DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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 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.
Priority
The instant application, filed 04/08/2020, is a 371 filing of PCT/US2018/057468, filed 10/25/2018, and claims domestic benefit to US provisional application numbers: 62/700,978, filed 07/20/2018; 62/693,517, filed 07/03/2018; 62/675,417, filed 05/23/2018; and 62/576,879, filed 10/25/2017.
Status of Application, Amendments, and/or Claims
Applicant’s response of 01/22/2026 is acknowledged. Claims 1, 8, 11-12, 15, 19-20, 24, 34, 40, and 60 are amended and claims 2-7, 9-10, 18, 21-22, 25, 28-33, 35-36, 38-39, 41-42, 44-45, 47, 49, and 51-58 are cancelled. Claims 1, 8, 11-17, 19-20, 23-24, 26-27, 34, 37, 40, 43, 46, 48, 50, and 59-60 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/22/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn Objections and Rejections
In the office action of 07/22/2025,
Claims 3 and 28 were objected to. The cancellation of the claims has rendered the objections moot and the objections are withdrawn.
Claims 15, 40-42, and 44-45 were objected to. Applicant’s amendment to claims 15 and 40 have overcome the objection of claims 15 and 40 and the objection is withdrawn. The cancellation of claims 42 and 44-45 have rendered the objection of claims 42 and 44-45 moot and the objections are withdrawn.
Claim 24 was objected to. Applicant’s amendment of the claim to recite “CD19” in place of “CD 19” has overcome the objection and the objection is withdrawn.
Claims 34-45, 50-52, and 56 were rejected under 35 USC 112(b). Applicant’s amendment to claim 34 to remove part (ii) and to remove the dosages from part (i) has overcome the rejections and the rejections are withdrawn.
Claims 4 and 29 were rejected under 35 USC 112(d). The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
Claims 5-7, 30-32, and 53-55 were rejected under 35 USC 112(d). The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
Claims 18-19 were rejected under 35 USC 112(d). The cancellation of claim 18 has rendered the rejection of claim 18 moot. The amendment to claim 19 to remove limitations in which the radiolabeled anti-CD45 antibody is administered after the CAR has overcome the rejection of claim 19 and the rejection is withdrawn.
Claims 25 and 33 were rejected under 35 USC 112(d). The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
Claim 56 was rejected under 35 USC 112(d). The cancellation of the claims has rendered the rejection moot and the rejection is withdrawn.
Claim 60 was rejected under 35 USC 112(d). Applicant’s amendment to make the claim an independent claim has overcome the rejection and the rejection is withdrawn.
The following grounds of objections and/or rejections are maintained or new or amended as necessitated by applicant’s amendment to the claims.
Drawing Objections
In the replacement drawings filed 01/22/2026, the text in figures 1B, 1C, 1D, 1E, and 3F is still low resolution and pixilated rending it difficult to read. Correction to make the text legible is required.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Interpretation
Independent claim 1 recites the limitation “depletes at least 50% of lymphocytes of the subject and depletes less than 10% of the neutrophils of the subject” and independent claim 34 recites the limitation “lymphodeplete the subject by at least 50% and wherein the non-myeloablative amount of a radiolabeled anti-CD45 antibody depletes less than 10% of the neutrophils of the subject”. The claims do not indicate a time frame for the limitations following administration of the radiolabeled anti-CD45 antibody, nor does the instant disclosure identify an applicable time frame.
In the instant office action, the limitations are interpreted as meaning that at any time point following administration, at least 50% of the lymphocytes must be depleted and at no time following administration can more than 10% of neutrophils be depleted.
Claim Objections
Claim 43 is objected to for the following informalities: the claims recite the antigen GD2 twice; once on line 4 as “GD2” and once on line 5 as “GD-2”. The extraneous “GD-2” should be removed. It is noted that GD2, without the dash, is the correct annotation for the tumor antigen.
It is also noted that, in the response, applicant has addressed the duplicate recitation in claims 15 and 40 but claim 43 still comprises the extraneous recitation. Applicant has not provided any specific arguments concerning the objection of claim 43.
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 20 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.
Claim 20 has been amended to depend on claim 1. The claim recites the limitation that the subject has not shown a CR after administration of “the population of cells expressing the CAR”, or the subject has relapsed or is identified as having relapsed after administration of “the population of cells expressing the CAR”. The antecedence of “the population of cells expressing the CAR” is unclear. The only recitation of “a population of cells expressing a CAR” prior to the instant claim is in the active step of claim 1, in which the cells are administered to a patient. While “the population of cells expressing the CAR” could be interpreted as having antecedence to this limitation in claim 1, claim 20 also recites “has not shown” suggesting prior administration of a population of cells expressing a CAR. It is unclear if it is applicant’s intention to claim a prior treatment with cells expressing a CAR or if applicant is claiming that the method of claim 1 results in the outcomes recited.
Appropriate correction/clarification is required.
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.
Claims 19 and 27 are 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 19, as amended, depends on claim 1 and recites the limitation that the effective amount of the anti-CD45 antibody is an amount sufficient to induce lymphodepletion in the subject. Claim 1, however, already requires that the amount be sufficient to induce lymphodepletion by stating that the subject is administered a single dose, “the single dose being sufficient to lymphodeplete the subject”. As such, claim 19 fails to further limit the claim upon which it depends.
