Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 17, 2026 has been entered.
DETAILED ACTION
The amendment filed July 17, 2026 in response to the Office Action of January 20, 2026 is acknowledged and has been entered.
Claims 2 and 4 have been amended.
Claim 138 and 139 has been added.
Claims 2, 4, 7, 14, 18, 24, 26, 28, 31, 32, 34, 36, 37, 41-44, 53, 130-136, 138, and 139 are pending.
Claim 134 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 2, 4, 7, 14, 18, 24, 26, 28, 31, 32, 34, 36, 37, 41-44, 53, 130-133, 135, 136, 138, and 139 are currently under consideration as drawn to the elected invention.
Information Disclosure Statement
The Information Disclosure Statement filed July 17, 2026 has been considered and entered by examiner.
Claim Objections
Claim 2 is objected to because of the following informalities: “to the subject” at line 3 should be “to the human subject” for clarity. Appropriate correction is required.
Claim 2 is objected to because of the following informalities: “in the subject” at lines 3-4 should be “in the human subject” for clarity. Appropriate correction is required.
Claim 4 is objected to because of the following informalities: “to the subject” at line 2 should be “to the human subject” for clarity. Appropriate correction is required.
Claim 4 is objected to because of the following informalities: “wherein the subject” at line 5 should be “wherein the human subject” for clarity. Appropriate correction is required.
MAINTAINED/MODIFIED REJECTIONS
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.
Claims 2, 4, 7, 14, 18, 24, 26, 28, 31, 32, 34, 36, 37, 41-44, 53, 130-133, 135, 136, 138, and 139 are rejected under 35 U.S.C. 103 as being unpatentable over Li (Li et al., US 2019/0277858 A1, which has an effective filing date of 2015-12-04, of record) in view of Brogdon (Brogdon et al., US 2016/0068601 A1, Appl. No.:14/830,392, Publication Date: 2016-03-10, in IDS, of record), Teachey (Teachey et al., Cancer Discov., 6(6): 664-679, Publication Date: 2016-04-13, of record), Das (Das et al., Blood, Vol. 127, number 13, 1666-1675, Publication Date: 03/31/2016, of record) and Lee (Lee et al., Blood, vol. 124, number 2, 188-195, Publication Date: 07/10/2014, of record).
Li teaches treatment of toxicity such as CRS or severe CRS ([0004]).
Li teaches methods of ameliorating the development of toxicity, including severe CRS, in a subject following administration of a CAR-T cell therapy. See [0006].
Li teaches methods of identifying subject is at risk for developing the toxicity and administering to the subject an agent or therapy that is capable of treating, preventing, delaying, or attenuating the development of the toxicity. See [0006].
Li teaches methods that are based on observations that certain biomarkers, such as certain cytokine biomarkers, are significantly altered as early as day 1 after administration of an adoptive cell therapy, e.g. CAR-T cell therapy in those patients who later developed a severe toxicity, CRS or neurotoxicity. Thus, such biomarkers as described herein can be used in predictive methods to identify subjects that are likely or more likely to develop a severe toxicity to the cell therapy in order to be able to intervene earlier in the treatment of the subject to reduce later severe toxicity. Such methods can inform rational strategies for early intervention and thereby facilitate the safe and effective clinical application of adoptive cell therapy, such as CAR-T cell therapy. See [0120].
Li teaches that higher IL-6, IL-15, IL-8, IL-10 and interferon-γ levels are associated with severe CRS. See [0069].
Li teaches that the subject is a human subject ([0312], [0656])
Li teaches that the agent that treats, prevents, delays, or attenuates the development of severe CRS, e.g. tocilizumab, tofacitinib, ruxolitinib. See [0088], claims 152, 180. One of ordinary skill in the art would have known that severe CRS is grade 4 or 5 CRS, as evidenced by paragraph [1001] of the instant publication (US 2019/0336504 A1), and the second paragraph of col. 1 on page 666 of Teachey.
Li teaches that the agent that treats or ameliorate CRS toxicity is a JAK/STAT inhibitor, e.g. ruxolitinib, tofacitinib. See [0409]. Li teaches that a JAK/STAT inhibitor can be administered at a dose of 4 mg or 8 mg. See [0397-0398].
