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
Amendments
In the reply filed 12/12/2025, Applicant has amended claim 7, newly canceled claim 8, and added new claims 13-15.
Claim Status
Claims 1-7 and 9-15 are pending.
Claims 1-6 and 9-12 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/23/2025.
Claims 7 and 13-15 are considered on the merits.
Withdrawn Claim Objections
The prior objection to claim 7 because of improper use of abbreviation is withdrawn in light of Applicant’s amendment to the claim.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of claim 7 under 35 U.S.C. 102 (a)(1) as being anticipated by Mihara et al is withdrawn in light of Applicant’s amendment to claim 7 to recite new limitations of a nicotinamide adenine dinucleotide (NAD+) precursor agonist, which is not taught by Mihara.
New Claim Rejections - 35 USC § 103
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 7 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Rabinowitz (WO 2019/006003 A1, published 03 January 2019).
With respect to claim 7, it is noted that the limitation “for the treatment of chronic myelogenous leukemia overexpressing CD19" is interpreted as intended use. MPEP 2111.02 II states “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention' s limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. Thus, the limitation “for the treatment of chronic myelogenous leukemia” is reasonably interpreted as a combination preparation that is capable of performing the intended use of “the treatment of chronic myelogenous leukemia overexpressing CD19” as recited in the preamble.
Furthermore, it is also noted that the phrase “a NAD+ precursor agonist” is not specially defined in the specification, with the closest disclosure being “for another example, the NAD+ precursor agonist may include but is not limited to one or more of Nicotinamide (NAM), nicotinic acid (NA), nicotinic acid mononucleotide (NAMN), tryptophan (TRP), Nicotinamide mononucleotide (NMN), quinolinic acid (QA), nicotinamide riboside (NR), etc” (p. 6, para 1). Therefore, under the broadest reasonable interpretation consistent with the specification, the phrase “a NAD+ precursor agonist” is interpreted as encompassing a substance that functions at a NAD+ precursor level and is “capable of increasing the intracellular level of NAD+ and/or increasing the activity of NAD+” (specification, p. 5, last line – p. 6, line 1).
Rabinowitz teaches compositions comprising an ex vivo population of immune cells expressing an exogenous enzyme that enhances immune cell function in nutrient poor environments, such as tumor microenvironment (abstract and [0003]), thus teaches a combination preparation.
In regard to CAR-T cells, Rabinowitz teaches the immune cells are activated T cells (e.g., CAR-T, Th1, and/or Th17 cells) ([0022], also see e.g., [0017]-[0020], [0025] and Figs 3-5 for CAR-T cells). Rabinowitz further teaches the CAR-T cells can be designed to recognize an antigen(s) on tumor cells ([0036]) and teaches a list of tumor antigens and their associated indication(s) in the table in [0039], including CD19 (see [0039] table, 1st row). Thus, Rabinowitz suggests compositions comprising CAR-T cells that recognize tumor antigen CD19 and thus are capable of performing the claimed intended use of “the treatment of chronic myelogenous leukemia overexpressing CD19”.
In regard to a NAD+ precursor agonist, Rabinowitz teaches an exogenous enzyme (e.g., NADH oxidase) that catalyzes the oxidation of nicotinamide adenine dinucleotide, reduced form (NADH) to nicotinamide adenine dinucleotide, oxidized form (NAD+) (e.g., [0005], [0025], [0026]). It is noted that this exogenous enzyme NADH oxidase functions at a NAD+ precursor level (i.e., nicotinamide adenine dinucleotide, reduced form (NADH) that is a NAD+ precursor) and is “capable of increasing the intracellular level of NAD+” (i.e., catalyzes the oxidation of NADH to NAD+), thus is encompassed within the scope of the claimed “NAD+ precursor agonist”.
Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen CAR-T cells that recognize tumor antigen CD19 in combination with NADH oxidase that catalyzes the oxidation of NAD+ precursor NADH to NAD+ to obtain a combination preparation for the treatment of chronic myelogenous leukemia overexpressing CD19 with a reasonable expectation of success. Since Rabinowitz suggests CD19 as one tumor antigen for CAR-T cell targeting (see [0039] table, 1st row) and treatment of cancers such as Chronic Myelogenous Leukemia (see p. 24), and teaches increasing levels of oxidized NAD (NAD+) creates a more favorable metabolic environment for immune cell activation and as a consequence, the levels, activation state, and/or cytotoxic capacity of immune cells, including CAR-T, Th1, and/or Th17 cells, in tumor and tumor microenvironment are increased (e.g., [0022]), one of ordinary skill in the art would have had a reason to choose CD19 CAR-T cells in combination with a NAD+ precursor agonist (i.e., NADH oxidase) to obtain a combination preparation that has increased cytotoxicity to chronic myelogenous leukemia cells overexpressing CD19.
With respect to claim 15 directed to the CAR-T cells comprising anti-CD19-41BB CAR-T cells, as stated supra, Rabinowitz suggests anti-CD19 CAR-T cells designed to recognize tumor antigen CD19 (see [0039] table, 1st row, and [0036]). Rabinowitz teaches an endodomain of a CAR may comprise intracellular signaling domains from receptors such as 41BB, or may comprise multiple signaling domains such as CD3z-CD28-41BB (e.g., [0035]).
Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen a 41BB endodomain of a CAR to obtain anti-CD19-41BB CAR-T cells with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to choose a 41BB endodomain as suggested by Rabinowitz because it is a well-known and widely-used endodomain in making CAR-T cells, thus one of ordinary skill in the art would have immediately envisaged the taught option of a 41BB endodomain among the limited genus of options as taught by Rabinowitz. See MPEP 2131.02 (III).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 12/12/2025 are acknowledged.
Applicant firstly argues that Mihara does not teach each and every element of the amended independent claim 7, such as an NAD+ precursor agonist or a therapy for CD19-overexpressing chronic myeloid leukemia (CML) (p. 6, last 2 para.).
Applicant’s arguments have been fully considered and they are persuasive. Therefore, the prior rejection by Mihara is withdrawn. However, as necessitated by amendment, a new ground of rejection has been made over Rabinowitz, who makes obvious a combination preparation comprising anti-CD19 CAR-T cells and an NAD+ precursor agonist NADH oxidase as discussed above.
Furthermore, as stated supra, Applicant is reminded that the limitation “for the treatment of chronic myelogenous leukemia overexpressing CD19" is interpreted as intended use, and is examined as a combination preparation that is capable of performing the intended use of “the treatment of chronic myelogenous leukemia overexpressing CD19” as recited in the preamble.
Applicant further argues that the “NAD+ precursor agonist” in this Application is a small-molecule metabolic modulator that increases NAD+ levels through chemical pathways thereby enhancing T cell activation (p. 7, last para).
Applicant’s arguments have been fully considered but they are not persuasive. As stated supra, it is noted that the phrase “a NAD+ precursor agonist” is not specially defined in the specification, with the closest disclosure being “for another example, the NAD+ precursor agonist may include but is not limited to one or more of Nicotinamide (NAM), …, etc” (p. 6, para 1). Therefore, under the broadest reasonable interpretation consistent with the specification, the phrase “a NAD+ precursor agonist” is interpreted as encompassing a substance that functions at a NAD+ precursor level and is “capable of increasing the intracellular level of NAD+ and/or increasing the activity of NAD+” (specification, p. 5, last line – p. 6, line 1), such as NADH oxidase taught by Rabinowitz.
Applicant finally argues that this Application demonstrates the combination preparation (i.e., the combination of CAR-T therapy and metabolic enhancement) produces an unexpected synergistic effect (p. 8, emphasis added).
Applicant’s arguments have been fully considered but they are not persuasive. As stated supra, Rabinowitz clearly teaches increasing levels of oxidized NAD (NAD+) creates a more favorable metabolic environment for immune cell activation and as a consequence, the levels, activation state, and/or cytotoxic capacity of immune cells, including CAR-T, Th1, and/or Th17 cells, in tumor and tumor microenvironment are increased ([0022], emphases added). Thus, Applicant’s results of enhanced efficacy of CAR-T therapy and potent killing against CD19-expressing CML (Remarks, p. 8, end of the paragraph) are expected by the teaching of Rabinowitz.
Claims 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Rabinowitz (WO 2019/006003 A1, published 03 January 2019) in view of El Khal (US 2016/0067272 A1. Cited in IDS 09/07/2022).
Claims 13 and 14 are directed to the NAD+ precursor agonist comprising nicotinamide (NAM).
However, Rabinowitz is silent on the NAD+ precursor agonist being nicotinamide.
El Khal teaches a method for treating an immune disease (such as a cancer, see [0009]) in a subject by administering a composition comprising a therapeutically effective amount of NAD+ or an analog thereof (e.g., abstract and [0007]). El Khal teaches treatment with NAD+ or an analog thereof activates the CD4+ helper T cells (e.g., [0018], [0069]). El Khal teaches the NAD related compound is preferably nicotinamide or nicotinic acid, and more preferably nicotinamide, that is capable of entering the enzymatic pathways available in the mammalian body resulting in the production of NAD (e.g., [0083]), thus teaches claims 13 and 14.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combination preparation comprising CAR-T cells and NADH oxidase suggested by Rabinowitz, by substituting the NADH oxidase with a NAD-related compound nicotinamide as suggested by El Khal with a reasonable expectation of success. Since both Rabinowitz’s NADH oxidase and El Khal’s nicotinamide are for the same purpose (i.e., to increase levels of NAD+), these substances are art-recognized obvious equivalents to each other. Therefore, it would have been obvious for one of ordinary skill in the art to have substituted El Khal’s nicotinamide for Rabinowitz’s NADH oxidase. See MPEP 2144.06. Furthermore, since El Khal teaches all of these chemicals (referring to the NAD-related compounds) are commercially available ([0083]), one of ordinary skill in the art would have had a reason to substitute with a commercially available nicotinamide to combine with the CAR-T cells of Rabinowitz to simplify the manufacturing process and to reduce the cost.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 12/12/2025 are acknowledged and have been discussed above.
Conclusion
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Douglas (Doug) Schultz can be reached on (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631