Claim 27 depends on claim 26 and, ultimately, on claim 1. Claim 27 recites the limitation “wherein the radiolabeled anti-CD45 antibody is radiolabeled BC8.” Claim 1, as amended, requires that the radiolabeled antibody be 131I-BC8. As such, claim 27 fails to further limit the claim upon which it depends.
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.
Claim Rejections - 35 USC § 112 (a) – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 8, 11-17, 19-20, 23-24, 26-27, 34, 37, 40, 43, 46, 48, 50 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claims 1 and 34 are drawn to methods of treating a human subject having a hematological malignancy or solid cancer comprising administering an effective amount of 131I-BC8 at a dose of 20 mCi to 50 mCi where the effective amount is sufficient to lymphodeplete the subject but not induce myeloablation in the subject. Thereafter, an effective amount of a population of cells expressing a CAR are administered. The claims further recite the functional limitation that the effective amount of radiolabeled anti-CD45 antibody “depletes at least 50% of lymphocytes in the subject and depletes less than 10% of the neutrophils of the subject”.
The instant disclosure, however, does not provide a single species of the claimed method resulting in the claimed function. See MPEP 2173.05(g). Additionally, the disclosure does not identify a structure-function relationship that would allow a person of ordinary skill in the art to predictably identify under what conditions encompassed by the claims, the claimed function would be achieved.
In the examples of the instant disclosure, the radiolabeled antibody 131I-BC8, also known as Iomab-B, was studied using single use doses for complete infusion during i.v. administration containing patient specific doses of radioactivity from 1 mCi to 200 mCi of 131I and 6.66-45 mg of BC8. BC8 antibody dosage was determined according to the ideal body weight at a level of 0.5 mg/kg (pages 32-33, [0152]-[0153]).
Example 3, which is the only example that discloses the effect of a radiolabeled anti-CD45 antibody on neutrophils, discloses that it would have been expected that all CD45-positive cell types would be equally susceptible to depletion following dosing with 131I-BC8. Fig. 2 depicts the relative absolute neutrophil counts at various time points following a 10 mCi dose of 131I-BC8 presented as a fold-increase or decrease. The example does not disclose the amount of the BC8 antibody administered, only the radioactive dose. The example states that, while absolute lymphocyte counts were significantly reduced and exhibited sustained depletion over time, median absolute neutrophil counts exhibited a minimal decrease following 131I-BC8 dosing with rapid recovery. It is noted that the example does not provide data concerning the percentage of lymphocytes depleted at the 10 mCi studied dose. The example states that the limited impact of 131I-BC8 on neutrophils and their rapid rebound would be expected to benefit patients by preventing infections that might otherwise occur (page 34, [0158]-[0159]). Fig. 2 from the instant disclosure is replicated below for convenience:
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The figure, however, does not report the % of neutrophils or the absolute number of neutrophils depleted such that a % could be calculated. Rather, the figure reports a fold-increase or decrease.
Example 4 provides clinical data demonstrating lymphodepletion and clearance using 131I-BC8 and discloses immune cell analysis in Figs. 3A-3F. The radiation dosages shown in the figures include 50, 100, and 200 μCi, all of which are shown to decrease white blood cells by a median of at least 50%, suggesting that the, higher, claimed dosages would result in at least 50% depletion of white blood cells. These results, however, do not demonstrate which dosages would also result in depletion of less than 10% of the neutrophils of the subject or that the claimed method would result in such an outcome.
The results provided in the disclosure do not demonstrate a single species of the claimed administration resulting in both depletion of at least 50% of lymphocytes and less than 10% neutrophils of the subject. As such, the examples of the disclosure do not support the claimed method in which 131I-BC8 is claimed to deplete at least 50% lymphocytes and less than 10% of the neutrophils in the subject.
The prior art also does not support the claimed functional limitations and suggests that such depletions are not predictable.
Louis, C.U., et al (2009) Enhancing the in vivo expansion of adoptively transferred EBV-specific CTL with lymphodepleting CD45 monoclonal antibodies in NPC patients Blood 113(11); 2442-2450 teaches that lymphodepleting patients with chemotherapy before T-cell transfer enhances in vivo T cell expansion, but results in nonspecific destruction of the resident immune system and can have significant toxicity. Louis, therefore, evaluated whether monoclonal antibodies can produce a more selective lymphodepletion. In a clinical study, patients received a pair of lymphodepleting mAbs targeted to the CD45 antigen before cytotoxic T cell infusion. Louis concludes that lymphodepleting mAbs prior to CTL transfer may represent an alternative to chemotherapy to enhance expansion of infused CTL (abstract).
Louis teaches that using mAbs to CD45, which can deplete all leukocyte lineages, depletion was prolonged in lymphoid lineages while neutrophils began recovering 48 hours after injection (page 2442, right column, paragraph 2). Louis teaches that CD45 mAb infusion induced transient neutropenia and lymphodepletion (Figure 1 caption). Figure 1A on page 2445 of Louis shows neutrophil counts during testing for 8 patients including the median counts (line) and is replicated below for convenience:
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Based on this data provided by Louis, lymphodepletion with even an anti-CD45 antibody alone, can cause depletion of neutrophils that is greater than 10% immediately following administration (within 0-2 days). It is noted that Louis does teach that neutrophil counts rapidly recovered. Louis teaches that administration caused transient neutropenia (absolute neutrophil count <0.5x109/L), which resolved within 48 hours as shown in Figure 1A (page 2444, right column, paragraph 2). The figure from Louis reproduced above, shows an increase in neutrophil cell numbers after 2 days and after 7 days the neutrophil count returned to baseline.