Li teaches that the agent that treat CRS can be an antagonist or inhibitor of IL6 or IL-6 receptor (IL-6R), e.g. tocilizumab. See [0401].
Li teaches compositions containing the CAR or TCR, and the agents that treat or ameliorate symptoms of CRS. See [0412].
Li teaches various embodiments to using the compositions to treat CRS. See [0571-0574], [0642-0646] in particular.
Li teaches various CAR T cell therapies, including CAR targeting CD123. See [0248-0252].
Li teaches a transmembrane domain, an intracellular signaling domain of CAR. See [0257-0258].
Li teaches as set forth above, Li does not teach treating with the JAK-STAT inhibitor ruxolitinib in combination with a CAR therapy, without impairing the anti-tumor effect of the CAR therapy, or the subject has been treated with tocilizumab.
Brogdon teaches a method of CAR-therapy to treat a disease or condition associated expression of CD123 ([0003]), a B cell antigen that is expressed on B cells. See [0291] and as evidenced by the instant specification (page 3, line 8).
Brogdon teaches the CAR comprises an anti-CD123 binding domain, a transmembrane domain, and an intracellular signaling domain ([0006]).
Brogdon teaches the method of treating a patient having a cancer associated with expression of CD123, or at risk of having a cancer associated with expression of CD123, using CD123 CAR-expressing cell ([0697]).
Brogdon teaches that the method can be used to treat hematologic diseases, including myelofibrosis ([0723]). Brogdon teaches B cell leukemia and lymphoma. See [0713] and [0742] and Example 7.
Brogdon teaches the CAR comprises an anti-CD123 binding domain, a transmembrane domain, and an intracellular signaling domain (claims 1-10, 12, 14-23).
Brogdon teaches that the subject can be administered an agent which reduces or ameliorates a side effect associated with the administration of a CAR-expressing cell. Side effects associated with the administration of a CAR-expressing cell include, but are not limited to CRS, and hemophagocytic lymphohistiocytosis (HLH), also termed Macrophage Activation Syndrome (MAS). Symptoms of CRS (cytokine release syndrome) include high fevers, nausea, transient hypotension, hypoxia, and the like. CRS may include clinical constitutional signs and symptoms such as fever, fatigue, anorexia, myalgias, arthalgias, nausea, vomiting, and headache. See ¶ [0833].
Brogdon teaches that accordingly, the methods described herein can comprise administering a CAR-expressing cell described herein to a subject and further administering one or more agents to manage elevated levels of a soluble factor resulting from treatment with a CAR-expressing cell. In one embodiment, the soluble factor elevated in the subject is one or more of IFN-γ, TNFα, IL-2 and IL-6 . . . Therefore, an agent administered to treat this side effect can be an agent that neutralizes one or more of these soluble factors. In one embodiment, the agent that neutralizes one or more of these soluble forms is an antibody or antigen binding fragment thereof. Examples of such agents include, but are not limited to a steroid (e.g., corticosteroid), an inhibitor of TNFα, and an inhibitor of IL-6 . . . An example of an IL-6 inhibitor is an anti-IL-6 antibody molecule such as tocilizumab (toc), sarilumab, elsilimomab, CNTO 328, ALD518/BMS-945429, CNTO 136, CPSI-2364, CDP6038, VX30, ARGX-109, FE301, and FM101. In one embodiment, the anti-IL-6 antibody molecule is tocilizumab. See ¶ [0834].
Brogdon does not teach administering a JAK-STAT inhibitor in combination with CAR-therapy, without impairing the anti-tumor effect of the CAR therapy.
Teachey teaches that cytokine release syndrome (CRS) is the most common severe toxicity seen after CAR T-cell treatment. See Abstract-Significance.
Teachey teaches that CRS can be successfully ameliorated with IL6R inhibitor tocilizumab, and its use has become commonplace after T-cell-engaging therapies. See page 665, col. 1, para. 2.
Teachey teaches that 24 cytokines, including IL6 were highly associated with CRS 4-5 compared to CRS 0-3. See Fig. 1. IFNγ, IL6, and sIL2Rα show a marked differential increase in patients with severe CRS as compared with patients without severe CRS. See page 674, col. 1, para. 1.
