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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 February 18, 2026 has been entered.
Applicants' arguments, filed February 18, 2026, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Specification
The disclosure s objected to because of the following informalities: the amendments to the specification removed new matter and provided appropriate generic terminology for KYMRIAH® and YESCARTA® but not appropriate generic terminology for FICOLL®. Therefore the specification remains objected to due to the lack of appropriate generic terminology for FICOLL®.
The use of the term FICOLL®, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 – Scope of Enablement
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 4, 5, 9 – 13, 27 and 28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the use of the anti-CD52 radiolabeled antibody alemtuzumab administered in preparation for subject undergoing adoptive cell therapy using cells engineered not to express CD52, does not reasonably provide enablement for the use of the anti-CD52 radiolabeled antibody alemtuzumab administered in preparation for subject undergoing adoptive cell therapy using conventional therapies such as tisagenlecleucel or axicabtagene ciloleucel. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The disclosure and claims of the application have been compared per the factors indicated in the decision In re Wands, 8 USPQ2nd 1400 (Fed. Cir. 1988) as to undue experimentation
The factors include:
1. The nature of the invention;
2. The breadth of the claims;
3. The predictability or unpredictability of the art;
4. The amount of direction or guidance presented;
5. The presence or absence of working examples
6. The quantity of experimentation necessary;
7. The state of the prior art; and
8. The relative skill of those skilled in the art.
Each relevant factor is addressed below on the basis of comparison of the disclosure, the claims and the state of the art in the assessment of undue experimentation.
The nature of the invention; the breadth of the claims:
The claims are drawn to a method in which the anti-CD52 radiolabeled antibody alemtuzumab is administered to subject in preparation for adoptive cell therapy (claim 27, from which all other claims depend). The claims do not explicitly require that the adoptive cell therapy take place, only that the subject is being prepared for such a treatment, therefore defining the scope of the subjects to whom the radiolabeled alemtuzumab is administered. Only claim 28 specifies any details of the adoptive cell therapy to take place, specifying that it is either tisagenlecleucel or axicabtagene ciloleucel which are known materials to be used for CAR-T (chimeric antigen receptors T-cell) cell therapy.
The predictability or unpredictability of the art; the amount of direction or guidance presented; the presence or absence of working examples; the quantity of experimentation necessary; the state of the prior art; the relative skill of those skilled in the art:
The level of skill in the art is high, such as an oncologist.
Poirot et al. (Cancer Res, 2015), the long half-life of alemtuzumab precludes its use a lymphodepletion agent for standard adoptive immunotherapy due to targeting of both host and adoptively transferred cells (p 3862, col 1, ¶ 3). The T cells used in Poirot et al. are engineered to be deficient in the expression of CD52 (e.g., abstract). The disrupted CD52 expression allows these T cells to be used following or in conjunction with alemtuzumab to simultaneously achieve host cell depletion an adoptive T cell engraftment, an approach of particular interested for patients with CLL (p 3862, col 1, ¶ 3). Their also similar discussion about the half-life and other potential issues on p 8 through the top of p 9 in the remarks filed February 18, 2026.
The specification as filed does not contain any examples in which alemtuzumab specifically or any other anti-CD52 antibody is used for preparation of subject that will receive tisagenlecleucel or axicabtagene ciloleucel as the adoptive cell therapy regimen. The examples in the disclosure as filed are limited to the use of radiolabeled BC8, an anti-CD45 antibody (¶ [0154] of the PGPub onward), which does not fall within the scope of the claims, as it does not target CD52.
Therefore the claims do not completely lack enablement but as they are open to adoptive cell therapy using materials engineered to not express CD52 but claim 28 specifically recites the standard adoptive immunotherapy treatment protocols using tisagenlecleucel or axicabtagene ciloleucel. Therefore claim 28 is not enabled and claims 4, 5, 9 – 13 and 27 are partially enabled given the lack of specificity for the adoptive cell therapy being used to treat the cancer in these claims and therefore encompass both enabled and non-enabled subject matter.
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.
Claim(s) 4, 5, 9 – 13 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over De Decker et al. (Nuclear Med Biol, 2008) in view of Maguire et al. (J Nuclear Med, 2014) and Poirot et al. (Cancer Res, 2015).
