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.
DETAILED ACTION
The amendments filed on 4/29/2026 which claim 1 was amended is acknowledged. Claim 2 was canceled.
Claims 1, 3-11, 14-19, and 21 are pending in the instant application.
Priority
This application is a 371 of PCT/EP2019/062806, filed on 5/17/2019 which claims priority to the European application EP18173145.6 filed on 5/18/2018.
Election/Restriction
Applicant’s election without traverse of Group I (claims 1-11 and 16-19) drawn to a method of treating a disease/disorder in the reply filed on 1/29/2024 remains in effect.
Claims 14-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/29/2024.
Claims 1, 3-11, 16-19, 21
Claims 1, 3-11, 16-19, and 21 are examined herein.
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.
Claims 1, 3-11, 16-19, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (doi: 10.1186/1756-8722-5-S1-A8), Lacy et al. (PMID: 25003566), Abts et al. (doi: 10.1016/0022-1759(89)90073-2), Engelberts et al. (US20170355767), Juan et al. (AU2017249698), and Michael et al. (doi: 10.1002/ijc.23626).
claim 1
Regarding claim 1, Wu teaches that EBV infection or reactivation may result in life-threatening diseases in immunocompromised people (pg 1, col 1, para 1). Wu teaches EBV infection and reactivation might be associated with a spectrum of clinical presentations ranging from fever to post-transplant lymphoproliferative diseases (PTLD), including viremia, pneumonia, encephalitis, myelitis, PTLD, and so on, in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) (pg 1, col 1, para 1), which arise as a consequence of infected B/T lymphocytes, epithelial cells and neural cells, and they are sustained by EBV latency products. Wu teaches in order to treat patients with EBV, the immune response to EBV must be restored via manipulating the immune system to target and eradicate these malignancies (pg 1, col 2, para 3). Wu teaches that allogenic-HSCT therapies aim to tilt the balance toward EBV immune responses by depleting the EBV-infected B-cells and/or by augmenting the cellular immune response to EBV (pg 1, col 2, para 3 – pg 2, col 1, para 1). Wu teaches the treatment of EBV-associated diseases includes rituximab, reducing immunosuppression, donor lymphocyte infusion (DLI), donor EBV-specific cytotoxic T cells (CTL) infusion, and/or chemotherapy (pg 2, col 1, para 1). Wu teaches that rituximab (an anti-CD20 antibody) has been applied widely as first-line drug of preemptive therapy for high-risk patients (pg 2, col 1, para 1).
Wu does not teach isolating the patient’s B cells, nor incubating these cells with a CD3 x CD20 triomab prior to reintroduction into the patient.
Lacy teaches that Epstein Barr Virus (EBV) infects B cells, T cells, and squamous epithelial cells, however the majority of EBV-associated malignancies derive from EBV-infected B cells (pg 358, para 1). Lacy teaches that EBV encodes an array of products that mimic or activate anti-apoptotic molecules, cytokines, and signal transducers, thereby promoting EBV infection, immortalization, and transformation, thus promoting neoplasm formation (pg 358, para 1). Lacy teaches EBV has been directly linked with cancer (pg 358, para 1), in particular, several different types of lymphomas and other lymphoproliferative disorders (pg 359, Table 1). Lacy teaches the proliferation of EBV-infected B cells is dysregulated, due to impaired EBV-specific T-cell mediated immune surveillance of infected B cells (pg 363, col 1, para 6-col 2, para 1). Under these conditions, Lacy teaches that recipients of solid organ and hematopoietic stem cell allografts can succumb to post-transplant lymphoproliferative disorder (PTLD): a life-threatening (pg 363, col 1, para 6) dramatic expansion of the EBV-infected B-cells (pg 363, col 2, para 1). Lacy teaches the success of adoptive immunotherapy with ex vivo expanded allogeneic or autologous EBV-specific cytotoxic T cells (CTLs) in post-transplant lymphoproliferative disorder (PTLD) has led to the application of this strategy in Hodgkin’s Lymphoma patients (pg 363, col 1, para 3). Lacy teaches that post-allogenic T-cell transplantation, Hodgkin’s lymphoma patients benefit from concomitant therapy with rituximab, an anti-CD20 antibody (pg 363, col 1, para 6).