Teachey teaches models that can predict which patients treated with CAR T cells are likely to become critically ill, sIL6R and sgp130 are likely clinically and biologically relevant. See page 672, col. 1, para. 4. The ability to predict which patients may develop severe CRS prior to its development may be helpful in mitigating toxicity, as cytokine-directed therapy could be instituted before a patient becomes critically ill. See page 672, col. 2, para. 3.
Teachey teaches that IL6-directed therapy is the cornerstone of cytokine-based therapy after treatment with CAR T cells. It has been shown to be effective and, importantly, does not appear to decrease efficacy of the CAR T cells. See page 675, col. 1, para. 2.
Teachey teaches that trans-IL6 signaling activates JAK/STAT pathway. See page 675, col. 1, para. 3.
Das teaches that resembling CRS, hemophagocytic lymphohistiocytosis (HLH) is characterized by the excessive production of cytokines, including interferon-γ, IL-2, IL-6, and IL-10 (see Abstract, and page 1666, col. 2, para. 1).
Das teaches that multiple cytokines (including interferon-γ, IL-2, IL-6) signal through Janus kinases (JAKs) (page 1666, col. 2, para. 2).
Das teaches that JAK1/2 inhibitor ruxolitinib reduce levels of interferon-γ, IL-2, IL-6 (see Fig. 2A).
Das teaches that mice were treated or not with ruxolitinib, 90 mg/kg twice daily by oral gavage starting on day 4. This dose results in a peak serum level of 3 to 4 mM, which is similar to a 25-mg oral dose in humans. See p. 1667- CpG-induced model of secondary HLH.
Das teaches that ruxolitinib reduced T-cell cytokine production but does not impair degranulation or cytotoxicity (see Fig. 6, and the bridging paragraph of cols. 1-2 on page 1670).
Das teaches that ruxolitinib is effective for hemophagocytic lymphohistiocytosis (HLH) (see § Ruxolitinib lessens the manifestations and enhances survival in LCMV-induced HLH, on pages 1670-1671).
Das teaches that blockade of IL-6 through use of tocilizumab, a monoclonal antibody recognizing the IL-6 receptor, results in rapid reversal of CRS in patients receiving T-cell-based immunotherapies. Therefore the combination of ruxolitinib with tocilizumab may prove even more beneficial as therapy for HLH. Ruxolitinib has a short half-life and its effects can be readily titrated. Consequently, it should be possible to identify a dose that does not abrogate JAK function, but instead allows for some degree of cytokine signaling. This residual signaling could minimize immune suppression. In addition, ruxolitinib is US FDA approved and has a well-defined toxicity profile. The clinical translation could thus be accelerated through the use of this agent, which has already been thoroughly tested in children and adults (see the bridging paragraph of cols. 1-2 on page 1674).
Lee teaches that CRS is associated with elevated levels of several cytokines (Abstract). Consistent with this Lee teaches that grade 3 and severe CRS patients have elevated IL-5, IL-10, IL-6 and interferon-γ (page 189, col. 1, para. 1; and page 189, col. 2, para. 2).
Lee teaches treating grade 2, 3, and 4 CRS patients with tocilizumab (Fig. 2).
