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 .
DETAILED ACTION
Claims 1-3, 11, 17-18, 22, 24, 28, 42-44, 49-50, 52, 54, 58, 61, 69-70, 73-74, 77, 83, 85, 88-91, 95, 107-111 are pending in the instant application.
Claims 107-111 are new.
Claim Interpretation
Claims to a range wherein the range is followed by “inclusive” will be interpreted as inclusive of the initial value, final value, and the intervening values in claims 3, 11, 28, 70, and 85.
Claim Objections and Rejections Withdrawn
The objections and rejections of claims 68, 92-93, 96, 99, 102, and 104-105 are moot in view of claim cancelation.
The rejection of claims 17-18, 50, 61, 73-74, and 95 under 35 U.S.C. 112(b) are withdrawn in view of claim amendment.
The rejection of claims 2 and 61 under 35 U.S.C. 112(a) are withdrawn in view of claim amendment.
The rejection of claims 1-3, 11, 17-18, 22, 24, 28, 42-44, 49-50, 52, 54, 58, 61, 69-70, 73-74, 77, 83, 85, 88-91, 95 under nonstatutory double patenting are withdrawn in view of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione in US Patent No. 12,263,190 has a different structure compared to the instantly claimed (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-lyl) methyl)benzyl)amino)isoindoline-1,3-dione.
Claim Rejections Maintained or Necessitated by Amendment
Claim Rejections – 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 95 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 95, the claim is dependent on a canceled claim. Thus, the meets and bounds of the claim are unclear and the claim is indefinite.
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.
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.
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.
The rejections of claims 1, 3, 11, 17, 42-43, 52, 54, 58, 61, 69, 74, 77, and 87 under 35 U.S.C. 103 as being unpatentable over Jessup HK et al. (Cancer Res (2019) 79 (13_Supplement): 2320 reference of record), Matyskiela ME et al. (J. Med. Chem. 2018, 61, 2, 535–542 reference of record), and US 2019/0322647 (Alexander MD et al. IDS reference) and evidenced by USAN et al. (LISOCABTAGENE MARALEUCEL 2024 https://searchusan.ama-assn.org/usan/documentDownload?uri=/unstructured/binary/usan/lisocabtagene-maraleucel.pdf reference of record) is maintained.
Jessup taught Lisocabtagene maraleucel (liso-cel) is composed of autologous CD8+ and CD4+ T cells expressing a CD19-specific chimeric antigen receptor (CAR) and combination approaches aimed at enhancing CAR T cell function may increase the rate, depth, and durability of clinical responses (abstract). The nucleotide sequence of Lisocabtagene maraleucel is evidenced by USAN to comprise a CD19-specific chimeric antigen receptor (CAR; comprised of an FMC63 monoclonal antibody-derived single chain variable fragment (scFv), lgG-derived spacer, CD28 transmembrane domain, CD137 [4-1BB] costimulatory domain, and CD3 zeta signaling domain)(USAN page 1, description), wherein the nucleotide sequence encodes a peptide CAR sequence of:
DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSESKYGPPCPPCPMFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
wherein the FMC63 scFv is italicized, the 12 amino acid IgG4 hinge is underlined, the CD28 transmembrane domain is bold, the 4-1BB costimulatory domain is shaded, and the CD3 zeta ITAM containing signaling domain is bold and italicized.
Jessup taught CC-122 is a CRBN E3 ligase modulatory drug (CELMoD) and can augment T cell function through Cereblon-mediated degradation of Ikaros and Aiolos (abstract). Jessup taught the CELMoD CC-122 increases effector function and reverses exhaustion in chronically stimulated lisocabtagene maraleucel anti-CD19 CAR T drug product (title). Jessup taught an effective method of cancer treatment in a disseminated tumor xenograft model, comprising administering the subject a pharmaceutical composition comprising concurrent or delayed dosing of the CELMoD CC-122, in combination with two doses of autologous CD8+ and CD4+ T cells expressing a CD19-specific chimeric antigen receptor (CAR), liso-cel, significantly increased median survival by 30 to 40 days and was effective (abstract), wherein a pharmaceutically acceptable excipient would also be required to be included. Jessup taught in some cases survival endpoints were not reached with the combination (abstract). Jessup taught CELMoD CC-122 treatment of CD19-directed CAR T cells was shown to enhance CAR T activation in acute stimulation assays; limit CAR T exhaustion onset during chronic stimulation as assessed by gene expression; and reverse an exhausted, hypofunctional CAR T state induced by chronic stimulation (abstract). Jessup taught that liso-cel pharmacologic activity may both be enhanced and extended by this combinatorial approach and supports an ongoing clinical investigation evaluating the addition of CC-122 to liso-cel in patients with R/R, aggressive Non-Hodgkin’s lymphoma (NHL) (NCT03310619)(abstract). Jessup taught CELMoD CC-122 dose-dependently increased cytokine production and restored cytolytic function of exhausted CAR T cells upon re-challenge with CD19+ tumor spheroids (abstract).
Jessup did not teach a method of treating a cancer expressing CD19 comprising administering: a) (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione; and a CD19 targeted CAR T cell, but this is obvious in view of Matyskiela and ’647.
Matyskiela taught the drugs lenalidomide, pomalidomide, and CC-220 (compound 6) bind to the protein cereblon, directing the CRL4–CRBN E3 ligase toward the transcription factors Ikaros and Aiolos to cause their ubiquitination and degradation (abstract). Thus, the drugs are known CRBN E3 ligase modulatory drugs (CELMoD).
Matyskiela taught the chemical structures of cereblon modulators
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(Fig. 1a).
Matyskiela taught structural studies have shown that cereblon modulators bind to cereblon through the glutarimide moiety, which docks into a hydrophobic tritryptophan pocket formed by Trp380, Trp386, and Trp400 (page 535-536, bridging paragraph).
Matyskiela taught the crystal structure of CC-220 (compound 6) bound to CRBN–DDB1 reveals that there are additional contacts with the surface of cereblon compared to lenalidomide or pomalidomide (page 536, second paragraph)
Matyskiela taught the extended chemical moieties relative to lenalidomide and pomalidomide appear to enhance the surface area of CC-220 (compound 6) that contacts cereblon, which correlates with the observed binding affinity increase in biochemical assays and increased potency of CC-220 (compound 6) in cellular degradation of Ikaros and Aiolos (page 538, left to right bridging paragraph). Matyskiela taught the cereblon binding compounds lenalidomide, pomalidomide, and CC-220 (compound 6) dose dependently decrease protein levels of Ikaros and Aiolos (Fig. 2).
