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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 28, 2026 has been entered. By way of this submission, Applicant has amended claims 3 and 22-24, and introduced new claims 26-32.
Claims 2-8, 10-13, 15-16, and 18-32 are currently pending in the application. Claims 7, 12, 19-22 and 24 remain withdrawn from consideration pursuant to the restriction requirement dated April 15, 2022.
Claims 2-6, 8, 10-11, 13, 15-16, 18, 23, and 25-32 are therefore under examination before the Office.
The rejections of record can be found in the previous Office action, dated January 28, 2026.
Response to Arguments
Applicant argues that the claims as amended now recite the specific limitation of "depletes less than 20% of neutrophils in the subject", and the claims are therefore definite.
Applicant's amendments to the claims have address this issue, and the rejection under 35 U.S.C. 112(b) to claims 1-6, 8, 10-11, 13, 15-16, 18 and 23 is hereby withdrawn.
Applicant argues that the reference to Beatty is non-analogous art, and the teachings of Beatty do not apply to the distinct problem addressed in the claims of depleting immune cells without depleting neutrophils.
Applicant further argues that the combination of references to Matthews, Louis, Qasim, the '738 patent or Beatty do not teach or suggest the result that the claimed method would deplete a subject’s immune cells without depleting neutrophils.
Applicant further argues that the unexpected results are directly supported by the claimed ratio of labeled to unlabeled antibody, as described in Examples 1 and 3 of the specification, and one of ordinary skill would not expect that the claimed method would deplete lymphocytes while sparing neutrophils.
Applicant further argues that one of ordinary skill would not have combined the '738 patent, which teaches that it is desirable to minimize distribution of radiation to off-target organs, with the teachings of Beatty, which teaches methods of improving biodistribution by combining radiolabeled and unlabeled antibody.
Applicant's arguments have been considered fully but are not found to be persuasive.
Beatty is concerned with the "therapeutic use of radioactively labeled antibodies specific to substances produced by or associated with tumors to detect or locate tumors" (col. 1, lines 15-18). This is directly pertinent to the claimed subject matter, and the references to Matthews, Louis, and the '738 patent are also concerned with the use of radiolabeled antibodies in the treatment of cancer.
The ability of radiolabeled BC8 to precondition a subject without myeloablation is taught by Matthews (page 743, left column, second paragraph: "131I conjugated to anti-CD45 antibody survived without infusion of donor marrow, demonstrating that the radiation delivered by these doses of isotope was not myeloablative and did not have fatal nonhematopoietic toxicity"). Additionally, Louis teaches that lymphodepleting antibodies are an attractive, less toxic option for lymphodepletion as opposed to chemotherapy or radiation because they are highly cell-specific and cause little bystander cell damage (page 2448, left column, second paragraph).
The only steps required by the claims are administering an effective amount of a radiolabeled anti-CD45 antibody in a single dose, and performing adoptive cell therapy on the subject. Both of these steps are taught by the art, as previously described. The ability of the claimed method to deplete less than 20% of neutrophils in the subject is at best a latent property present, but not recognized in the teaches of the references. Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). MPEP 2145(II).
Likewise, the properties cited by the newly added claims 26-33 of recovery of neutrophils to baseline levels and a lack of depletion of red blood cells and hematopoietic stem cells are also latent properties, for the above reasons.
In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). If the prior art discloses identical chemical structure, the properties applicant discloses and/or claims are necessarily present, In re Spada, 911 F.2d 705, 709, 15 USPQ2d. The instantly claimed active method steps are identical to the method steps taught by Matthews and Louis and would therefore elicit identical functional properties whenever performed. In other words, lymphodepletion with less than 20% depletion of neutrophils is a natural result of the prior art. Applicant has not met this burden.
Examples 1 and 3 of the specification are completely silent as to the ratio of labeled to unlabeled antibody used. The specification cites no examples or evidence of the claimed ratio of labeled to unlabeled antibody being responsible for the functionality recited in the claims. It is Applicant's responsibility to prove nexus by showing that the evidence of secondary considerations is the direct result of the unique characteristics of the claimed invention. MPEP 716.01(b). Applicant has not met this burden. It is also noted that Applicant's claim amendment dated October 13, 2022, and the accompanying arguments, asserted that an effective amount of a radiolabeled anti-CD45 antibody, without any recitation of ratio of labeled to unlabeled antibody, does not deplete neutrophils.