It would have been prima facie obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the method of Li to use a JAK-STAT inhibitor, such as ruxolitinib, in the CAR-therapy, to prevent or treat CRS or severe CRS (e.g. grade 4 CRS) associated with CAR-T therapy, as taught by Li, and applied to the method to treat a CD123 associated disease, e.g. B-cell leukemia and lymphoma or MF, with a CD123-targeted CAR-T therapy, as taught by Brogdon because CD123 is expressed in B-cell leukemia and anti-CD123 CART cells are active against human B-ALL in vitro and in vivo (see Example 7 – Results). Based on the teaching of Teachey and Das, one ordinary skill in the art would have recognized that ruxolitinib could be effective in treating CRS without impairing efficacy of the CAR T cells, because JAK/STAT can inhibit IL-6 signaling and does not decrease efficacy of the CAR T cells ruxolitinib reduced T-cell cytokine production but does not impair cytotoxicity. One of skill in the art would have known to adjust dosage and/or schedule of ruxolitinib administration to maintain anti-tumor effect of the CAR-expressing cell, as recognized by Das. One of ordinary skill in the art would have applied the treatment to a subject (e.g. subjects with grade 3 or 4 CRS as taught by Lee) who has been treated with tocilizumab (essentially substituting tocilizumab with ruxolitinib), because Das teaches: 1) tocilizumab is specific for IL-6 signaling, but ruxolitinib inhibit JAK signaling pathway which regulated multiple cytokines (such as IL-6 and interferon-γ), thus ruxolitinib may be more effective than tocilizumab; 2) ruxolitinib does not impact T-cell toxicity; 3) ruxolitinib has a short half-life and its effects can be readily titrated; 4) ruxolitinib is effective for HLH, a condition resembling CRS; 5) ruxolitinib is well-tested and FDA approved; and Lee teaches that both grade 3 and severe CRS have higher levels of multiple cytokines (such as IL-6 and interferon-γ). Based on the teachings of the references, one of ordinary skill in the art would have a reasonable expectation that ruxolitinib would be effective and safe for a tocilizumab-treated subject with grade 3 and 4 CRS. Given that ruxolitinib and CART therapy are well known in the art, as evidenced by the references one of skill in the art would have had a reasonable expectation of success of using the compounds in combination. The motivation would have been to expand the options for treating CRS (including grade 3 and grade 4 CRS) and to develop a better and safer treatment for CRS. Regarding to the specific administration regimen: a dose of 5-10mg twice daily, one of skill in the art could modify the dose of antibody depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like to reach the specific regimens as claimed. In addition, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Regarding claims 14 and 18, in combination administration, the JAK-STAT inhibitor can only be administered sequentially, prior to, or concurrently to the CAR. And Li teaches that the agent is administered at a time which a clinical risk for CRS is detected to be present following the administration of cell therapy. In some embodiments, the agent is administered immediately prior to said administration of the cell therapy. In some embodiments, the agent is administered at a time at which the subject does not exhibit CRS, or does not exhibit CRS above grade 3. See [0374].
Regarding claims 130-133, Li teaches that T cells maybe autologous or allogeneic ([0308], [0314], [0363], Examples 1-4).
Regarding claims 24, 26, 28 and 31, applicant elected a specific CD123 binding domain comprising HC CDRs 1-3 of SEQ ID NO: 517 + 522 + 527 and LC CDRs 1-3 of SEQ ID NO: 532 + 537 + 542; e.g. SEQ ID NO: 480.
Brogdon teaches the same CD123 binding domain as SED ID NO: 480 of the instant claims (claim 32):
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Brogdon teaches the CD123 binding domain comprising HC CDRs 1-3 of SEQ ID NO: 517 + 522 + 527:
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Claim 32 recites the transmembrane domain comprises the amino acid of SEQ ID NO: 6 (the elected species). Brogdon teaches a transmembrane domain comprises SEQ ID NO:6 ([0338], claim 34), that is identical to the SEQ ID NO:6 of the instant claim:
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Claim 34 recites the CD 123 binding domain is connected to the transmembrane domain by a hinge region, comprising SEQ ID NO:2. Brogdon teaches an exemplary hinge/spacer sequence of SEQ ID NO:2 ([0338], claim 35), which is identical to the instant claim:
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Regarding claim 36, Brogdon teaches the encoded intracellular domain comprises a costimulatory domain, wherein the co stimulatory domain comprises a functional signaling domain obtained derived from a protein selected from the group consisting of a MHC class I molecule, a TNF receptor protein, an Immunoglobulin-like protein, a cytokine receptor, an integrin, a signaling lymphocytic activation molecule (SLAM protein), an activating NK cell receptor, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CDlla/CD18), 4-lBB (CD137), B7-H3, CDS, ICAM-1, ICOS(CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRFl), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL 7R alpha, ITGA4, VLAl, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDlld, ITGAE, CD103, ITGAL, CDlla, LFA-1, ITGAM, CDllb, ITGAX, CDllc, ITGBl, CD29, ITGB2, CD18, LFA-1, ITGB7,
NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAMl (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAMl, CRTAM, Ly9 (CD229), CD160 (BY55), PSGLl, CDl00 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMFl, CD150, IPO-3), BLAME (SLAMFS), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, and a ligand that specifically binds with CD83 (claim 37).