The teachings of Louis suggest that targeting CD45, even with an unlabeled antibody, can result in neutrophil depletion that is greater than 10% immediately following administration suggesting that achieving the claimed function would not be predictable. Louis does not provide a structure-function relationship that would allow an ordinarily skilled artisan to predictably identify which scope of the claimed method would perform the claimed function, if any.
Neither the instant disclosure, nor the prior art, support the functional limitations recited in the instant claims in which 131I-BC8 administration at a dose of 20-50 mCi results in at least 50% lymphocyte depletion with less than 10% neutrophil depletion. The instant disclosure and the prior art also do not provide a structure-function relationship that would allow an ordinarily skilled artisan to identify under what conditions the instantly claimed method would result in the claimed function. Therefore, the claims were not found to meet the written description requirement of 35 USC 112(a).
Response to Arguments
In the response of 01/22/2026, applicant argues that the amendments to claims 1 and 34 have addressed the rejection.
In the response, applicant amended claims 1 and 34 to limit the radiolabeled antibody to 131I-BC8. While the amended limitations do add structure to the claim; applicant has not provided any evidence or disclosure of how the newly added structure correlates to the functions that are claimed, as discussed above. As discussed in detail in the written description rejection, the instant disclosure does not demonstrate a single species of the claimed method performing the claimed function and the prior art suggests that even an unlabeled anti-CD45 antibody alone can cause depletion of neutrophils that is greater than 10% immediately following administration. As such, it is not predictable under what conditions within the scope of the instantly claimed invention the claimed function would be achieved.
If applicant has any data that demonstrates the claimed method resulting in the claimed function, such data could be provided, for instance, in the form of a declaration and would be fully considered.
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 59-60 are rejected under 35 U.S.C. 103 as being unpatentable over Maus, M.V. and D.J. Powell (2015) CAR T Cells: New approaches to improve their efficacy and reduce toxicity Cancer J. 21(6); 475-479; pages 1-12 view of Matthews, D.C., Martin, P.J., et al (1999) Marrow Ablative and Immunosuppressive Effects of 131I-Anti-CD45 Antibody in Congenic and H2-Mismatched Murine Transplant Models Blood 93(2); 737-745 (herein “Martin”), Matthews D.C., et al (1999) Phase I Study of 131I-Anti-CD45 Antibody Plus Cyclophosphamide and Total Body Irradiation for Advanced Acute Leukemia and Myelodysplastic Syndrome Blood 94(4); 1237-1247 (herein “Matthews”), Kaminski, M.S., et al (1996) Iodine-131-Anti-B1 Radioimmunotherapy for B-cell lymphoma Journal of Clinical Oncology (14)7; 1974-1981 and Louis, C.U., et al (2009) Enhancing the in vivo expansion of adoptively transferred EBV-specific CTL with lymphodepleting CD45 monoclonal antibodies in NPC patients Blood 113(11); 2442-2450.
Maus teaches that durable remissions of B-cell leukemia and lymphoma following chimeric antigen receptor (CART) cell therapy has brought this new form of adoptive immunotherapy to center stage with the expectation that CART cell therapy may provide similar efficacy in other hematological and solid cancers. Maus provides a review of recent advances in the areas of CAR design that improve CART proliferation, engraftment and efficacy, as well as clinical strategies that are designed to improve clinical efficacy while reducing risk of toxicity and broaden patient access to the promising form of cancer immunotherapy (abstract).
Maus teaches that the advent of advanced gene transfer and cell cultivation technologies makes it possible to redirect the effector functions of a patient’s T cells against an antigen on the cancer cell surface via a CAR which commonly comprises an extracellular antigen binding moiety, such as an antibody svFv, fused to intracellular signaling domains for T cell activation. Maus teaches that CAR T cells redirected against CD19 can result in durable, complete remission of B cell lymphomas and leukemias, including a nearly 90% response rate in ALL (page 1, paragraph 1). Maus further teaches that the T cells are allogeneic or autologous (page 7, paragraph 1).
Maus teaches that one way to increase the efficacy of CART cell therapy is to condition the host with chemotherapy and/or radiation, resulting in lymphodepletion prior to administering CAR T cells. Maus teaches that lymphodepletion may exert its effects in three ways: (1) reduction in regulatory T cells (Treg) and immunosuppressive macrophages; (2) reduction in disease burden; and/or (3) facilitating homeostatic proliferation by increased availability of endogenous cytokines, including IL-7. Maus teaches that although chemotherapy with or without radiation is a common conditioning strategy, it is relatively non-specific and that alternative, mechanism-based conditioning regimens such as Treg-reducing strategies could be considered, for example an anti-CD25 antibody (page 2, paragraph 3).
Maus, however, does not disclose that the lymphodepletion agent is 131I-BC8 administered in a single dose from 20-30 mCi which depletes at least 50% of lymphocytes without inducing myeloablation.