De Decker et al. discloses that chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of neoplastic B lymphocytes and is the most common form of leukemia in adults in the Western world (¶ bridging p 599 and 600). The characteristic phenotype of CLL cells provide an excellent target for monoclonal antibody therapy (p 600, col 1, ¶ 2). Alemtuzumab has been approved by the Food and Drug Administration as a single agent for patients with fludarabine-refractory CLL (p 600, col 1, ¶ 3). Radioimmunotherapy combines the action of the cold antibody with the radiation delivered directly to those cells carrying the epitope recognized by the antibody and β particles result in a cross-firing effect with antigen-negative tumor cells or cells that cannot be reached by the antibody (p 600, col 1, ¶ 4). 188Re direct labeling is a convenient method in which disulfide bonds in the antibody are reduced to sulfhydryl and then labeled with a radiometal (p 600, col 1, ¶ 7). The aim was to develop an instant preparation method for 188Re-alemtuzumab in a high radiochemical yield for use as a therapeutic agent in CLL (p 600, col 1, ¶ 8). The construct 188Re-alemtuzumab showed favorable biodistribution and a low radiation dose (p 603, col 2, ¶ 5). The prepared compounds would be an ideal candidate for radioimmunotherapy of CLL (abstract). 188Re is a beta emitter with a half-life of 16.9 hours (p 603, col 1, ¶ 5). The reduction of disulfide bonds may impair the antibodies but the direct methods are simple to conduct and require minimal antibody manipulations (p 603, col 1, ¶ 6).
Labelling of alemtuzumab with 225Ac that is administered to a subject with CLL about to undergo adoptive cell therapy is not disclosed.
Maguire et al. discloses that radionuclides that emit α particles are promising agents for anticancer therapy with α particles having a high energy of 5 – 8 MeV, a 50 – 80 µm path length and they have the potential to effectively and selectively target single cells, residual disease and micrometastatic lesions (p 1492, col 2, ¶ 1). 225Ac has a 10 day half-life which is well-suited to the time needed for radiolabeling, injection and tumor targeting and delivering massive toxicity to target cells from the release of 4 net α particles per atom of 225Ac (p 1492, col 2, ¶ 1). Despite a 2 chemical step labeling procedure for chelator DOTA antibodies being known, a more efficient procedure for actinium-antibody constructs is necessary (p 1492, col 2, ¶ 2). The disclosed labeling method is 1 step carried out at 37°C and achieves up to 10-fold higher radiochemical yield and 30-fold higher specific activity to produce a product that is stable in vitro and in vivo (¶ bridging p 1492 and 1493). As shown in figure 1, an amine group on the antibody is reacted with the chelator DOTA that then chelates the radioisotope. In vitro experiments were carried out with a megakaryoblastic leukemia cell lie stably expressing luciferase treated with the radiolabeled constructs as doses of 0.555 and 1.11 kBq and showed significant responses (¶ bridging p 1495 and 1496). Short term toxicity was mild in mice used in the biodistribution experiments even at the relatively high dose of 11.1 kBq (p 1496, col 2, last ¶).
Poirot et al. discloses that adoptive immunotherapy using autologous T cells endowed with chimeric antigen receptors (CAR) has emerged as a powerful method for treating cancer although these cells must be custom made (abstract). A gene editing approach to develop cells deficient in both αß T-cell receptor and CD52 was used with CD52 being a protein targeted by alemtuzumab, a chemotherapeutic agent (abstract). These deficient cells can be administered with, or following, alemtuzumab treatment, which mediates lymphodepletion/immunosuppression thereby promoting engraftment (¶ bridging p 3853 and 3854). The long half-life of alemtuzumab precludes its use a lymphodepletion agent for standard adoptive immunotherapy due to targeting of both host and adoptively transferred cells but the disrupted CD52 expression allow T cells to be used following or in conjunction with alemtuzumab to simultaneously achieve host cell depletion an adoptive T cell engraftment, an approach of particular interest for patients with CLL (p 3862, col 1, ¶ 3).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the 225Ac-DOTA labeling strategy of Maguire et al. with the anti-CD52 antibody disclosed by De Decker et al. and to administer that radiolabeled construct to a subject to bring about host cell depletion an adoptive T cell engraftment in a patient with CLL in preparation for adoptive cell therapy using the materials prepared by Poirot et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because 188Re has a very short half-life and was conjugated directed to an antibody with reduced disulfide bonds that may impair antibody function. The 225Ac is an α particle emitter with a 10 day half-life that is well suited to the time need to label, inject and target tumor cells and can be conjugated to antibodies via an amine group using the single step procedure disclosed by Maguire et al. The procedure produces a product with a high radiochemical yield and high specific activities that would reasonably expect to improve the therapeutic effects of the radiolabeled construct used in De Decker et al. The 225Ac radiolabeled alemtuzumab can be used for initial treatment of the CLL or in preparation for adoptive cell therapy as alemtuzumab administration will also result in lymphodepletion by the action of the antibody and the radioisotope as discussed by De Decker et al. An appropriate adoptive cell therapy can be carried out as taught by Poirot et al. using cells that have been engineered to be deficient in CD52, which renders the preparatory treatment with alemtuzumab compatible with the adoptive cell therapy.
