were known to depend on the entire structure, particularly a full complement of six CDRs. It is understood by one of ordinary skill in the art that that mutation to CDRs is unpredictable and that each construct requires function testing.
Sela-Culang, Kunik, and Ofran (Fron. Immuno., Vol. 4, Article 302, Oct. 2013), hereinafter “Sela-Culang”, reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring antibodies have six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition [e.g., pg. 1, abstract; pg. 3, “The Role of CDRs and their Definition”]. A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, that the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized [e.g., pg. 1, “The Motivations for…”].
Further, Herold et al. (Nature Scientific Reports, 7:12276, 25 Sep 2017), hereinafter “Herold”, teaches that it should be emphasized that there is no correlation between experimentally determined change in antibody binding affinity and a given mutation and additionally that no such correlation is expected because antigen binding is “affected by each CDR loop differently” and changes thereto “can in principle affect antigen binding affinity in an unpredictable way” [e.g., pg. 14, paragraph 2]. Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex [e.g., pg. 14, paragraph 3].
Thus, making changes to the CDR sequence of an antibody and/or CAR T sequence is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
Conclusion
As indicated by the art, a full complement of 6 CDRs are required for antigen binding and one cannot predict which CDR residues may be changed and still result in a CAR that binds CD30. Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims. Above, the art indicates that the 6 CDRs in a CAR antigen-binding domain are the minimal structure that binds to a target antigen. Specifically, Applicant claim(s) 7-8 and 13 would need to recite the 6 CDRs in the CAR that bind CD30, without variability in the sequences thereof.
Response to Arguments
Applicant argues that the Office Action's interpretation of the art is inaccurate and readily refuted by the art it cites. The Office Action asserts, in no uncertain terms, that "[a]s indicated by the art, a full complement of 6 CDRs are required for antigen binding .... " Office Action at page 10 ( emphasis added). One of the references cited by the Office Action is Sela-Culang, Kunik, and Ofran (Fron. lmmuno., Vol. 4, Article 302, Oct. 2013) (hereinafter "Sela-Culang"). Sela-Culang teaches that "Several linear peptides containing one or more of the CDRs that retained Ag specificity have been reported." Sela-Culang at page 7. Thus, Sela-Culang indicates that a full complement of 6 CDRs is not required for antigen binding, refuting the Office Action's assertion.
The Office Action additionally asserts, in no uncertain terms, that "one skilled in the art could not a priori make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s)." Office Action at page 10 (emphasis added). To this point, Sela-Culang teaches that "[w]e have shown that CDRs that are able to bind the Ag on their own have unique characteristics and, thus, can be computationally identified given the Ab-Ag complex structure. This may enhance the design of CDR-derived peptides that are not necessarily based on CDR-H3." Sela-Culang at page 7 (emphasis added) (internal citation omitted). Thus, Sela-Culang teaches available computational methods that may enhance the design of CDR-derived peptides. Sela-Culang refutes the Office Action's assertion that a skilled artisan "could not a priori make any predications" regarding mutations to CDRs.
In response, when taken in context Sela-Culang teaches:
“According to the commonly accepted hotspot hypothesis, the binding energy of two proteins is largely determined by a very small number of critical residues (12,88-90). Thus, one may wonder whether an individual CDR could bind the Ag on its own provided that it harbors hotspots. Several linear peptides containing one or more of the CDRs that retained Ag specificity have been reported (91–98). Although their affinity was usually in the micromolar range, it could be significantly improved by introducing relatively minor modifications (91, 99). However, many attempts to isolate and design such CDR derived peptides failed (100, 101). One possible reason is that a CDR, on its own, may not fold to the same conformation as in the context of the entire Fab, which may be crucial for binding….In addition, while ABR-H3 was shown to have the highest contribution to Ag binding energy on average (52), there are individual cases in which other CDRs are the dominant ones (52, 102). It is also possible that in some cases the binding depends on specific contacts from residues in different CDRs, which may preclude the design of CDR-derived peptides that maintain specificity. We have shown (102) that CDRS that are able to bind the Ag on their own have unique characteristics and, thus, can be computationally identified given the Ab-Ag complex structure. This may enhance the design of CDR-derived peptides that are not necessarily based on CDR-H3.” [e.g., pg. 7, col. 1, ¶ 2].