Beatty teaches that combinations of radiolabeled and unlabeled antibody enhance the accumulation of radiolabeled antibody in a lesion (claim 1). This would result in less distribution of radiation to off-target organs, which is consonant with the teachings of the '738 patent.
In the absence of evidence to the contrary, there is nothing to suggest that the elements of the claimed combination are performing anything other than their expected, usual functions to affect a predictable result.
The rejection under 35 U.S.C. 103 over Matthews in view of Louis, Qasim, U.S. patent 5,273,738, and Beatty is therefore maintained and extended to encompass new claims 25-32.
Claim Rejections - 35 USC § 112
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 29-30 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.
The claims recite that the steps of the claimed method recited in claim 3 depletes less than 20% of red blood cells or platelets in the subject (claim 29) and depletes less than 20% of hematopoietic stem cells in the subject's bone marrow (claim 30). There is insufficient support in the disclosure for such claim limitations.
Use of percentages to describe depletion is limited to paragraph 0049, which only describes neutrophils and not red blood cells, platelets, or hematopoietic stem cells. Applicant's citation of Figure 2 does not state that the method less than 20% of red blood cells or platelets in the subject. Figure 2 merely describes absolute levels of red blood cells and platelets, without clear indication of the baseline of which they are to be compared to.
Applicant's citation of paragraph 0080 states that the claimed method will have limited impact on hematopoietic stem cells in the bone marrow, but recites no percentage in change.
As such, the claims now recite a limitation which was not clearly disclosed in the specification as-filed and now change the scope of the instant disclosure as-filed. Such a limitation recited in the present claims, which did not appear in the specification as-filed, introduces a new concept and violates the description requirement of the first paragraph of 35 U.S.C. 112.
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.
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 2-6, 8, 10-11, 13, 15-16, 18, 23, and 25-32 are rejected under 35 U.S.C. 103 as being unpatentable over Matthews (Blood. 1999 Jan 15;93(2):737-45, cited in IDS) in view of Louis (Blood. 2009 Mar 12;113(1 1):2442-50, cited in IDS), Qasim (Sci Transl Med. 2017 Jan 25;9(374), U.S. patent 5,273,738 (cited in IDS, hereafter referred to as "the '738 patent"), and Beatty (U.S. patent 4,921,690).
Matthews teaches the use of radiolabeled antibodies against CD45 to deliver irradiation selectively to lymphohematopoietic tissues (page 737, left column, second paragraph). Matthews also teaches that treatment with 131I-anti-CD45 antibody alone is sufficient to allow engraftment of donor cells at 131I doses that are well tolerated, and that 131I-labeled anti-CD45 antibody may provide a less toxic method for selective ablation of marrow and may enable reconstitution with autologous hematopoietic cells modified by gene therapy (page 744, left column, second paragraph).
Matthews further teaches that treatment with an 131I-labeled anti-CD45 antibody results in over eighty percent engraftment of donor granulocytes (Table 2), which indicates that at least fifty percent of the subject's native cells were depleted, which is pertinent to claim 2.
Matthews further teaches that treatment with low doses of an 131I-labeled anti-CD45 antibody is not myeloablative and does not result in fatal nonhematopoietic toxicity (page 743, left column, second paragraph), which is pertinent to claim 3.
However, Matthews does not explicitly teach that the above method is useful for depleting a subject's immune cells in preparation of the subject undergoing adoptive cell therapy, nor the doses of radiation.
Loius teaches that lymphoid depletion is used prior to adoptive cell therapy; for example, melanoma patients receiving chemotherapy before the 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 (page 2442, right column, first paragraph).
Louis also teaches the use of an anti-CD45 antibody for lymphodepletion prior to treatment with autologous cytotoxic T cells which target an antigen of interest (CAR-T), which is pertinent to claims 10 and 11. Louis further teaches that lymphodepleting antibodies are an attractive, less toxic option for lymphodepletion as opposed to chemotherapy or radiation because they are highly cell-specific and cause little bystander cell damage (page 2448, left column, second paragraph). Louis also teaches that this method of lymphodepletion increases the level of antigen-specific cytotoxic T cells post-infusion (page 2448, left column, fourth paragraph).
Louis also teaches administration of cytotoxic T cells which target an antigen of interest seven days after the first treatment with the anti-CD45 antibody (page 2443, left column, fourth paragraph), which is pertinent to claim 16.