‘647 taught a method of killing cancer cells comprising administering (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione
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or its enantiomer (R)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione to cancer cells to effectively dose-dependently inhibit SU-DHL-4 DLBCL cancer cell proliferation, wherein the IC50 value was below 200 nM (page 39, [0305] and page 99, Table 1). ‘647 taught each isoindolinedione compound referred to herein can be provided in the form of any of the pharmaceutically acceptable salts discussed herein (page 7, [0061]) and that the salt forms were useful for treatment (pages 1-2, [0012]). Thus, ‘647 taught (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione or its enantiomer in a pharmaceutically acceptable salt form.
Regarding instant claims 1, 3, 11, 17, 42-43, 52, 54, 58, 61, 69, 74, 77, and 87, it would have been obvious for a person having ordinary skill in the art to take the effective method of cancer treatment of Jessup in a subject with cancer, comprising administering the subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and concurrent or delayed dosing of: a) the CELMoD CC-122; and b) two doses of liso-cel, which is an autologous CD8+ and CD4+ T cells expressing a CD19-specific chimeric antigen receptor (CAR), wherein the CELMoD C-122 had delayed or concurrent dosing – and:
1) exchange the CELMoD CC-122 with other molecules that would be CELMoDs such as (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione in view of ‘647 and Matyskiela;
2) treat a cancer that expresses CD19 in view of Jessup;
3) Use a consistently effective dose, that is the same, of CELMoD for each concurrent or delayed administration with the two doses of CAR T cells in view of Jessup;
4) treat a human subject with a CD19 expressing cancer in view of Jessup; and
5) administer (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione in a pharmaceutically acceptable salt form in view of ‘647.
This is obvious because:
1a) Matyskiela taught structural studies have shown that cereblon modulators bind to cereblon through the glutarimide moiety, which docks into a hydrophobic tritryptophan pocket formed by Trp380, Trp386, and Trp400;
1b) Matyskiela taught extended chemical moieties relative to lenalidomide and pomalidomide appear to enhance the surface area of CC-220 (compound 6) that contacts cereblon, which correlates with the observed binding affinity increase in biochemical assays and increased potency of CC-220 (compound 6) in cellular degradation of Ikaros and Aiolos;
1c) ‘647 taught (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione effectively dose-dependently inhibit SU-DHL-4 DLBCL cancer cell proliferation, wherein the structure contains a glutarimide moiety and an extended chemical moiety with a morpholine ring that would contact cereblon which would be expected to be an effective cereblon CELMoD;
2) Jessup taught CELMoD CC-122 dose-dependently increased cytokine production and restored cytolytic function of exhausted CAR T cells upon re-challenge with CD19+ tumor spheroids;
3) A consistently effective dose, that is the same, of CELMoD would bind cereblon and decrease exhaustion in CAR T cells for concurrent or delayed administration of CAR T cells;
4) combination treatment of a CELMoD and a CD19 targeted CAR T cell was effective in a subject with cancer and would also be expected to be effective in humans in view of Jessup; and
5) ‘647 taught (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione in a pharmaceutically acceptable salt form.
There is a reasonable expectation of success because:
1a) Matyskiela taught structural studies have shown that cereblon modulators bind to cereblon through the glutarimide moiety, which docks into a hydrophobic tritryptophan pocket formed by Trp380, Trp386, and Trp400. Thus, (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione would be expected to be an effective cereblon CELMoD;
1b) Matyskiela taught extended chemical moieties relative to lenalidomide and pomalidomide appear to enhance the surface area of CC-220 (compound 6) that contacts cereblon, which correlates with the observed binding affinity increase in biochemical assays and increased potency of CC-220 (compound 6) in cellular degradation of Ikaros and Aiolos. Thus, (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione would be expected to be an effective cereblon CELMoD with increased potency and degradation of Ikaros and Aiolos as well;
1c) ‘647 taught (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione effectively dose-dependently inhibit SU-DHL-4 DLBCL cancer cell proliferation, wherein the structure contains a glutarimide moiety and an extended chemical moiety with a morpholine ring that would contact cereblon which would be expected to be an effective cereblon CELMoD;
2) Jessup taught CELMoD CC-122 dose-dependently increased cytokine production and restored cytolytic function of exhausted CAR T cells upon re-challenge with CD19+ tumor spheroids. Thus, the CAR T cells would target the CD19 expressing cancer cells;
3) A consistently effective dose, that is the same, of CELMoD would bind cereblon and decrease exhaustion in CAR T cells for each concurrent or delayed administration with the two doses of CAR T cells;
4) combination treatment of a CELMoD and a CD19 targeted CAR T cell was effective in a subject with cancer and would also be expected to be effective in humans in view of Jessup; and
5) a pharmaceutically acceptable salt form of (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione would increase solubility.
This would produce a method of effectively treating a human subject (instant claim 87) with a human CD19 expressing cancer (instant claim 52), comprising administering the subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and concurrent or delayed dosing of:
a) a compound that is (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione or a pharmaceutically acceptable salt form (instant claim 42); and
b) a T cell therapy of two doses of liso-cel, which is an autologous (instant claim 74) CD8+ and CD4+ T cells expressing a CD19-specific chimeric antigen receptor (CAR) (instant claim 77),
wherein the (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione (instant claim 43) was dosed with each dose of the liso-cel CAR T cells with delayed, subsequently initiated (instant claim 3), or concurrent administration, which would start administration on Day 1 (instant claim 11), wherein the administration of liso-cel would initially occur on Day 1, wherein the two of the same doses of (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione would thus be a plurality of intermittent doses (instant claim 17) (instant claim 1), and wherein the sequence of the liso-cel is:
DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSESKYGPPCPPCPMFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
wherein the FMC63 scFv is italicized, the 12 amino acid IgG4 hinge is underlined, the CD28 transmembrane domain is bold, the 4-1BB costimulatory domain is shaded, and the CD3 zeta ITAM containing signaling domain is bold and italicized, which is comprised of an identical sequence to instant SEQ ID NO:41-43 and meets the claim limitations of instant claim 54, 58, 61, and 69.
Response to Arguments
Applicant respectfully submits that the cited references do not establish that such a substitution would have produced predictable results or that a person of ordinary skill in the art would have had a reasonable expectation that Compound C would provide the effects on CAR-Tcell function reported by Jessup for CC-122.
Applicant argues the cited references do not establish that Compound C would predictably reproduce the CAR-T effects of CC-122.
Applicant argues Jessup concerns CC-122, rather than Compound C. As summarized in the Office Action, Jessup reports that CC-122 enhanced activation of CD 19-directed CAR-T cells limited the onset of exhaustion during chronic stimulation, reversed an exhausted CAR-T state, and restored cytolytic function of exhausted CAR-T cells upon rechallenge with CD 19-positive tumor spheroids. The Examiner does not identify a teaching in Jessup concerning Compound C.