Martin studied targeted hematopoietic irradiation delivery by 131I-anti-CD45 antibody with and without the addition of total body irradiation (TBI) (abstract). Martin teaches that the success of marrow transplant cellular therapy has been limited by the high relapse rates seen in patients transplanted for advanced malignancies caused by the toxicity of preparative regimens and teaches that this limitation could be addressed by the use of radiolabeled monoclonal antibodies (MoAbs) used to increase the irradiation to specific tissues while minimizing exposure of normal organs (page 737, left column, paragraph 1). Martin teaches that in the initial clinical studies, treatment with radiolabeled antibody was combined with standard preparative regimens containing cyclophosphamide and either TIB or busulfan, because it is unknown whether the relatively low dose rate radiation delivered by the antibody has sufficient antileukemic efficacy to prevent relapse and sufficient immunosuppressive activity to prevent rejection of allogenic marrow (page 737, left column, paragraph 2). Martin performed a study to address the relative biological effects of low dose rate radiation resulting from the administration of radiolabeled antibodies by studying a 131I-labeled anti-CD45 antibody, with or without external beam TBI, as a preparative regimen in two models of murine transplantation (page 737, right column, paragraph 2). In the study, Martin delivered 100 μg of the labeled antibody four days before marrow infusion (page 738, right column, paragraph 2), indicating a single dose of the radiolabeled antibody. Martin further teaches that the radiation delivered at the doses of isotopes studied the lymphodepletion was not myeloablative and did not have fatal nonhematopoietic toxicity (page 743, left column, paragraph 2).
Martin’s study demonstrates that treatment with 131I-anti-CD45 antibody alone is sufficient to allow engraftment of donor cells at 131I doses that are well tolerated. Martin states that the results raise the possibility that 131I-labeled anti-CD45 antibody might provide a less toxic method for selective ablation of marrow and might enable reconstitution with autologous hematopoietic cells modified by gene therapy (page 744, left column, paragraph 2).
Matthews conducted a phase I study that examined the biodistribution of 131I-labeled anti-CD45, specifically BC8, antibody in patients with hematopoietic malignancies to determine the toxicity of escalating doses of targeted radiation combined with cyclophosphamide and total body irradiation (abstract). Matthews teaches that BC8 is a murine IgG1 antibody reactive with all CD45 isoforms (page 1238, left column, paragraph 3). In the study, thirty-four patients received a therapeutic dose of 131I-BC8 labeled with 76-612 mCi 131I (abstract). Matthews teaches that the study demonstrates that 84% of 44 patients undergoing biodistribution studies had good localization of antibody and that a maximum dose of 10.5 Gy delivered by the radiolabeled antibody to the liver could be tolerated in addition to other treatments (page 1238, left column, paragraph 1).
Kaminski studied 131I labeled antibody in the treatment of lymphoma and teaches that an anti-CD20 antibody was labeled with 131I and given in trace doses comprising 5 mCi. Twenty eight patients received radioimmunotherapeutic doses of 34-161 mCi (abstract, patients and methods; results). Kaminski teaches that the results presented indicate that a single dose of nonmyeloablative 131I radioimmunotherapy is capable of inducing durable clinical remissions with minimal or modest toxicity (page 1975, left column, paragraph 2).
Louis studied infused EBV-specific cytotoxic T cells and teaches that one of the primary obstacles in the treatment of cancer with the CTLs is the lack of expansion of the cells in the peripheral blood after infusion, so that the numbers of effector T cells available may be sufficient only for patients without bulky disease. Louis teaches that lymphoid depletion as a strategy to create space for the expansion of adoptively transferred cells has already shown evidence of success. Louis teaches that in melanoma patients receiving cyclophosphamide and fludarabine before adoptive transfer of ex vivo expanded melanoma specific tumor-infiltrating lymphocytes (TILs), showed enhanced repopulation and proliferation of the transferred cells as well as regression of metastatic melanoma. However, some of these patients remained profoundly immunocompromised and failed to regenerate an effective immune system. Louis teaches that this poor immune reconstitution resulted in part from the extensive and nonspecific destruction of the resident immune system by the lymphodepleting cytotoxic drugs (page 2442, paragraph bridging left and right columns).
Louis teaches that monoclonal antibodies that are cytolytic for lymphocytes may be an alternative means of producing lymphodepletion and that the ideal antibody for T cell depletion before CTL infusion should be effective but short lived in vivo to permit rapid infusion and repopulation with infused CTL. Louis used rat mAbs directed to the common leukocyte antigen CD45, which can deplete all leukocyte linages and teaches that the depletion was prolonged only in lymphoid linages, as neutrophils began to recover 48 hours after injection (page 2442, right column, paragraph 2). Louis discloses studies in which CD45 mAbs were administered immediately before EBV-specific CTL infusion and teaches that results indicated that the approach was safe, results in transient lymphodepletion, and allows adoptively transferred CTL to expand (page 2443, left column, paragraph 1).