Claim 37 recites the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 10 (the elected species). Brogdon teaches an intracellular signaling domain comprising the amino acid sequence of SEQ ID NO:10 (claims 40), which is identical to the instant claim:
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Regarding claim 41, Brogdon teaches that the CAR further comprises a leader sequence of SEQ ID NO:1, which is identical to the instant claim:
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Regarding claim 42, Brogdon teaches the CAR comprises SEQ ID NO:99 (claim 43), alignment between the instant SEQ ID NO: 99 (elected species) and SEQ ID NO:99 of Brogdon shown below:
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Regarding claim 44, Brogdon teaches a vector comprising the nucleic acid molecule of the CAR, wherein the vector is a DNA vector, an RNA vector, a plasmid, a lentivirus vector, adenoviral vector or a retrovirus vector (claim 46)
Regarding claims 43, Brogdon teaches an immune effector cell (e.g. T cells or NK cells) comprising the nucleic acid molecules of a CAR, and a method of making an immune effector cell, comprising transducing the immune effector cell with the vector of a CAR ([0003], claims 49 and 50).
Response to Arguments
For the rejections under 35 U.S.C. 103, Applicant argues:
Li does not teach or suggest a ruxolitinib dose of 5-10 mg twice daily, as required by the instant claims; in fact Li does not teach any particular dose of ruxolitinib. In addition, none of Brogdon, Teachey, or Lee supply these teachings, as none of Brogdon, Teachey, or Lee recite ruxolitinib. Therefore, none of Li, Brogdon, Teachy, or Lee, alone or in combination, teach or suggest the presently claimed methods.
Das does not remedy the deficiencies of Li, Brogdon, Teachy, and Lee, as Das does not recite a dose of ruxolitinib of 5-10 mg twice daily. Accordingly, the presently claimed methods are not taught or suggested by the cited publications, alone or in combination, and the claims are nonobvious over the cited publications for this reason alone.
Moreover, Das relates to hemophagocytic lymphohistiocytosis (HLH), which was modeled using PrJ1-1-/- mice which were infected with LCMV. There is no teaching in Das to indicate that the effects observed in the experiments of Das using a model of HLH would be readily applicable to treatment of grade 3 or 4 CRS, which is associated with a CAR-expressing cell. As such, the skilled artisan would not be motivated to combine Das with Li, Brogdon, Teachey, and Lee.
Finally, none of the cited publications provide any data using ruxolitinib to treat CRS in any
subject, animal model, or ex vivo model system. For at least the reasons provided in previous
responses, it would not have been obvious to treat CRS with ruxolitinib at all, much less to do so for
the particular grades of CRS recited in the claims, without impairing the anti-tumor effect of the CAR-expressing cell as recited in the claims. The addition of a particular dosage regimen to the
claims provides still another point of non-obviousness.
Applicant’s arguments have been fully considered but they are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In addition, as set forth above, Li explicitly teaches that ruxolitinib can be used to treat CRS or severe CRS. Li provides methods of classifying CRS in patients, for example inflammatory cytokines can be used as biomarker for CRS. As set forth above, combining teachings from Li, Brogdon, Teachey, Das and Lee, one of ordinary skill in the art would have applied the treatment to a human subject (e.g. subjects with grade 3 or 4 CRS as taught by Lee) who has been treated with tocilizumab (essentially substituting tocilizumab with ruxolitinib). Although HLH is not CRS, but it is a condition resembling CRS. In addition, Das teaches many good properties associated with ruxolitinib: 1) tocilizumab is specific for IL-6 signaling, but ruxolitinib inhibit JAK signaling pathway which regulated multiple cytokines (such as IL-6 and interferon-γ), thus ruxolitinib may be more effective than tocilizumab; 2) ruxolitinib does not impact T-cell toxicity; 3) ruxolitinib has a short half-life and its effects can be readily titrated; 4) ruxolitinib is well-tested and FDA approved; and Lee teaches that both grade 3 and severe CRS have higher levels of multiple cytokines (such as IL-6 and interferon-γ). Taken together, based on all the teachings of Das and other references cited above, one of ordinary skill in the art would have reasonable expectation of success that ruxolitinib can be used for treatment of severe CRS without impairing the anti-tumor effect of the CAR-expressing cell. In addition, the combination of the reference teaches the same method (using ruxolitinib) of treating severe CRS, which would lead to the same impact on the anti-tumor effect of the CAR-expressing cell as instantly claimed.