Applicant argues neither Matyskiela nor Alexander establishes that Compound C would produce the same effects on CAR T cells. The Examiner points to Matyskiela for teachings concerning cereblon modulators, including their binding to cereblon and degradation of Ikaros and Aiolos. Matyskiela, however, concerns compounds such as lenalidomide, pomalidomide, and CC-220, rather than Compound C. Moreover, the Office Action recognizes that structural differences among cereblon modulators can affect their interaction with cereblon and their cellular potency. For example, the Examiner notes that structural features of CC-220 increase contacts with cereblon, which correlate with increased binding affinity and increased potency in degradation oflkaros and Aiolos (Office Action page 15, last paragraph; page 16, first paragraph). Thus, Matyskiela does not establish that different cereblon modulators are functionally interchangeable with respect to their effects on CART cells.
Applicant argues the Examiner relies on Alexander for the teaching that Compound C dose-dependently inhibits proliferation of SU-DHL-4 DLBCL cells. Applicant submits that Alexander does not remedy the deficiencies of Jessup and Matyskiela. Direct anti proliferative activity against a tumor cell is distinct from modulation of the functional state of chronically antigen-stimulated CAR-T cells. Alexander does not teach administration of Compound C in combination with CD 19-directed CAR-T cells and does not evaluate the effect of Compound Con CAR-T-cell activation, persistence, exhaustion, cytolytic function, or activity upon repeated antigen stimulation.
Applicant submits the cited references do not establish that the favorable CAR-T effects reported by Jessup for CC-122 would have been a predictable result of substituting Compound C for CC-122, nor do they establish a reasonable expectation that Compound C would reproduce those effects merely because Compound C was expected to act as a cereblon modulator.
Applicant argues the Working Examples further support the nonobviousness of the claimed Compound C/CAR-T combination. Even assuming, arguendo, that the cited references establish a prima facie case of obviousness, which Applicant does not concede, the Working Examples of the present specification provide experimental evidence that further supports the nonobviousness of the claimed combination.
The Working Examples demonstrate beneficial effects of Compound Con anti-CD19 CAR T cells subjected to chronic antigen stimulation. Figures 3A-3J evaluate Compound C in chronically stimulated anti-CD19 CART cells, including its effects on cytokine production, cytolytic function, CD 19-positive tumor spheroid killing, and gene-expression pathways. These experiments demonstrate beneficial effects of Compound C on the functional performance of anti-CD 19 CAR T cells under repeated stimulation. Figures 4A-4G further examine Compound Cina "rescue" experiment using chronically stimulated CART cells. These data show that Compound C can restore activity in chronically stimulated T cells exhibiting features of exhaustion. Figures SA and SB provide an additional functional assessment by examining tumor-cell control following rechallenge of CAR T cells that had undergone chronic stimulation in the presence of Compound C or had subsequently received Compound C rescue treatment. Taken together, these experiments demonstrate preservation or restoration of CAR T cell activity against CD 19-positive target cells under chronic-stimulation and rechallenge conditions.
The Working Examples further identify an advantageous Compound C exposure profile. Figures 6A-6D examine Compound C exposure and target modulation over time, while Figures 7 A- 7C assess anti-CD19 CART cell activity following different Compound C exposure profiles. Example 7 shows pronounced CAR T cytolytic activity following a transient higher Compound C exposure followed by lower exposure. These results demonstrate that the beneficial interaction between Compound C and anti-CD19 CART cells depends on the particular biological properties and exposure profile of Compound C, rather than following simply from its classification as a cereblon modulator.
These results are directly relevant to the Examiner's proposed substitution. Jessup reports favorable CART results for CC-122, but the cited art does not disclose or predict the favorable functional effects demonstrated for Compound C in the present Working Examples, including its effects in chronically stimulated CAR-T cells, its ability to restore CAR-T activity, and its favorable performance upon antigen rechallenge. Thus, the Working Examples provide evidence that the claimed Compound C/CAR-T combination exhibits beneficial functional properties that were not taught or predicted by the cited references.
When the cited references and the experimental evidence are considered as a whole, Applicant respectfully submits that the Examiner has not established that the claimed combination would have been obvious to a person of ordinary skill in the art and thus, withdrawal of the rejection is requested.
In response, Applicant's arguments filed 8/19/2026 have been fully considered but they are not persuasive. The obvious rational is above and details the obviousness and reasonable expectation of success.
Regarding Jessup, Jessup taught CC-122 is a CRBN E3 ligase modulatory drug (CELMoD) and can augment T cell function through Cereblon-mediated degradation of Ikaros and Aiolos (abstract). Jessup taught the CELMoD CC-122 increases effector function and reverses exhaustion in chronically stimulated lisocabtagene maraleucel anti-CD19 CAR T drug product (title). Thus, it was known to the prior art that anti-CD19 CAR T cells combined with agents that are CRBN E3 ligase modulatory drugs (CELMoD) can augment T cell function through Cereblon-mediated degradation of Ikaros and Aiolos.
Regarding Matyskiela, Alexander (‘647), and exchange of CC-122 for (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione
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or its enantiomer (R)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione:
The structural features of cereblon modulators are known to the prior art. Matyskiela taught the drugs lenalidomide, pomalidomide, and CC-220 (compound 6) bind to the protein cereblon, directing the CRL4–CRBN E3 ligase toward the transcription factors Ikaros and Aiolos to cause their ubiquitination and degradation (abstract). Thus, the drugs are known CRBN E3 ligase modulatory drugs (CELMoD). Matyskiela taught the chemical structures of cereblon modulators
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(Fig. 1a). Matyskiela taught structural studies have shown that cereblon modulators bind to cereblon through the glutarimide moiety, which docks into a hydrophobic tritryptophan pocket formed by Trp380, Trp386, and Trp400 (page 535-536, bridging paragraph). Matyskiela taught the crystal structure of CC-220 (compound 6) bound to CRBN–DDB1 reveals that there are additional contacts with the surface of cereblon compared to lenalidomide or pomalidomide (page 536, second paragraph). Matyskiela taught the extended chemical moieties relative to lenalidomide and pomalidomide appear to enhance the surface area of CC-220 (compound 6) that contacts cereblon, which correlates with the observed binding affinity increase in biochemical assays and increased potency of CC-220 (compound 6) in cellular degradation of Ikaros and Aiolos (page 538, left to right bridging paragraph). Matyskiela taught the cereblon binding compounds lenalidomide, pomalidomide, and CC-220 (compound 6) dose dependently decrease protein levels of Ikaros and Aiolos (Fig. 2);
Alexander (‘647) taught a method of killing cancer cells comprising administering (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione
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or its enantiomer (R)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione to cancer cells to effectively dose-dependently inhibit SU-DHL-4 DLBCL cancer cell proliferation, wherein the IC50 value was below 200 nM (page 39, [0305] and page 99, Table 1). The structure of (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione contains a glutarimide moiety and an extended chemical moiety with a morpholine ring that are known to contact cereblon as seen in CC-220. Thus, (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione would be expected to be an effective cereblon CELMoD with increased potency and degradation of Ikaros and Aiolos as well.