Louis teaches that one of the possible mechanisms underlying the CTL expansion may be the loss of Tregs. Louis teaches that removal of Tregs before vaccination or T-cell transfer has resulted in enhanced antitumor effects in preclinical animal models and one clinical study has reported encouraging results in humans. Louis teaches that a decrease in Tregs after CD45 mAb infusion was observed without rebound as seen after the administration of cytotoxic agents, so it is possible that the perturbation of Treg also contributed to the observed expansion (page 2448, right column, paragraph 2). Louis teaches that, following CD45 mAb infusion, no increase in Treg cells were observed during the recovery phase, in contrast to the rebound of Tregs after chemotherapy-mediated lymphodepletion (page 2445, right column, paragraph 2).
Louis further teaches that CD45 mAb infusion profoundly decreased all lymphocyte subsets including B cells, natural killer cells, CD4+ and CD8+ T cells. Louis teaches that at the time of CTL infusion, 48 hours after the last CD45 mAb dose, patients remained lymphopenic with a significantly reduced CD4+ and CD8+ T cell count (page 2444, right column, paragraph 3; page 2445, Figure 1B-E). In figure 1B-E of Louis, the administration of the mAb is shown to reduce lymphocytes to more than 50% by day 0 when CTLs were infused.
Louis further teaches that CD45 mAbs produced lymphodepletion in these patients consistent with a previous study in which the mAbs were given to 12 patients who were to receive hematopoietic stem cell transplants (page 2448, left column, paragraph 3).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have modified the method taught by Maus, in which lymphodepletion is performed prior to administering CAR T cells, to perform the lymphodepletion using a 131I anti-CD45 antibody as disclosed by Martin, where the antibody is BC8 as taught by Matthews, with a radiation dose of 34-161 mCi as taught by Kaminski, where the 131I-BC8 is the only lymphodepletion agent based on the teachings of Louis.
An ordinarily skilled artisan would have been motivated to use the 131I anti-CD45 antibody of Martin to increase the irradiation to specific tissues while minimizing exposure of normal organs (Martin, page 737, left column, paragraph 1). Louis provides further motivation to use a CD45 targeting agent for lymphodepletion in cell therapies, particularly those involving the transfer of T cells, teaching that some patients treated with lymphodepleting chemotherapies resulted in extensive and nonspecific destruction of the resident immune system which could be avoided using monoclonal antibodies as an alternative means of producing lymphodepletion (page 2442, right column, paragraphs 1-2). An ordinarily skilled artisan would have had a reasonable expectation of success in using the radiolabeled antibody taught by Martin in the method disclosed by Maus as Maus teaches that lymphodepletion may exert effects by reducing Tregs and that alternative mechanism-based conditioning regimens such as Treg-reducing strategies and/or antibodies could be considered and Louis demonstrates that targeting CD45 reduces Tregs for lymphodepletion in the adoptive transfer of T cells. Additionally, Louis and Martin demonstrate that the use of anti-CD45 antibodies both alone and radiolabeled are effective for inducing lymphodepletion prior to adoptive cell transfer.
It would have been obvious to use BC8 as the anti-CD45 antibody as Matthews teaches that BC8 is an anti-CD45 antibody and demonstrates that BC8 has been radiolabeled with 131I and administered for the targeted delivery of the radionucleotide in methods of lymphodepletion. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
It would have been further obvious to use a radiation dose of 34 mCi as taught by Kaminski as Kaminski demonstrates that a single dose of nonmyeloablative 131I labeled antibody at this dose was capable of inducing effective clinical responses. The radiation dose of 34 mCi taught by Kaminski is close to the claimed range of 20-30 mCi, rendering the claimed range obvious. See MPEP 2144.05 I. An ordinarily skilled artisan would have had a reasonable expectation of success as Kaminski demonstrates that a dose of 34 mCi results in therapeutic response. Additionally, an ordinarily skilled artisan would have had a reasonable expectation of success as Louis demonstrates that even an anti-CD45 antibody alone, without a radiolabel, is capable of providing sufficient lymphodepletion. It is further noted that the determination of an optimal radiation dose is considered to be routine optimization where considerations were known in the art. See MPEP 2144.05 II. In this case, Kaminski teaches a radiation dose that is close to the claimed 30 mCi, specifically 34 mCi. It would have been obvious to one of ordinary skill in the art to use this dosage as a starting point for routine optimization to determine the optimal radiation dose for lymphodepletion in the method disclosed by Maus prior to CAR T cell therapy. Based on the teachings of Louis, an ordinarily skilled artisan would also have expected that dosages lower than 34 mCi would still be functional as Louis demonstrates that an unlabeled anti-CD45 antibody is also capable of providing lymphodepletion.
An ordinarily skilled artisan would have reasonably expected that the method taught by the combination of Maus, Martin, Kaminski, and Louis would result in the depletion of at least 50% of lymphocytes in the subject without inducing myeloablation based on the combination of the applied references. For instance, the reference Louis teaches that even with anti-CD45 antibody alone, profound decreases in all lymphocyte subsets, including B cells, natural killer cells, and CD4+ and CD8+ T cells, are observed. Louis teaches that at the time of CTL infusion, 48 hours after the last CD45 mAb dose, patients remained lymphopenic with a significantly reduced CD4+ and CD8+ T cell count (page 2444, right columns, paragraphs 2-3). Figure 1 of Louis, on page 2445, demonstrates that lymphocytes were reduced beyond 50%. As this reduction was observed using the anti-CD45 antibody alone, an ordinarily skilled artisan would reasonably expect that such result would also be achieved with the addition of a 131I to the antibody. Particularly as the antibody would also deliver selective radiation to the lymphocytes. An ordinarily skilled artisan would reasonably expect that the dosage would not induce myeloablation as Kaminski teaches that the doses of radiation disclosed were nonmyeloablative (page 1979, right column, paragraph 2); Martin teaches that in studies of 131I labeled CD45 antibody, targeted delivery of the radiotherapeutic delivered radiation that was not myeloablative and did not have fatal nonhematopoetic toxicity (page 743, left column, paragraph 2); and Louis teaches that lymphodepletion with an anti-CD45 antibody alone resulted in transient lymphopenia and that all lymphocyte subsets returned to baseline within 9 days of infusion (page 2444, right column, paragraph 3; abstract).