Abts describes a method of isolating B cells from Peripheral Blood Mononuclear Cells (PBMCs) comprising a first step of removing the CD3+ T cells using an anti-CD3 antibody, followed by a second step of selecting for the B cells using a biotinylated anti-CD20 antibody (Abstract, Fig 1). Abts teaches that by following this process, the B cells were enriched to 97%, and the isolated B cells were amenable to further proliferation and antibody stimulation (abstract). Abts teaches this method has a potential application in the depletion of human lymphocytes for therapeutic procedures such as bone marrow transplantation and the treatment of tumors by lymphokine activated cells (pg 27, col 1, para 3).
Engelberts teaches autoimmune diseases, such as multiple sclerosis can be treated by targeting CD20, e.g. using rituximab (pg 1, para 007). Engelberts teaches that the CD3 x CD20 bispecific antibodies of the invention are to be used for the treatment of Epstein-Barr virus infection (pg 38, para 0548), a virus that infects B cells (pg 40, para 0566). Engelberts teaches that autoimmune disorders such as multiple sclerosis and Crohn’s disease involve CD20-expressing B cells (pg 40, para 0585). Engelberts teaches CD20 is expressed on B lymphocytes and is involved in the proliferation and/or differentiation of these cells, which function as immunomodulators, thus CD20 is an important target for antibody mediated therapy to target or kill B lymphocytes (pg 39, para 0552). Engelberts teaches CD20 is expressed on greater than 90% of B cell non-Hodgkin’s lymphomas (pg 1, para 0006). Engelberts teaches that the addition of the CD3 x CD20 antibody selectively kills CD20+ B cells (pg 1, para 0017). Engelberts teaches bispecific antibodies that bind to both CD3 and CD20 are useful in the T cell-mediated killing of cells that express CD20, such as CD20 positive tumors (pg 1, para 0017). Engelberts teaches the CD3 x CD20 bispecific antibodies can be used to mediate apoptosis of a cell expressing CD20 in vitro (pg 37, para 0540). Engelberts teaches that the bispecific antibodies can be administered to cells ex vivo (pg 39, para 0560).
Juan teaches adoptive cell therapy (ACT) is a process involving collecting immune cells from a patient, expanding those cells, and reintroducing those cells into the same patient (pg 1, para 1). Juan teaches the cancer-killing T cells are generated forming an ex vivo reaction mixture comprising the patient’s T cells and a proximity immuno-coaching factor (pICF) under conditions sufficient to activate the T cell (pg 2, para 3). Juan teaches that bispecific antibodies are an exemplary pICF (pg 62, para 2), wherein bispecific antibodies include triomabs that target CD3 (pg 62, para 3) or bispecific antibody fragments that target CD3 and CD19 (pg 63, para 2). Juan teaches the pICF comprises a first element that targets the T cell (pg 26, para 9) and a second element that targets a cancer cell, such as CD20 (pg 27, para 1). Juan teaches the hematological sample may comprise cancer cells expressing CD20 (pg 4, para 5). Juan teaches that ACT of donor-derived, ex vivo expanded human cytotoxic T lymphocytes (CTLs) has emerged as a promising approach to treating cancer (pg 1, para 1). Juan teaches the cancer-killing T cells are autologous (pg 2, para 1). Juan teaches the cells are administer to the subject subcutaneously (pg 80, para 4).
It would have been obvious to combine the teachings of the references because (1) Wu teaches that treatment of EBV requires depleting the population of EBV-infected B cells and re-activating the T cell’s immune response using a combination therapy regime that includes allo-HSCT and rituximab; (2) Lacy teaches that ex vivo expanded allogeneic or autologous EBV-specific cytotoxic T cells are effective in treating patients with EBV-related disorders (such as cancer) and concomitant therapy with rituximab prevents the risk of uncontrolled expansion of infected B cells (PTLD); (3) Abts teaches a method of isolating and enriching B cells from PMBCs for the purpose of transplant therapies; (4) Engelberts teaches that CD3 x CD20 triomabs are effective in depleting CD20+ B cells, via targeting B cells using the anti-CD20 arm and recruiting T cells using the anti-CD3 arm; and (5) Juan teaches that autologous T cells can be stimulated using triomabs that target CD3 for the treatment of lymphomas and cell preparations can be administered subcutaneously. Given the teachings of the references, it was known in the prior art that in order to treat EBV-related diseases, the population of EBV-infected B cells needed to be depleted and the patient’s T cells needed to be re-activated towards regulating the B cells. Because EBV-predominantly affects B cells, one of skill in the art would have found it obvious to first deplete the EBV-infected B cells and re-activate the patient’s T cells prior to reintroducing these cells back into the patient in order to avoid the life-threatening post-transplant complication of PTLD. The step of adding more PBMCs to the isolated B cells would have been obvious as a means of adding T cells to the therapy, which were taught by Wu and Lacy as critical for regulating B cells.