The effects of such administration on cell populations and amount of radiation dose delivered to a particular tissue is determined by the amount and structure of the administered radiolabeled antibody. It is noted that 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). “As a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” MPEP 2113 Given that CD52 is a cell surface protein expressed at a high density on most normal and malignant B and T lymphocytes but not on hematopoietic stem cells (p 600, col 1, ¶ 3), it would be expected that a greater depletion of the immune cells compared to stem cells would occur. There is no evidence of record that the dosages administered in De Decker et al. do not result in the required depletion of immune cells and stems cell, lack myeloablation and bone marrow delivery as required by the instant claims or other evidence as to the criticality of the dosing regimen. One of ordinary skill in the art would optimize the dosing amount and regimen to bring about the required immune system depletion prior to carrying out the adoptive cell therapy.
Applicants argue that no prima facie case of obviousness has been made without a reasoned explanation.
These arguments are unpersuasive. As set forth previously and above, a conclusion and addition reasoned explanation as to the basis for reaching the conclusion of obviousness has been set forth by the Examiner.
Applicants also argue that a skilled artisan would have understood the nature of the art to be unpredictable and the impact of the unpredictability of the art has not been adequately recognized in the rejection and does not overcome the predictability required for an obviousness rationale.
These arguments are unpersuasive. Only a reasonable and not an absolute expectation of success is required for a prima facie case of obviousness and one of ordinary skill in the art would expect that a given treatment regimen would work for every single patient but there is sufficient expectation that switching to 225Ac and using such as radiolabeled anti CD52 antibody alemtuzumab could be used for lymphodepletion/immunosuppression prior to adoptive cell therapy to promote engraftment. The general statements do not provide sufficient evidence as to such a degree of unpredictability that there is not even a reasonable expectation of success.
Applicants argue that the rejection relies on improper hindsight reconstruction effectively using the inventor’s own disclosure as a road and the claims are examined in isolation, instead of as a whole including its interrelationship.
These arguments are unpersuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, 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). The claims as a whole have been analyzed and all limitations considered and addressed.
Applicants briefly discuss the teachings of the applied prior art documents. Tisagenlecleucel requires harvesting of the patients own T cells that would be so depleted by alemtuzumab that the cells required for T cell therapy could not be collected. The cross firing effect mentioned in De Decker for 188Re would be even stronger for 225Ac since that is an alpha emitting radionuclide, potentially causing more profound and potentially lasting damage to the hematopoietic compartment, further reducing the likelihood of obtaining viable T cells for CAR-T manufacturing. The claimed combination would be expected to be therapeutically counterproductive. Should the combination be attempted, there would be no reasonable expectation of success with the slow blood clearance of alemtuzumab suggests persistence in the blood stream with continued depletion of regenerating lymphocytes for an extended period of time. The bone marrow toxicity noted by De Decker for CLL treatment would further impair the ability of the patient to regenerate functional T cells suitable for CAR-T cell harvesting and manufacturing.
These arguments are not fully persuasive. In view of these statements and the teachings of Poirot et al., there is no longer an art rejection against claims 28 that specifies that the adoptive cell therapy that subject is being prepared for is tisagenlecleucel or axicabtagene ciloleucel. There is no explicit requirement that the adoptive cell therapy being prepared for is autologous CAR-T cell therapy and that the only possible use of the agents in claim 28 requires such a protocol. Claim 27 is generic to any adoptive cell therapy regimen that can use materials such as in Poirot et al. that are deficient in CD52 production and when using such a therapy, one of ordinary skill in the art would have the requisite reasonable expectation of success in using alemtuzumab for immunodepletion in preparation for such adoptive cell therapy.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618
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