Regarding claim 60, MPEP 2111.02 states that “The transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps ‘and those that do not materially affect the basic and novel characteristic(s)’ of the claimed invention.” MPEP 2111.03 III states that “For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising." The originally filed disclosure does not indicate what additional steps or components would materially change the characteristics of applicant’s invention. Because of this, the term “consisting essentially of” is construed as equivalent to “comprising” for the purposes of searching prior art. Therefore, the combined teachings of Maus, Martin, Matthews, Kaminsky, and Louis meet the limitations of instant claim 60.
Response to Arguments
Applicant’s arguments in the response filed 01/22/2026 have been fully considered, but were not persuasive.
With regards to the rejection of claims 59-60 under 35 USC 103, applicant argues the following.
Applicant argues that rather than providing a reasoned explanation for the rejection, the Office “simply states in a conclusory fashion that claims 59 and 60 are obvious in view of the cited references.”
This argument is not persuasive.
Contrary to applicant’s arguments, the rejection does not simply state that the claims are obvious over the cited references, but rather discuss in detail the state of the art prior to the effective filing date of the claimed invention and provides a detailed explanation regarding why one of ordinary skill in the art would have arrived at the instantly claimed method with a reasonable expectation of success in view of the combination of applied references and what the combination would have suggested to one of ordinary skill in the art. Applicant does not provide any detail regarding why the rejections are not considered to provide a reasoned explanation for the rejection or any specific aspect of the rejection that is considered to be insufficient.
Applicant further argues that the combination of applied references does not suggest the claimed invention. Specifically, applicant argues that none of the cited references teach or suggest that the radiolabeled anti-CD45 antibody is 131-BC8 where the effective amount is administered in a single dose of 20 to 30 mCi. Applicant argues that; therefore, one of ordinary skill in the art would not have been motivated to or have had a reasonable expectation of success in combining the references as proposed. Applicant further argues that there is no motivation to combine the applied references and that the cited references would not result in the claimed invention or deplete at least 50% of lymphocytes of the subject without inducing myeloablation.
In response, it is first noted that none of the applied references are individually required to teach each and every limitation of the claimed method or to exemplify the claimed method in order to establish a prima facie case of obviousness. Rather, the rejection is based on the combination of the applied references and what the combination would have suggested to one of ordinary skill in the art prior to the effective filing date of the claimed invention. See MPEP 2145 (IV). Furthermore, the standard of obviousness is a reasonable expectation of success and conclusive proof of efficacy is not required. See MPEP 2143.02 (I).
As discussed in detail in the rejections of the instant office action, the reference Martin teaches the administration of a single dose of 131I- labeled anti-CD45 antibody as a preparative regimen for the purposes of targeted hematopoietic irradiation, Matthews teaches 131I-BC8, and Kaminiski teaches 131I dosages of 34 mCi. As discussed in the rejection, 34 mCi is close to the claimed 30 mCi rendering the claimed range obvious per MPEP 2144.05 II. Additionally, as discussed in the rejection, one of ordinary skill in the art would have been able to use this teaching as a starting point for routine optimization to determine the optimal radiation dosage for lymphodepletion prior to CAR T cell therapy. It is also noted in the rejection that one of ordinary skill in the art would have had a reasonable expectation of success in using lower dosages because the cited reference Louis demonstrates that unlabeled anti-CD45 antibody was also capable of providing lymphodepletion.
With regards to applicant’s arguments concerning motivation in the prior art, it is first noted that explicit motivation in the prior art is not required in order to establish a prima facie case of obviousness. MPEP 2143 provides 7 exemplary rationales that may be used to support a conclusion of obviousness, KSR (A)-(G), only one of which requires that there be some teaching, suggestion, or motivation in the prior art.