claim 3
Regarding claim 3, Engelberts teaches the triomabs of their invention have the ability to bind to an antigen under typical physiological conditions within 30 minutes (pg 10, para 0039). Thus rendering obvious the instantly claimed triomab incubation time of 1-60 minutes. See MPEP § 2144.05(I).
claim 4
Regarding claim 4, Engelberts teaches a dosage of 0.1, 1, and 10 ug of the CD3 x CD20 antibody, bslgG1-huCD3-H1Ll-FEALxCD20-7D8-FEAR (pg 50, Table 7).
claim 5, 19
Regarding claims 5 and 19, Michael teaches the triomab, Bi20, binds B cells and T cells via its variable regions, and recruits FcγRI+ accessory immune cells via its Fc region (abstract). Michael teaches that Bi20 mediates efficient and specific lysis of B-cell lines and B cells with low CD20 expression levels (abstract). Michael teaches that Bi20 is an effective therapeutic for B cell lymphomas (abstract). Michael teaches a bispecific triomab comprising mouse IgG2a and rat IgG2b isotypes (pg 1181, col 1, last para).
claim 6
Regarding claim 6, Michael teaches the Fc portion of the triomab binds type I FcγR (pg 1182, col 2, last para). The antibody of Michael, called Bi20, is the same used in all of the instant examples (instant Example 1, pg 24-25; also examples 2-17), thus this is also an inherent property. See MPEP § 2112.
claim 7
Regarding claim 7, Michael teaches the Fc portion of the triomab can bind monocytes via the type I FcγR (pg 1182, col 2, last para). The antibody of Michael, called Bi20, is the same used in all of the instant examples, thus this is also an inherent property. See MPEP § 2112.
claim 8
Regarding claim 8, Michael teaches the triomab comprising mouse IgG2a and rat IgG2b isotypes (pg 1181, col 1, last para). The antibody of Michael, called Bi20, is the same used in all of the instant examples, thus this is also an inherent property. See MPEP § 2112.
claim 9-11, 16-18
Regarding claims 9-11 and 16-18, Michael teaches the triomab, Bi20, binds B cells via CD20-binding arm and T cells via the CD3-binding arm, and recruits FcγRI+ accessory immune cells via its Fc region (abstract; pg 1182, col 2, last para). The antibody of Michael, called Bi20, is the same used in all of the instant examples, thus this is also an inherent property. See MPEP § 2112.
It would have been obvious to combine the teachings of the references because (1) Wu teaches treating EBV-diseases via depleting infected B cells and stimulating T cells; (2) Abts teaches a method for isolating and expanding B cells; (3) Lacy teaches autologous T cells are an effective treatment for EBV-related disorders however suppression of B cell growth must be suppressed using an anti-CD20 antibody (rituximab); (4) Engelberts teaches that CD3 x CD20 triomabs are able to recruit T cells via the CD3 arm in order to deplete CD20+ B cells; and (5) Michael teaches the CD3 x CD20 triomab, called Bi20, is effective in depleting B cells in B cell lymphomas. Additionally, Engelberts provides the appropriate dosage and triomab incubation conditions. One of skill in the art would have had a reasonable expectation of success because this two pronged approach of depleting B cells and stimulating T cells for the treatment of EBV-related diseases was already known to be effective as taught by Wu. Furthermore, the same instantly claimed CD3 x CD20 triomabs were already known to bind both B cells and T cells, for the dual purpose of stimulating CD3-expressing T cells to target CD20-expressing B cells. This strategy comes with the added benefit of avoiding PTLD, by ensuring that the B cell population remains suppressed, which the references taught could be achieved using rituximab or a CD3 x CD20 triomab.