Based on the teachings of the references, one of ordinary skill in the art would have a reasonable expectation that ruxolitinib would be effective and safe for a tocilizumab-treated subject with grade 3 and 4 CRS. Given that ruxolitinib and CART therapy are well known in the art, as evidenced by the references one of skill in the art would have had a reasonable expectation of success of using the compounds in combination. The motivation would have been to expand the options for treating CRS (including grade 3 and grade 4 CRS) and to develop a better and safer treatment for CRS.
Regarding to the specific administration regimen: a dose of 5-10mg twice daily, one of skill in the art could modify the dose of antibody depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like to reach the specific regimens as claimed. In addition, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Applicant further argues:
The application as filed and post-filing data demonstrate that ruxolitinib is effective for treating
severe CRS
In particular, Example 1 describes the development of a clinically relevant AML xenograft mouse model to study CRS. Example 1 further demonstrates that treatment with ruxolinitib ameliorated the CRS symptoms in these mice. For instance, "ruxolitinib treatment reduced levels of inflammatory cytokines (Figure 2F) and led to long-term disease free survival (figure 20)." These results provide evidence that ruxolitinib can be combined with CART cell therapy for the treatment of serious CRS. Grades 3 and 4 CRS are the two most serious forms of CRS, except for grade 5 which indicates the death of the subject.
In addition, post-filing data further demonstrates that ruxolitinib is effective at treating CRS after CART therapy with several additional types of CART in human patients. For instance, in Pan et al (J Cell Mol Med. 2021; 25: 1089-1099. https://doi.org/10.1111/jcmm.16176; submitted on November 20, 2025 as Exhibit C; hereinafter "Pan"), patients treated with either CD19 or CD22 CART therapy for relapsed/refractory B-ALL and that developed severe(>= grade 3) CRS which was not alleviated with tocilizumab and/or high-dose steroids were treated with ruxolitinib. These patients showed "[r]apid resolution of CRS symptoms" and "achieved complete remission on day 30 after infusion," while Pan "could still detect CAR T expansion in vivo despite usage of ruxolitinib." The dosage of ruxolitinib in this study was 5 mg twice a day.
In Zi et al. (Medicine 2021;100:19(e25786); submitted on November 20, 2025 as Exhibit D;
hereinafter "Zi"), a case study of a patient with B-ALL is presented. The patient developed CRS
after CD19/CD22 bispecific CAR-T treatment. Treatment with tocilizumab and methylprednisolone did not resolve the CRS symptoms, so ruxolitinib was administered to the patient; Zi states that "the symptoms associated with CRS were resolved rapidly" and "the levels of cytokines decreased dramatically in the following days." In addition, "expansion of the CAR-T cells in the peripheral blood was sustained"16 and the patient achieved complete remission. The patient was given ruxolitinib at 10 mg twice a day for 11 days, then 5 mg twice a day for 11 days.
Lastly, Li et al. (Clinical Cancer Research 2021;27:1242-6 submitted on November 20, 2025
as Exhibit E; hereinafter "Li 2") presents case studies of two patients with relapsed/refractory TALL.
Both patients developed Grade 3 CRS after treatment with CD7-targeted CAR cells. Ruxolitinib was administered to both patients and the CRS symptoms resolved. In addition, at days 21 and 30 for patient 1 and days 14 and 28 for patient 2 "[n]o evidence of disease was observed in bone marrow."17 Li 2 further states that "[a]s of data cutoff ... patient 1 remains in ongoing remission for over 1 year." Moreover, Li 2 states that "[r]obust expansion of CAR-T cells was observed in both patients," that "[f]requent ruxolitinib use did not seem to impact CART-cell expansion and efficacy of the CAR-T therapy," and that "[t]his is a critical finding for future approaches for the potential use of ruxolitinib for CRS prevention and management."