Thus, exchange of CC-122 for (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione
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or its enantiomer (R)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione exchanges one known cereblon modulator with a known mechanism of action for enhancing CD19 CAR T cell effectiveness for another molecule that is known to be effective against cancer and possesses the required structural features of a cereblon modulator. Thus, the exchange is obvious to a person having ordinary skill in the art with a reasonable expectation of success. The combination of CD19 CAR T cells and (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione
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would be expected to have the same effects as other cereblon modulators.
Regarding the working Examples, Fig. 3A-3J, 4A-4G, Fig. 5A-5B, 6A-6D, and 7A-7C, Jessup taught: A) an effective method of cancer treatment in a disseminated tumor xenograft model, comprising administering the subject a pharmaceutical composition comprising concurrent or delayed dosing of a CELMoD, in combination with two doses of autologous CD8+ and CD4+ T cells expressing a CD19-specific chimeric antigen receptor (CAR), liso-cel, significantly increased median survival by 30 to 40 days and was effective (abstract), wherein a pharmaceutically acceptable excipient would also be required to be included, and wherein in some cases survival endpoints were not reached with the combination (abstract); B) CELMoD treatment of CD19-directed CAR T cells was shown to enhance CAR T activation in acute stimulation assays; limit CAR T exhaustion onset during chronic stimulation as assessed by gene expression; and reverse an exhausted, hypofunctional CAR T state induced by chronic stimulation (abstract); C) that liso-cel pharmacologic activity may both be enhanced and extended by this combinatorial approach and supports an ongoing clinical investigation evaluating the addition of a CELMoD to liso-cel in patients with R/R, aggressive Non-Hodgkin’s lymphoma (NHL) (NCT03310619)(abstract); D) CELMoD dose-dependently increased cytokine production and restored cytolytic function of exhausted CAR T cells upon re-challenge with CD19+ tumor spheroids (abstract). Thus, combination treatment of a subject with a cancer expressing CD19 with an anti-CD19 CAR T cell and a CELMoD is known to have beneficial effects on T cell exhaustion, cytokine production, cytolytic function, restored cytolytic function, a dose-dependent response, and CD19-positive cancer cell killing in cell based assays and in vivo in view of Jessup. The obviousness rational above indicates the obviousness and reasonable expectation of success for exchange of one CELMoD for another.
The instant specification does not show unexpected results of a method of treating a cancer expressing CD19 in a subject. The Examiner invites the Applicant to show any unexpected results of effectiveness in the subjects treated with the combination therapy in Example 8. The Examiner would like to remind the Applicant that any unexpected results are required to be commensurate in scope with claimed invention. MPEP 716.02(d) states, “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support. In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range."
Claims 1, 3, 11, 17, 42-43, 52, 54, 58, 61, 69, 74, 77, 87, and 107-111 are rejected under 35 U.S.C. 103 as being unpatentable over Jessup HK et al. (Cancer Res (2019) 79 (13_Supplement): 2320 reference of record), Matyskiela ME et al. (J. Med. Chem. 2018, 61, 2, 535–542 reference of record), and US 2019/0322647 (Alexander MD et al. IDS reference) and evidenced by USAN et al. (LISOCABTAGENE MARALEUCEL 2024 https://searchusan.ama-assn.org/usan/documentDownload?uri=/unstructured/binary/usan/lisocabtagene-maraleucel.pdf reference of record) as applied to claims 1, 3, 11, 17, 42-43, 52, 54, 58, 61, 69, 74, 77, and 87 above.
Jessup, Matyskiela, ‘647, and USAN are described above.
The obvious rational is above.
The method of Jessup, Matyskiela, and ‘647 above comprises a T cell therapy of two doses of liso-cel, which is an autologous CD8+ and CD4+ T cells expressing a CD19-specific chimeric antigen receptor (CAR), wherein the sequence of the liso-cel is:
DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSESKYGPPCPPCPMFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
wherein the FMC63 scFv is italicized, the 12 amino acid IgG4 hinge is underlined, the CD28 transmembrane domain is bold, the 4-1BB costimulatory domain is shaded, and the CD3 zeta ITAM containing signaling domain is bold and italicized, which is comprised of an identical sequence to instant SEQ ID NO:1, 12, 13, and 35-42 and meets the claim limitations of instant claims 107-111.
The rejection of claims 1-3, 11, 17, 42-43, 50, 52, 54, 58, 61, 69-70, 74, 77, 83, 85, 87, and 89-90 under 35 U.S.C. 103 as being unpatentable over Jessup HK et al. (Cancer Res (2019) 79 (13_Supplement): 2320 reference of record), Matyskiela ME et al. (J. Med. Chem. 2018, 61, 2, 535–542 reference of record), and US 2019/0322647 (Alexander MD et al. IDS reference) as applied to claims 1, 3, 11, 17, 42-43, 52, 54, 58, 61, 69, 74, 77, and 87 above, and further in view of Chow VA et al. (Blood. 2018 Jun 18;132(8):777–781 reference of record) and Abramson JS et al. (Blood (2017) 130 (Supplement 1): 581 reference of record) is maintained.
Jessup, Matyskiela, and ’647 are described above.
Jessup does not teach: 1) a method of treating a NHL lymphoma expressing CD19 or a double/triple hit lymphoma with 1x108 cells CAR T cells; 2) prior to the administration of the T cell therapy, the subject has been preconditioned with a lymphodepleting therapy comprising the administration of about 20-40 mg/m2 fludarabine and about 200-400 mg/m2 cyclophosphamide for 2-4 days; 3) prior to the time of the administration of the dose of engineered cells, the subject has relapsed following remission after treatment with, or become refractory to, one or more prior therapies for the lymphoma, but this is obvious in view of Chow and Abramson.