In this case, each of the modifications proposed in the rejections is accompanied by the reason and reasonable expectation of success that an ordinarily skilled artisan would have had in making said modification. Applicant’s arguments do not specifically identify any error in any single reason or reasonable expectation of success used in the rejection nor does applicant provide any evidence to rebut the reasons and reasonable expectation of success used in the rejection to establish obviousness. With regards to the claimed depletion of at least 50% of lymphocytes of the subject without inducing myeloablation, this outcome is also discussed in detail in the rejection. Specifically, the rejection discusses that such outcome would have been reasonably expected based on the combined teachings of the applied references. Particularly the teachings of Louis which demonstrate that, even without the radiolabel, anti-CD45 antibody demonstrated profound decreases in all lymphocyte subsets and demonstrates a reduction in lymphocytes below 50%. As the reduction was observed with naked anti-CD45 antibody, an ordinarily skilled artisan would have reasonably expected that such result would have been achieved with the addition of a 131I radiolabel as such an addition would also deliver selective radiation to the lymphocytes. An ordinarily skilled artisan would have also reasonably expected that the dose would not induce myeloablation based on the teachings of Kaminski, Martin, and Louis which demonstrate that at 34 mCi, 131I radiation was nonmyeloablative, that 131I-anti-CD45 antibody provides targeted radiotherapeutic delivered radiation that was not myeloablative, and that lymphodepletion with an anti-CD45 antibody results in transient lymphopenia with lymphocyte subsets returning to baseline within 9 days of infusion. Applicant does not provide any specific arguments to this conclusion, which is discussed in detail in the rejections of the instant office action, nor does applicant provide any evidence that an ordinarily skilled artisan would not have reasonably expected the claimed function based on these teachings of the prior art.
Applicant further argues that one of ordinary skill in the art would not have had a reasonable expectation of success. Applicant argues that the obviousness rationale regarding the claimed dosages in the office action are based on obvious to try and routine optimization, citing MPEP 2141 and 2143. Applicant argues that “unlimited and undefined ranges of anti-CD45 antibody are so broad in light of the dissimilar characteristics of all possible drugs, dosages, and dosing times as to not invite optimization by one of skill in the art.”
It is first noted that the rejection does not rely on KSR(E), obvious to try, but rather on the obviousness of overlapping, approaching, and similar ranges, amounts and proportions as discussed in MPEP 2144.05 I. The MPEP section states that “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” The rejection also relies on routine optimization, as discussed in MPEP 2144.05 II.A. As the rejection does not rely on KSR(E), a showing of a finite number of predictable solutions is not required.
The rejection also does not rely on unlimited and undefined ranges of anti-CD45 antibody as suggested by applicant. The rejections cite the teachings of Kaminski which demonstrate a dosage of 34 mCi of 131I labeled antibody had been studied in the art. The rejection also relies on the teachings of Louis, which demonstrates effective lymphodepletion with anti-CD45 antibody alone, suggesting that lower dosages of radiolabel could also be effective.
MPEP 2144.05 III. provides evidence that could be provided to rebut a prima facie case of obviousness regarding claimed ranges including A. showing that the range is critical; B showing that the art teaches away; C. showing that the claimed parameter was not recognized as result-effective; or D. showing that a claimed parameter is disclosed in a very broad range in the prior art.
Applicant, however, has provided no evidence that effectively rebuts the prima facie case of obviousness. Applicant does cite a portion of MPEP 2144.05 III D, which states that “one factor that may weigh against maintaining an obviousness rejection based on optimization of a variable disclosed in a range in the prior art is where an applicant establishes that the prior art disclosure of the variable is within a range that is so broad in light of the dissimilar characteristics of the members of the range as to not invite optimization by one of skill in the art.” However, applicant does not provide any evidence to support dissimilar characteristics of the members of the range or to demonstrate the range in the art is so broad that one of ordinary skill in the art would not have pursued optimization. Additionally, while applicant states that the ranges are unlimited and undefined, the rejection does provide specific dosages and ranges used in the art and support for using lower dosages, therefore, the rejection does not present unlimited or undefined dosages.
Applicant further argues that the rejection does not cite any portion of the cited references that shows that an ordinarily skilled artisan would have known how to optimize the proper dose and proper dose timing of the claimed composition. Applicant argues that none of the references describe any range of a proper dose or proper timing.
In response to this argument, it is first noted that the instantly claimed methods do not require any specific dose timing other than the radiolabeled antibody be administered prior to the CAR T cell therapy, a timing which is distinctly taught by the applied references. For instance, Maus, which teaches that one way to increase the efficacy of CART cell therapy is to ‘condition’ the host with prior to administering CAR T cells and goes on to suggest that alternative conditioning regimens could include antibodies. Teachings which are further supported by Louis which teaches lymphodepleting mAbs prior to cytotoxic T cell transfer as an alternative to chemotherapy to enhance expansion of infused CTL. The applied prior art also demonstrates that the dosages of 131I close to the claimed range had been studied in patients. As such, the references provide dosage information that can be used as a starting point for optimization to determine an optimal dosage for lymphodepletion prior to CAR T cell therapy. Applicant provides no evidence that the claimed dosage is critical or that the claimed dosage provides an unexpected result compared to that disclosed in the prior art.
Applicant further argues that rejection relies on improper hindsight and, in this regard, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues that dosing and timing is unpredictable, but does not provide any specific portion of the references cited, or any other evidence, to demonstrate that this is the case. Applicant also argues that the rejection does not explain why an ordinarily skilled artisan would have been directed to administer the claimed composition as a single dose when numerous other modifications of the cited references would have failed, but, again, does not provide any specific modification that would have failed or any evidence to support the speculatory statements made.
Applicant further argues that the claimed invention provides unexpected results.