Given the full context, the Application’s citations of Sela-Culang are considered to teach that 6 CDRs are required for binding. Specifically, Sela-Culang teaching that “several linear peptides containing one or more of the CDRs that retained Ag specificity have been reported” is preceded by a requirement for critical residue hotspots, and followed by the teaching that attempts to isolate and design such CDR derived peptides failed. In the context of the instant invention, the Applicant has not provided evidence of critical residue testing, and Sela-Culang teaches that attempts to design such CDR derived peptides have failed. Secondly, regarding Sela-Culang’s teachings that “We have shown (102) that CDRS that are able to bind the Ag on their own have unique characteristics and, thus, can be computationally identified given the Ab-Ag complex structure. This may enhance the design of CDR-derived peptides that are not necessarily based on CDR-H3”, is preceded by the teaching that ABR-H3 had the highest contribution to Ag binding, and that there are individual cases in which other CDRS are the dominant ones(e.g., atypical occurrence), and that it in some cases the binding depends on specific contacts from residues in different CDRs which may preclude the design of CDR-derived peptides that maintain specificity. Therefore, Sela-Culang teaches that in very specific instances that computationally identified CDRs may enhance the design of CDRs, but does not teach that a skilled artisan could a priori make predictions regarding amino acids in the CDRs may retain antigen binding in all instances. In summary, when taken in the full context, Sela-Culang is considered to teach that 6 CDRs are required for binding and that a skilled artisan cannot a priori predict which residue(s) are necessary for antigen binding.
Applicant arguments have been thoroughly reviewed but are not persuasive. The rejection(s) of claim(s) 7-8 and 13 are maintained.
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+ tumor cells [e.g., figure 2]. 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 the CAR 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., figures 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 CD-30 directed CAR taught by Dotti, with the CD30-directed CAR sequence taught by WO444, in the context of designing and developing a CD30 directed CAR to treat cancer. A PHOSITA would have been motivated to substitute the anti-CD30 CAR of Dotti with the anti-CD30 CAR construct as taught by WO444, because booth 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 anti-CD30 CAR comprises a hinge, a tm, a CD28 ICD, and a CD3z (comprises ITAMs) domain, 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 anti-CD30 CAR construct of WO444 in place of the CD30 directed CAR taught by Dotti, because Dotti teaches the general CD30 directed CAR 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 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:
There is nothing in Dotti and WO444, either alone or in combination, that teaches or suggests treating a cancer comprising administering to a subject a therapeutically effective quantity of the specific combination of a virus-specific immune cell with a CD30-specific CAR with a signaling Ing domain comprising (a) an amino acid sequence derived from the intracellular domain of CD28, and (b) an amino acid sequence comprising an ITAM. The skilled artisan would have no motivation to select this specific combination of features and certainly no reasonable expectation of success that by combining these features they would obtain CAR-expressing virus-specific immune cells with the surprising effects discussed in detail below.
In response, briefly, Dotti was relied upon to teach the administration of a therapeutically effect amount of anti-CD30 CAR EBV T cells to treat cancer comprising a HRS3 scFv CD30 antigen binding domain [e.g., abstract; introduction; patients, materials and methods; fig. 2] and WO444 was relied upon to teach the components of a CD30 directed CAR comprising a HRS3 scFv, including (a) an amino acid sequence derived from the intracellular CD28 domain and (b) an amino acid sequence comprising an ITAM (see 35 USC 103 rejection, and in particular the CD30 directed CAR alignment, above). As discussed in greater detail above; Dotti taught the benefits of anti-CD30 CAR EBV T cells in cancer therapy; both Dotti and WO444 teach CD30 directed CARs comprising a HRS3 scFv that binds CD30, but Dotti did not teach the entire CAR sequence or the comprising subunits thereof and WO444 filled this gap by teaching the same scFv as well as the comprising subunits of the CAR (see rejection for further details). Remarks regarding “surprising effects” are addressed below. For the reasons provided above, the applicant’s argument(s) is/are not considered persuasive.