Chow taught a method of treatment of Non-Hodgkin’ lymphoma comprising administration of 1x108 cells of Lisocabtagene maraleucel (JCAR017 or liso-cel) to patients with B-cell Non-Hodgkin Lymphoma (TRANSCEND-NHL-001), wherein patients underwent lymphodepletion comprised of cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 for 3 days, wherein the treatment was effective and led to complete a complete response rate of about 50% at 6 months (Table 1 and page 778, left to right column bridging paragraph). Chow taught following engagement of the CAR T cell to its target antigen, T-cell activation promotes cytokine release, mediating symptoms of CRS, wherein onset commonly occurs within the first week, peaking 1 to 2 weeks after administration, but may differ according to the product, wherein the TRANSCEND trial identified median onsets of 5 days with JCAR017 (liso-cel) (pages 778-779 bridging paragraph). Chow taught CRS is characterized by fevers, hypoxia, hypotension and, rarely, multiorgan failure or evolution of hemophagocytic lymphohistiocytosis (pages 778-779 bridging paragraph).
Abramson taught a method of treatment of Relapsed/Refractory (R/R) Aggressive B-Non-Hodgkin’s lymphoma (NHL) comprising administration of JCAR017 (Lisocabtagene maraleucel or liso-cel) led to high durable complete response rates in the TRANSCEND NHL 001 trial, wherein only 21 patients (30%) had cytokine release syndrome (CRS), with a single serious CRS event (1%; Gr 4) (abstract). Abramson taught among 16 double/triple hit lymphoma patients administered JCAR017, best ORR was 81%, and 3-month CR rate was 60% (abstract).
Regarding instant claims 2, 50, 70, 83, 85, 89-90, it would have been obvious for a person having ordinary skill in the art to take the method of Jessup, Matyskiela, and ’647 above for treating a human subject with a human CD19 expressing cancer comprising administering the subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and concurrent or delayed dosing of:
a) a compound that is (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione or a pharmaceutically acceptable salt form; and
b) a T cell therapy of two doses of liso-cel, which is an autologous CD8+ and CD4+ T cells expressing a CD19-specific chimeric antigen receptor (CAR),
wherein the (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione was dosed with each of dose of the liso-cel CAR T cells with delayed, subsequently initiated, or concurrent administration, which would start administration on Day 1, wherein the administration of liso-cel would initially occur on Day 1, wherein the two doses of (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione would thus be a plurality of intermittent doses – and:
1) use the method for treating an NHL lymphoma expressing CD19 or a double/triple hit lymphoma expressing CD19 with administration of 1x108 cells of Lisocabtagene maraleucel in view of Chow and Abramson;
2) prior to the administration of the T cell therapy preconditioned with a lymphodepleting therapy comprising the administration of about 20-40 mg/m2 fludarabine and about 200-400 mg/m2 cyclophosphamide for 2-4 days in view of Chow and Abramson; and
3) prior to the time of the administration of the dose of engineered cells, administer the treatment to a subject that has relapsed following remission after treatment with, or become refractory to, one or more prior therapies for the lymphoma in view of Chow and Abramson.
This is obvious because:
1-3a) Chow taught a method of treatment of Non-Hodgkin’ lymphoma comprising administration of 1x108 cells of Lisocabtagene maraleucel (JCAR017 or liso-cel) to patients with B-cell Non-Hodgkin Lymphoma (TRANSCEND-NHL-001), wherein patients underwent lymphodepletion comprised of cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 for 3 days, wherein the treatment was effective and led to complete a complete response rate of about 50% at 6 months.
1-3b) Abramson taught an effective method of treatment of Relapsed/Refractory (R/R) Aggressive B-Non-Hodgkin’s lymphoma (NHL) comprising administration of JCAR017 (Lisocabtagene maraleucel or liso-cel) led to high durable complete response rates in the TRANSCEND NHL 001 trial, wherein only 21 patients (30%) had cytokine release syndrome (CRS), with a single serious CRS event (1%; Gr 4). Abramson taught among 16 double/triple hit lymphoma patients administered JCAR017, the best ORR was 81%, and 3-month CR rate was 60%.
Thus, administration of 1x108 cells JCAR017 (Lisocabtagene maraleucel or liso-cel) is effective in Relapsed/Refractory (R/R) Aggressive B-Non-Hodgkin’s lymphoma and double/triple hit lymphoma patients and (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione would inhibit CAR T cell exhaustion and make the treatment more effective.
There is a reasonable expectation of success because:
1-3a) Chow taught a method of treatment of Non-Hodgkin’ lymphoma comprising administration of 1x108 cells of Lisocabtagene maraleucel (JCAR017 or liso-cel) to patients with B-cell Non-Hodgkin Lymphoma (TRANSCEND-NHL-001), wherein patients underwent lymphodepletion comprised of cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 for 3 days, wherein the treatment was effective and led to complete a complete response rate of about 50% at 6 months.
1-3b) Abramson taught an effective method of treatment of Relapsed/Refractory (R/R) Aggressive B-Non-Hodgkin’s lymphoma (NHL) comprising administration of JCAR017 (Lisocabtagene maraleucel or liso-cel) led to high durable complete response rates in the TRANSCEND NHL 001 trial, wherein only 21 patients (30%) had cytokine release syndrome (CRS), with a single serious CRS event (1%; Gr 4). Abramson taught among 16 double/triple hit lymphoma patients administered JCAR017, the best ORR was 81%, and 3-month CR rate was 60%.
Thus, administration of 1x108 cells JCAR017 (Lisocabtagene maraleucel or liso-cel) is effective in Relapsed/Refractory (R/R) Aggressive B-Non-Hodgkin’s lymphoma and double/triple hit lymphoma patients and (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione would inhibit CAR T cell exhaustion and make the treatment more effective.
This would produce a method of treating a human subject with a human CD19 expressing Relapsed/Refractory (R/R) (instant claim 89) NHL (instant claim 50) lymphoma (instant claim 2) or a double/triple hit lymphoma (instant claim 90) expressing CD19 cancer comprising administering the subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and concurrent or delayed dosing of:
a) a compound that is (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione or a pharmaceutically acceptable salt form; and
b) a T cell therapy of two 1x108 cells (instant claim 70) of liso-cel, which is an autologous CD8+ and CD4+ T cells expressing a CD19-specific chimeric antigen receptor (CAR),
wherein the (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione was dosed with each of dose of the liso-cel CAR T cells with delayed, subsequently initiated, or concurrent administration, which would start administration on Day 1, wherein the administration of liso-cel would initially occur on Day 1, wherein the two doses of (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione would thus be a plurality of intermittent doses, wherein prior to the administration of the T cell therapy preconditioned with a lymphodepleting therapy comprising administering 300 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine for 3 days (instant claim 83 and 85), wherein R/R lymphoma patients are administered the treatment to a subject that has relapsed following remission after treatment with, or become refractory to, one or more prior therapies for the lymphoma.