The results in the instant specification and the post-filing data in Pan, Zi, and Li 2 demonstrate that ruxolitinib can treat severe CRS associated with multiple types of CAR expressing cells and in patients with multiple types of cancers, without impairing the anti-tumor effect of the CAR-expressing cell. Moreover, Pan and Zi demonstrate that the recited dose of 5-l0 mg twice daily is effective in treating CRS.
Applicant’s arguments and post-filing data have been fully considered but they are not persuasive. As set forth above, combining teachings from Li, Brogdon, Teachey, Das and Lee, one of ordinary skill in the art would have reasonable expectation that ruxolitinib would be effective for grade 3 and grade 4 CRS, in particular, Das teaches that ruxolitinib reduced T-cell cytokine production but does not impair degranulation or cytotoxicity and is effective in treating hemophagocytic lymphohistiocytosis (HLH), which is a condition resembling CRS.
Example 1 of instant specification shows mice with a specific condition: AML treated with a specific CAR T cell therapy: CART123 in combination with ruxolitinib, wherein the mice has not been treated with tocilizumab. Treatment of ruxolitinib started on the day of CART123 injection and continued for a week before development of grade 3 or grade 4 CRS. The treatment with ruxolitinib reduced levels of inflammatory cytokines in mice of AML model. It is noted that the effective dosage for the reducing inflammatory cytokines (Fig. 2F) is 60mg/kg (also see [1090] and [1091]). This dosage is much higher that the dosage recited by the instant claims. Fig. 2G shows treatment with ruxolitinib leads to long term survival in the mice AML model, however, the effect is shown in only one example (AML model, CART123) which has not developed/shown grade 3 or grade 4 CRS and has been treated with 60 mg/kg ruxolitinib. Thus, Example 1 does not demonstrate that treatment with ruxolitinib would be able to treat grade 3 or grade 4 CRS in a subject associated with all CART therapies with ruxolitinib at a dosage of 5-10mg twice daily.
Pan teaches treating severe CRS induced by CD19 or CD22 targeting CAR T cells in four patients with a dosage 5 mg twice daily (B-ALL patients, see Table 1). Zi teaches treating CD19/CD22 severe CRS induced by CD19/CD22 targeting CAR T cells in one B-ALL patient with a dosage of 10 mg twice a day for 11 days, then 5 mg twice a day for 11 days. Li2 teaches treating severe CRS induced by CD7 targeting CAR T cells in 2 patients (T-ALL) with an adjustable dosage regimens, comprising mainly 5 mg of ruxolitinib three times daily, twice daily, or once daily (Fig. 1D). For the two patients, different dosages were used. In addition, the CAR T cells respond to ruxolitinib differently. For example, Pan teaches that CAR T cell level quickly dropped after ruxolitinib treatment, implicating that ruxolitinib can suppress CAR T cell expansion in vivo (see page 1097, col. 2, para. 1; and Fig. 2D). However, Li2 teaches that robust expansion of CAR-T cells was observed in ruxolitinib treated patients (page 1243, the bottom paragraph of col. 2). Taken together, Pan, Zi, and Li2 showed: 1) dosage of ruxolitinib is adjusted based on the disease, CAR T cells used, and patient conditions to achieve the best results; 2) different CAR T cells respond differently to ruxolitinib (e.g. CAR T cells of Pan vs. CAR T cells of Li2). The claims encompass a broad genus of CAR-expressing cells, including different CAR constructs and different cell types. The evidence of nonobviousness must be commensurate in scope with the claims to rebut the prima facie case of obviousness. See MPEP 716.02 (d). Taken together, Examples of the instant specification and post-filing data are not sufficient to overcome obviousness rejection set forth above.
NEW REJECTIONS
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 18 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 18, which depends on claim 2, recites “(i) wherein the dose of the JAK-STAT inhibitor are administered twice a day (BID)”, as an alternative option. However, amended claim 2 recites “wherein the JAK-STAT inhibitor is administered at a dose of 5-10 mg twice daily”. Thus, claim 18 fails to further limit the subject matter of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Conclusion
No claims are allowed.
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/CHENG LU/ Examiner, Art Unit 1642
/PETER J REDDIG/Primary Examiner, Art Unit 1646
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