Applicant argues that CAR T cell therapies require conditioning regimens prior to CAR-T cell infusion and that the current state of care relies on non-targeted chemotherapeutic condition agents including Flu/Cy. However, CAR T cell therapies are associated with serious, well-documented toxicities- specifically ICANS and CRS. Applicant argues that one of ordinary skill in the art would have expected that any conditioning agent would face similar ICAN and CRS challenges. Applicant states that the prior art had consistently failed to produce clinically meaningful improvements over chemotherapy-based conditioning. In support, applicant cites two references from Neelapu regarding the ZUMA-1 trial which details neurological and CRS events observed during the study. In contrast, applicant argues that, in clinical trials for the instantly claimed invention, lomab—ACT achieved unexpected and remarkable outcomes compared to the expectations set by Neelapu. Applicant argues that in a clinical trial of lomab-ACT with CD19 CAR-T therapy, involving heavily pretreated patients with relapsed and refractory B-ALL or DLBCL, no patients (0/4), developed ICANS of any grade and experienced only minimal CRS. Applicant argues that, in the reference, the results are characterized as negligible rates of CAR-T toxicities ICANS and CRS.
These arguments, however, are not persuasive in view of MPEP 716.02, which sets the standards for demonstrating unexpected results.
Applicant states that the prior art had consistently failed to produce clinically meaningful improvements over chemotherapy-based conditioning; however, applicant provides no evidence to support this statement or to demonstrate what alternative conditioning regimens had been considered, tested, and failed to have a clinically meaningful improvement. The article provided with the response regarding the Iomab-ACT clinical trial states that multiple targeted conditioning approaches, including monoclonal antibodies and antibody drug conjugates directed against a variety of targets, have not achieved clinical success, but does not provide any details regarding what these antibodies/conjugates were, what they targeted, or under what conditions and why they were considered to not achieve clinical success.
In the response, applicant compares trials from Neelapu, in which patients received lymphodepleting chemotherapy followed by axi-cel (a CD19 CAR T cell therapy) for the treatment of hematological cancers with discussion from the release by Actinium regarding the Iomab-ACT clinical trial in which Iomab-ACT was used in place of chemotherapeutic conditioning regimens in the treatment of hematological malignancies with CD19 targeting CAR T cells. While the results provided do suggest that Iomab-ACT could potentially act to reduce the levels of ICANS and CRS compared to chemotherapeutic conditioning, such a comparison is not a comparison to the closest prior art.
MPEP 716.02 (b)(III) states “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims.” MPEP 716.02 (e) states “An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979).”
In this case, while chemotherapeutic lymphodepletion may have been the standard of care, the applied references clearly demonstrate a movement towards non-chemotherapeutic options in an effort towards a more targeted lymphodepletion.
For instance, Martin teaches that infusion of radiolabeled antibodies against CD45 delivers radiation selectively to lymphohematopoietic tissues while minimizing the exposure to normal organs. Martin also teaches that the targeted irradiation of lymphohematopoietic organs should decrease the need for high-dose chemotherapy or TBI to prevent rejection of marrow allografts (page 737, left column, paragraphs 1 and 2). Martin studied the use of 131I-labeled anti-CD45 antibody, with or without TBI, as a preparative regimen in two models of murine transplantation (page 737, right column, paragraph 2). Along these same lines, Matthew teaches that the delivery of targeted hematopoietic irradiation using radiolabeled antibodies may improve the outcome of marrow transplant for advanced leukemia by decreasing relapse without increasing toxicity and also studied 131I-labeled anti-CD45 antibody for conditioning therapy (page 1237). Louis teaches that lymphoid depletion as a strategy to create space for the expansion of adoptively transferred cells has shown evidence of success and that melanoma patients receiving cy/flu before adoptive cell transfer of ex-vivo expanded TILs has showed enhanced repopulation and proliferation of the transformed cells as well as regression of metastatic melanoma. However, some of these patients remained profoundly immunocompromised and failed to regenerate an effective immune system. This poor immune reconstitution resulted in part from the extensive and nonspecific destruction of the resident immune system by the lymphodepleting cytotoxic drugs. Therefore, Louis teaches that mAbs that are cytolytic for lymphocytes may be an alternative means of producing lymphodepletion. The ideal antibody for T-cell depletion before CTL infusion should be effective but short lived in vivo. Louis studied the use of a CD45 antibody to achieve such lymphodepletion prior to T cell administration and teaches transient depletion (page 2442; abstract; page 2444).
In this case, Louis studied the use of an anti-CD45 antibody for lymphodepletion prior to T cell adoptive cell therapy and could be considered to be the closest prior art for comparison.
Additionally, even if the results were identified as being unexpected, it is not clear that the claims are commensurate in scope with the results presented.
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.”
As discussed above, the article provided with the response regarding the Iomab-ACT clinical trial does not provide details regarding the trial in which negligible rates of CAR-T toxicities ICANS and CRS were observed. For instance, the results do not provide the amount of antibody that was administered, the dosage of the radiolabel administered, the CD19 CAR T cell that was used, or the amount of CAR T cells administered. As such, it is not possible to ascertain whether the claims are commensurate in scope with the results provided.
Additionally, the instant claims encompass the treatment of any hematological malignancy or solid cancer using any CAR T cell. The results, however, only demonstrate a reduction in toxicities when a specific CD19 CAR T cell is used to treat hematological malignancies. The results do not demonstrate similar results across any hematological malignancy with any CAR T cell or the treatment of solid tumors.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 mailing date of this final action.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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