Response to Arguments
Applicant’s arguments regarding Jessup, Matyskiela, and Alexander are discussed above. Further, the obvious rational is above and details the obviousness and reasonable expectation of success.
The rejection of claims 1, 3, 11, 17, 28, 42-43, 52, 54, 58, 61, 69, 74, 77, 87-88, 91, and 95 are rejected under 35 U.S.C. 103 as being unpatentable over Jessup HK et al. (Cancer Res (2019) 79 (13_Supplement): 2320 reference of record), Matyskiela ME et al. (J. Med. Chem. 2018, 61, 2, 535–542 reference of record), and US 2019/0322647 (Alexander MD et al. IDS reference) as applied to claims 1, 3, 11, 17, 42-43, 52, 54, 58, 61, 69, 74, 77, and 87 above, and further in view of Lonial S et al. (Blood (2019) 134 (Supplement_1): 3119 reference of record) is maintained.
Jessup, Matyskiela, and ’647 are described above.
Jessup does not teach: 1) the concentration of the CELMoD compound, but this is obvious in view of Lonial Blood.
Lonial Blood taught: a) the clinical dosing of the CELMoD Iberdomide (CC-220) ranges from 0.3 to 1.3 mg; b) clinical activity has been observed across all dose levels with an overall response rate (ORR) of 29%, clinical benefit rate of 45%, and disease control rate of 80% in relapsed/refractory multiple myeloma; and c) the maximum tolerated dose has not been reached (abstract).
Regarding instant claims 28, 88, 91, and 95, it would have been obvious for a person having ordinary skill in the art to take the method of Jessup, Matyskiela, and ’647 above for treating a human subject with a human CD19 expressing cancer comprising administering the subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and concurrent or delayed dosing of:
a) a compound that is (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione; and
b) a T cell therapy of two doses of liso-cel, which is an autologous CD8+ and CD4+ T cells expressing a CD19-specific chimeric antigen receptor (CAR),
wherein the (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione was dosed with each of dose of the liso-cel CAR T cells with delayed, subsequently initiated, or concurrent administration, which would start administration on Day 1, wherein the administration of liso-cel would initially occur on Day 1, wherein the two doses of (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione would thus be a plurality of intermittent doses – and:
1) administer a 0.3 to 1.3 mg dose of the CELMoD (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione in view of Lonial Blood.
This is obvious because: 1) Lonial Blood taught: a) the clinical dosing of the CELMoD Iberdomide (CC-220) ranges from 0.3 to 1.3 mg; b) clinical activity has been observed across all dose levels with an overall response rate (ORR) of 29%, clinical benefit rate of 45%, and disease control rate of 80% in relapsed/refractory multiple myeloma; and c) the maximum tolerated dose has not been reached. Thus, a dose of 0.3 to 1.3 mg is known to be clinically effective.
There is a reasonable expectation of success because: 1) Lonial Blood taught: a) the clinical dosing of the CELMoD Iberdomide (CC-220) ranges from 0.3 to 1.3 mg; b) clinical activity has been observed across all dose levels with an overall response rate (ORR) of 29%, clinical benefit rate of 45%, and disease control rate of 80% in relapsed/refractory multiple myeloma; and c) the maximum tolerated dose has not been reached. Thus, a dose of 0.3 to 1.3 mg is known to be clinically effective.
This would produce a method of effectively treating a human subject with a human CD19 expressing cancer, comprising administering the subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and concurrent or delayed dosing of:
a) 0.3 to 1.3 mg (instant claim 28) of a compound that is (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione; and
b) a T cell therapy of two doses of liso-cel, which is an autologous CD8+ and CD4+ T cells expressing a CD19-specific chimeric antigen receptor (CAR),
wherein the (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione was dosed with each of dose of the liso-cel CAR T cells with delayed, subsequently initiated, or concurrent administration, which would start administration on Day 1, wherein the administration of liso-cel would initially occur on Day 1, wherein the two doses of (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione would thus be a plurality of intermittent doses, wherein the method would naturally inhibit or delay the onset of an exhaustion phenotype in CAR T cells in the subject following exposure of the T cells to CD19 antigen present on the target cancer cells in the subject as compared to the absence of said administration of said compound (instant claims 91 and 95), wherein the exhaustion phenotype, with reference to a T cell or population of T cells, naturally comprises: an increase in the level of surface expression on T cells of one or more exhaustion markers of one or more exhaustion markers is selected from among PD-1, CTLA-4, TIM-3, LAG-3, BTLA, 2B4, CD160, CD39, VISTA, and TIGIT by about or greater than 1.2-fold or a decrease in the level of proliferation activity exhibited by CAR T cells upon exposure to CD19 antigen present on the target cancer cells in the subject compared to a reference T cell population under the same conditions wherein the decrease in the level is about or greater than 1.2 fold, wherein the reference T cell population is a population of T cells known to have a non-exhausted phenotype, and wherein initiation of the administration of the compound carried out subsequently to the administration of the T cell therapy and, following administration of the compound or initiation thereof, the subject naturally exhibits a restoration or rescue of an antigen- or tumor-specific activity or function of the CAR-expressing T cells in said subject, wherein at least 35% of subjects treated according to the method naturally achieve a complete response (CR) that is durable (instant claim 88).
Response to Arguments
Applicant’s arguments regarding Jessup, Matyskiela, and Alexander are discussed above. Further, the obvious rational is above and details the obviousness and reasonable expectation of success.
The rejection of claims 1, 3, 11, 17, 22, 28, 42-44, 49, 52, 54, 58, 61, 69, 74, 77, 87-88, 91, 95 under 35 U.S.C. 103 as being unpatentable over Jessup HK et al. (Cancer Res (2019) 79 (13_Supplement): 2320 reference of record), Matyskiela ME et al. (J. Med. Chem. 2018, 61, 2, 535–542 reference of record), US 2019/0322647 (Alexander MD et al. IDS reference), and Lonial S et al. (Blood (2019) 134 (Supplement_1): 3119 reference of record) as applied to claims 1, 3, 11, 17, 28, 42-43, 52, 54, 58, 61, 69, 74, 77, 87-88, 91, and 95 above, and further in view of Lonial S et al. (J Clin Oncol 2019 37, Number 15_suppl 8006 reference of record) and Kurtin S et al. (J Adv Pract Oncol. 2012 Jul 1;3(4):209–224 reference of record) is maintained.
Jessup, Matyskiela, ’647, and Lonial Blood are described above.