Unexpected Results: (1) Example 3 describes that virus-specific immune cells expressing CD30.CAR were shown to have the ability to reduce the number of alloreactive T cells, and to be protected against allorejection. Further, Example 5 demonstrates that the effectivity of these virus specific immune cells derived from healthy donors in cancer patients. Clinical responses were observed despite the limited persistence of CAR-expressing cells in the peripheral blood, and in the absence of evidence of epitope spreading to other TAAs. (2) Further evidence in Quach et al.: (a) EBVSTs would be expected to undergo severe fratricide, but this was not observed and it was shown that CD30 is bound in cis and protects host cell from fratricide, whereas other activation antigens such as CD70 are not tolerated by EBVSTs which undergo severe fratricide and cannot be grown; (b) CD30.CAR EBVSTs maintained EBV specificity via TCRs even when expanded by stimulation of the CAR which made manufacturing easier whereas without the CAR, the EBVSTs lost their EBV specificity; and (c) the authors found that EBVSTs could eliminate NK cells.
In response, to example 3 teaching killing of alloreactive T cells, one of ordinary skill in the art would have expected CD30 directed CAR EBV T cells kill alloreactive T cells, because alloreactive T cells were known in the art to express CD30 (see Martinez et al., Transplantation, 1998 May 15, 65(9): 1240-7; e.g., title and abstract). Further, Dotti teaches an anti-CD30 CAR EBV T cell that is effective in treating cancer and results showed sustained immune responses (see rejection above for details), which a skilled artisan would not expect to see with high levels of fratricide (e.g., no significant fratricide observed for CD30 CAR EBV T cells in Dotti’s results). Therefore example 3 and Quach et al. (a) as recited above are not considered unexpected results. Regarding Quach et al. (b) as recited above, 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 CD30 directed CAR EBV T cells, not a method of making said CAR T cells and thus do not require the recited properties. Therefore these properties are not considered part of the instant invention and subsequently have not been examined on the merits. Regarding Quach et al. (c) as recited above, the claims are not commensurate with the scope of the unexpected data as the claims of the instant invention do not require the recited property; however, at the time of filing, the property of CD30 directed CAR EBV T cells being capable of eliminating NK cells would have been expected by one of ordinary skill in the art because NK cells were known in the art to express CD30 prior to the time of filing (see BD Biosciences, CD Markers, 2016; e.g., pg. 5). 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.
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 wherein the one is a CD30 directed CAR and the other is 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 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 is also silent about virus-specific immune cells. Claims 14-19 depend either directly or indirectly from independent claim 3, and therefore, inherit every element of claim 3. Accordingly, dependent claims 14-19 are patentable at least for the reasons set forth with respect to independent claim 3.
In response, Dotti was relied upon to teach virus-specific immune cells, 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 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 CD30+ tumor cells [e.g., figure 2]. 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 as taught by Dotti, in the context of designing and developing a method to treat CD30+ cancers with CAR T cells. 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+ 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+ 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 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+ tumor cells [e.g., figure 2]. 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 disease (e.g., cancer) treated by the administration of the CD30 CAR EBV T cell of A171 with the CD30+ cancers treated by CD30 CAR EBV T cells as taught by Dotti, in the context of designing and developing a method to treat CD30+ cancers with CAR T cells. A PHOSITA would have been motivated to substitute the disease (e.g., cancer) treated with CD30 CAR EBV T cell as taught by A171 with 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+ cancer therapeutic. There would have been a reasonable expectation of success for a PHOSITA to substitute the disease (e.g., cancer) treated by administration of a CD30 CAR EBV T cell as taught by A171 with the methods to treat CD30+ cancers as taught by Dotti, because Dotti teaches a similar CD30 CAR EBV T cell as an effective anti-CD30+ cancer therapeutic, and additionally teaches CD30 as a tumor target is beneficial because CD30 di