Louis also teaches that lymphocyte counts returned to normal within nine days after the administration of an anti-CD45 antibody (page 2448, left column, third paragraph).
Qasim teaches the use of gene editing with TALEN to disrupt cell surface expression of the alpha-beta T cell receptor in CAR-T cells which target CD19 (page 1, right column, second paragraph), which is pertinent to claims 13 and 15. Qasim further teaches that this modification to CAR-T cells is useful in treating patients with refractory relapsed B cell acute lymphoblastic leukemia after lymphodepletion by offering a more “universal” CAR-T cell therapy with reduced graft-versus-host disease (see, generally, page 5).
The '738 patent teaches BC8, an antibody against CD45 (col. 7, lines 3-35). The '738 patent also teaches radiolabeling the above antibody with iodine-131 at a therapeutic dose of 100 millicuries (col. 8, lines 42-68), which is pertinent to claims 4-6. According to Applicant's specification at paragraph 0149 and Table 2, 100 millicuries of iodine-131 results in a total marrow absorbed dose of 217 centrigrays. The '738 patent therefore inherently teaches this aspect of claims 8 and 23.
The '738 patent further teaches that the above radiolabeled antibody is useful for selectively delivering radiation homogenously to lymphoid and marrow tissues (claim 1).
The '738 patent further teaches that the effective dose of the above antibody may be between 0.1-2 mg/kg (col. 5, lines 7-27), which is pertinent to claim 18.
The '738 patent further teaches that it is desirable to minimize delivery of radiation to off-target organs, such as the liver (col. 3, lines 19-40).
Beatty teaches administering combinations of labeled and unlabeled antibodies in order to enhance biodistribution of the antibody (e.g. claim 6 and col. 4, lines 10-16: "It is also possible to increase biodistribution by combining the pretreatment and treatment steps so as to administer unlabeled and labeled antibody simultaneously.").
Beatty further teaches that the label may be a radionuclide (col. 4, lines 33-37). Beatty also teaches the use of iodine-131 (col. 14, lines 36-44),
Beatty further teaches ratios of 1:1000 to 1:1 of radiolabeled to unlabeled antibody (Table 2 and col. 8, lines 7-21), which is within the range of claim 3.
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the teachings of the cited references to arrive at the claimed invention. An ordinary artisan would have been motivated to do so, and have a reasonable expectation of success, since both Matthews and Louis teach the use of an anti-CD45 antibody as a lymphodepleting agent, and Louis further explains that such an agent is a useful alternative to chemotherapy prior to adoptive cell transfer within the nine-day window of relative lymphodepletion after administration of the antibody. Louis also notes the advantages of combining a lymphodepleting anti-CD45 antibody with autologous CAR-T cell therapy, while Qasim teaches the advantages of deleting a TCR receptor in a CAR-expressing T cell. Additionally, according to Matthews and the '738 patent, anti-CD45 antibodies radiolabeled with 131I were known in the art, and both Matthews and the ‘738 patent are concerned with efficient delivery of radiation selectively to lymphohematopoietic tissues. The dosages taught by the ‘738 patent would inform a person of ordinary skill as to administer the anti-CD45 antibody BC8 to accomplish this desired task. Likewise, the advantages of simultaneous treatment (i.e. in a single dose) with an unlabeled version of the same antibody to promote uptake of the radiolabeled antibody were taught by Beatty. Beatty teaches the advantage of using combinations of radiolabeled and unlabeled antibody to reduce delivery of radiation to undesired target, such as the liver. This was a known problem in the art according to the '738 patent.
While the above references do not teach that the treatment with low doses of an 131I-labeled anti-CD45 antibody does not deplete neutrophils, red blood cells, platelets, or hematopoietic stem cells in the subject, nor do the references teach that neutrophils in the subject recover to baseline levels within about seven days after administration of the radiolabeled antibody, the instantly claimed active method steps are identical to the method steps taught by Matthews and Beatty, and would therefore elicit identical functional properties whenever performed. The preservation of neutrophils and other cell types is a natural result of the prior art. The references therefore inherently teach this aspect of the claims.
The skilled artisan could combine the teachings of the above references to arrive at the claimed invention, with each component of the combination performing its known, predicted function, and the combination would yield a predictable result.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER JOHANSEN whose telephone number is (571)272-0280. The examiner can normally be reached Monday-Friday, 6:00 to 2:00.
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/PETER JOHANSEN/Primary Examiner, Art Unit 1642
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