Jessup does not teach: 1) administration of the CELMoD compound for at least 12 weeks, wherein a plurality of doses are given over the 12 weeks; and 2) suspension of administration if the subject exhibits a toxicity following the administration of the compound, wherein the toxicity is severe thrombocytopenia or severe neutropenia and administration of the compound is restarted after the subject no longer exhibits toxicity, but this is obvious in view of Lonial JCO and Kurtin.
Lonial JCO taught: a) the clinical dosing of the CELMoD Iberdomide (CC-220) ranges from 0.3 to 1.3 mg; b) patients were dosed for more than 12 weeks with the CELMoD with daily administration for 21 days in a 28 day cycle; and c) favorable efficacy and safety of the CELMoD Iberdomide (CC-220) in heavily pretreated pts with RRMM who failed multiple prior therapies (abstract). Lonial JCO taught Grade 3–4 neutropenia and thrombocytopenia occurred in 26% and 11%, of patients administered the CELMoD Iberdomide (CC-220), respectively (abstract).
Kurtin taught myeloid cytopenias, including neutropenia, thrombocytopenia, and anemia, are the most common manifestations of treatment-related myelotoxicity and one of the most common reasons for dose modifications, dose delays, or discontinuation of therapy (abstract).
Regarding instant claims 22, 44, and 49, it would have been obvious for a person having ordinary skill in the art to take the method of Jessup, Matyskiela, ’647, and Lonial Blood above for treating a human subject with a human CD19 expressing cancer comprising administering the subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and concurrent or delayed dosing of:
a) 0.3 to 1.3 mg of a compound that is (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione or a pharmaceutically acceptable salt form; and
b) a T cell therapy of two doses of liso-cel, which is an autologous CD8+ and CD4+ T cells expressing a CD19-specific chimeric antigen receptor (CAR),
wherein the (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione was dosed with each of dose of the liso-cel CAR T cells with delayed, subsequently initiated, or concurrent administration, which would start administration on Day 1, wherein the administration of liso-cel would initially occur on Day 1, wherein the two doses of (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione would thus be a plurality of intermittent doses – and:
1a) administer the CELMoD compound for at least 12 weeks after the CAR T cell administration, wherein a plurality of doses are given over the 12 weeks in view of Lonial JCO;
1b) administer only one dose of liso-cel CAR T cells in view of a plurality of the CELMoD dosing above would be expected to block CAR T cell exhaustion.
2) suspend administration if the subject exhibits a toxicity following the administration of the compound, wherein the toxicity is severe thrombocytopenia or severe neutropenia and administration of the compound is restarted after the subject no longer exhibits toxicity in view of Lonial JCO and Kurtin;
This is obvious because:
1a) Lonial JCO taught: a) the clinical dosing of the CELMoD Iberdomide (CC-220) ranges from 0.3 to 1.3 mg; b) patients were dosed for more than 12 weeks with the CELMoD with daily administration for 21 days in a 28 day cycle; and c) favorable efficacy and safety of the CELMoD Iberdomide (CC-220) in heavily pretreated pts with RRMM who failed multiple prior therapies. Thus, treatment of patients for more than 12 weeks with a CELMoD was effective and would continue to prevent CAR T cell exhaustion when used in combination;
1b) only one dose of liso-cel CAR T cells would be necessary in view of a plurality of the CELMoD dosing above would be expected to block CAR T cell exhaustion;
2a) Lonial JCO taught Grade 3–4 neutropenia and thrombocytopenia occurred in 26% and 11%, of patients administered the CELMoD Iberdomide (CC-220), respectively; and
2b) Kurtin taught myeloid cytopenias, including neutropenia, thrombocytopenia, and anemia, are the most common manifestations of treatment-related myelotoxicity and one of the most common reasons for dose modifications, dose delays, or discontinuation of therapy. Thus, neutropenia and thrombocytopenia are known to occur when patients are administered a CELMoD and a dose delay is a clinically used method for patients with neutropenia and thrombocytopenia.
There is a reasonable expectation of success because: This is obvious because:
1a) Lonial JCO taught: a) the clinical dosing of the CELMoD Iberdomide (CC-220) ranges from 0.3 to 1.3 mg; b) patients were dosed for more than 12 weeks with the CELMoD with daily administration for 21 days in a 28 day cycle; and c) favorable efficacy and safety of the CELMoD Iberdomide (CC-220) in heavily pretreated pts with RRMM who failed multiple prior therapies. Thus, treatment of patients for more than 12 weeks with a CELMoD was effective and would continue to prevent CAR T cell exhaustion when used in combination;
1b) only one dose of liso-cel CAR T cells would be necessary in view of a plurality of the CELMoD dosing above would be expected to block CAR T cell exhaustion;
2a) Lonial JCO taught Grade 3–4 neutropenia and thrombocytopenia occurred in 26% and 11%, of patients administered the CELMoD Iberdomide (CC-220), respectively; and
2b) Kurtin taught myeloid cytopenias, including neutropenia, thrombocytopenia, and anemia, are the most common manifestations of treatment-related myelotoxicity and one of the most common reasons for dose modifications, dose delays, or discontinuation of therapy. Thus, neutropenia and thrombocytopenia are known to occur when patients are administered a CELMoD and a dose delay is a clinically used method for patients with neutropenia and thrombocytopenia.
This would produce a method of effectively treating a human subject with a human CD19 expressing cancer, comprising administering the subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and concurrent or delayed dosing of:
a) 0.3 to 1.3 mg of a compound that is (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione or a pharmaceutically acceptable salt form; and
b) a T cell therapy of one dose of liso-cel, which is an autologous CD8+ and CD4+ T cells expressing a CD19-specific chimeric antigen receptor (CAR), wherein the (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione was dosed with the liso-cel CAR T cells with delayed, subsequently initiated, or concurrent administration, which would start administration on Day 1, wherein the administration of liso-cel would initially occur on Day 1, wherein the CELMoD compound is dosed for a plurality of doses for at least 12 weeks after CAR T cell administration to prevent CAR T cell exhaustion (instant claim 22), wherein administration is suspended if the subject exhibits a toxicity following the administration of the compound, wherein the toxicity is severe thrombocytopenia or severe neutropenia and administration of the compound is restarted after the subject no longer exhibits toxicity (instant claims 44 and 49).
Response to Arguments
Applicant’s arguments regarding Jessup, Matyskiela, and Alexander are discussed above. Further, the obvious rational is above and details the obviousness and reasonable expectation of success.
The rejection of claims 1, 3, 11, 17-18, 22, 24, 28, 42-44, 49, 52, 54, 58, 61, 69, 73-74, 77, 87-88, 91, and 95 under 35 U.S.C. 103 as being unpatentable over Jessup HK et al. (Cancer Res (2019) 79 (13_Supplement): 2320 reference of record), Matyskiela ME et al. (J. Med. Chem. 2018, 61, 2, 535–542 reference of record), US 2019/0322647 (Alexander MD et al. IDS reference), Lonial S et al. (Blood (2019) 134 (Supplement_1): 3119 reference of record), Lonial S et al. (J Clin Oncol 2019 37, Number 15_suppl 8006 reference of record), and Kurtin S et al. (J Adv Pract Oncol. 2012 Jul 1;3(4):209–224 reference of record) as applied to claims 1, 3, 11, 17, 22, 28, 42-44, 49, 52, 54, 58, 61, 69, 74, 77, 87-88, 91, and 95 above, and further in view of WO 2018/204427 (Ports et al. IDS reference) is maintained.
Jessup, Matyskiela, ’647, Lonial Blood, Lonial JCO, and Kurtin are described above.
Jessup does not teach: 1) intravenous injection of a T cell therapy; 2) treating with a CELMoD once per week, but this is obvious in view of ‘427.
‘427 taught an immunomodulatory compound, such as a structural or functional analog or derivative of thalidomide and/or an inhibitor of E3 ubiquitin ligase, e.g. lenalidomide, promotes continued function and/or survival of cells of a T cell therapy (e.g. CAR-T cells) after activation, including after encounter with antigen, wherein, lenalidomide increases the ability of such T cells to persist or function long-term, such as by preventing exhaustion or cell death (page 53, [0200]). ‘427 taught combination treatment of CAR T cells and lenalidomide resulted in a greater degree of target cancer cell killing by CAR T cells compared to CAR T cells alone, wherein the results were consistent with a role of lenalidomide in promoting continued function and/or survival (such as by preventing exhaustion or cell death) of CAR-T cells after initial activation (page 216, [0638] and Fig. 1). ‘427 taught lenalidomide as reducing exhaustion-like phenotype in the antigen pre-stimulated CAR-T cells. (page 239, [0707] and Fig. 24). ‘427 taught intravenous injection of CAR T cells was effective for cancer treatment (page 226, [0671] and Table E3). ‘427 taught weekly administration of the CELMoD lenalidomide prior to or subsequently to initiation of administration of the T cell therapy (page 100, [0347]). ‘427 taught the combination therapy can include one or more screening steps for continuing the combination therapy, and/or monitoring treatment outcomes, wherein the screening step and/or assessment of treatment outcomes can be used to determine the dose, frequency, duration, timing and/or order of the combination therapy provided (page 158, [0550]).
Regarding instant claims 18 and 24, it would have been obvious for a person having ordinary skill in the art to take the method of Jessup, Matyskiela, ’647, Lonial Blood, Lonial JCO, and Kurtin above of effectively treating a human subject with a human CD19 expressing cancer, comprising administering the subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and concurrent or delayed dosing of:
a) 0.3 to 1.3 mg of a compound that is (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione or a pharmaceutically acceptable salt form; and
b) intravenous injection of a T cell therapy of one dose of liso-cel, which is an autologous CD8+ and CD4+ T cells expressing a CD19-specific chimeric antigen receptor (CAR),
wherein the (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione was dosed with the liso-cel CAR T cells with delayed, subsequently initiated, or concurrent administration, which would start administration on Day 1, wherein the administration of liso-cel would initially occur on Day 1, wherein the CELMoD compound is dosed for a plurality of doses for at least 12 weeks after CAR T cell administration to prevent CAR T cell exhaustion, wherein administration is suspended if the subject exhibits a toxicity following the administration of the compound, wherein the toxicity is severe thrombocytopenia or severe neutropenia and administration of the compound is restarted after the subject no longer exhibits toxicity – and:
1) Inject the CAR T cells intravenously in view of ‘427; and
2) treating with a CELMoD once per week in view of ‘427.
This is obvious because ‘427 taught combination treatment of CAR T cells and the CELMoD lenalidomide resulted in a greater degree of target cancer cell killing by CAR T cells and decreased CAR T cell exhaustion and:
1) Intravenous injection of CAR T cells is effective in view of ‘427; and
2a) ‘427 taught weekly administration of the CELMoD lenalidomide prior to or subsequently to initiation of administration of the T cell therapy;
2b) ‘427 taught the combination therapy can include one or more screening steps for continuing the combination therapy, and/or monitoring treatment outcomes, wherein the screening step and/or assessment of treatment outcomes can be used to determine the dose, frequency, duration, timing and/or order of the combination therapy provided, Thus, monitoring for exhaustion is within the skill of a person having ordinary skill in the art to determine weekly dosing.
There is a reasonable expectation of success because ‘427 taught combination treatment of CAR T cells and the CELMoD lenalidomide resulted in a greater degree of target cancer cell killing by CAR T cells and decreased CAR T cell exhaustion and:
1) Intravenous injection of CAR T cells is effective in view of ‘427;
2) ‘427 taught the combination therapy can include one or more screening steps for continuing the combination therapy, and/or monitoring treatment outcomes, wherein the screening step and/or assessment of treatment outcomes can be used to determine the dose, frequency, duration, timing and/or order of the combination therapy provided, Thus, monitoring for exhaustion with weekly dosing of the compound is within the skill of a person having ordinary skill in the art to determine weekly dosing.
This would produce a method of treating a human subject with a human CD19 expressing cancer, comprising administering the subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and concurrent or delayed dosing of:
a) 0.3 to 1.3 mg of a compound that is (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione or a pharmaceutically acceptable salt form; and
b) a weekly intravenous (instant claim 73) injection of a T cell therapy of one dose of liso-cel, which is an autologous CD8+ and CD4+ T cells expressing a CD19-specific chimeric antigen receptor (CAR),
wherein the (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2- fluoro-4-((3-morpholinoazetidin-l-yl)methyl)benzyl) amino)isoindoline-1,3-dione was dosed with the liso-cel CAR T cells with delayed, subsequently initiated, or concurrent administration, which would start administration on Day 1, wherein the administration of liso-cel would initially occur on Day 1, wherein the CELMoD compound is dosed for a plurality of doses once per week (instant claim 18) for at least 12 weeks after CAR T cell administration to prevent CAR T cell exhaustion, wherein the 12 week dose schedule would be on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85 (instant claim 24), wherein administration is suspended if the subject exhibits a toxicity following the administration of the compound, wherein the toxicity is severe thrombocytopenia or severe neutropenia and administration of the compound is restarted after the subject no longer exhibits toxicity.
Response to Arguments
Applicant’s arguments regarding Jessup, Matyskiela, and Alexander are discussed above. Further, the obvious rational is above and details the obviousness and reasonable expectation of success.
Conclusion
All claims are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