Claim 21
Regarding claim 21, Wu is silent on how long the antibody must be incubated with the cells.
Michael teaches a bifunctional anti-CD20 x anti-CD3 triomab called Bi20 (abstract) that was incubated for 30 min (pg 1182, col 1, para 6-7). In Michael’s procedure, a 30 minute incubation time was sufficient to separate a population of PBMCs using FACS analysis (pg 1182, col 2, para 1-2), thus establishing 30 minutes as “sufficient to establish a physical interaction between said trifunctional bispecific antibody and said enriched B cells”. Generally, differences in antibody incubation time will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such incubation time is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In the instant case, applicant has not provided any evidence of criticality, thus arriving at an optimal incubation time of 5-20 minutes is considered a matter of routine experimentation. See MPEP § 2144.05(II)(A). Furthermore, MPEP § 2144.05(I) states “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” In the instant case, Michael’s 30 minute incubation time is very close to the 20 minute incubation time instantly claimed. Additionally, MPEP § 2112.01(II) states “A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.” In the instant case, the triomab of Michael meets all of the structural limitations of the claim, thus it must necessarily have the same binding properties as the instantly claimed generic “trifunctional bispecific antibody (a.k.a. triomab), absent the declaration of some structural element that enables the instantly claimed triomab to bind with faster kinetics.
Response to Arguments
Applicant’s arguments filed on 4/29/2026 have been fully considered but they are not persuasive.
103; pg 7, para 1
Applicant argues incorporation of the limitations of claim 2 into instant claim 1 renders the instantly claimed invention non-obvious. Applicant states there is no disclosure in the cited references, either alone or m combination, that would have led one of ordinary skill in the art to the instantly claimed method. Applicant argues the “enriched B cell population” contains some EBV-infected B cells, thus is not “depleted” as the references state.
The limitations of claim 2 were addressed in the previously made 103 rejection in the office action mailed on 10/29/2025. The newly added limitation of “subcutaneous” has also been addressed in the newly modified 103 rejection above. Instant claim 1 refers to the “enriched B cell population” comprising infected B cells that are contacted with a triomab that is known in the prior art to deplete EBV-effected cells. Importantly, applicant’s terminology “enriched” does not imply a homogenous population nor does the term “depleted” imply a purified population of B cells either. Despite a difference in wording, these populations are considered the same as they are the same cells treated with the same triomab, thus must inherently produce the same product. In other words, both the references and the instant application add the same triomab to the same population of cells. Applicant calls this population of cells “enriched (in EBV active B cells)” versus the references call this population of cells “depleted (in EBV-inactivated cells)”.
In evidence of these facts, Michaels teaches an exemplary CD3 x CD20 triomab called Bi20, that when administered to mixtures of CD20+ B cells from diseased patients and those from healthy donors, the triomab selectively destroyed the diseased B cells (a.k.a. CLL tumor cells). Michael recites:
“Cells from 9 different donors were incubated with PBMCs from healthy donors and Bi20 (5, 50 or 250 ng/ml) or control antibodies as illustrated in Figure 7. Increasing concentrations of Bi20 led to improved elimination (up to 99%) of CLL B cells. Rituximab also induced significant B-cell depletion, but even at a concentration of 250 ng/ml, nearly half of the B cells were viable. This shows that, at least in our experimental setting, the trAb Bi20 is much more potent than rituximab with respect to the elimination of primary tumor cells from CLL patients. In this case, unspecific B-cell depletion mediated by catumaxomab was substantially decreased compared with that in previous experiments with B-cell lines (Figs. 3 and 7).”
Michael’s Figure 7 has been reproduced below.
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Given the generic structure of the triomab claimed, and that described in the instant specification (e.g. instant Example 1 also describes a CD3 x CD20 triomab), selective B cell depletion is a requirement for the instantly claimed invention to function. If applicant is arguing the instantly claimed CD3 x CD20 triomab does not possess the property of selective B cell depletion, then applicant must specify what structures are responsible for the instantly claimed triomab possessing different properties than CD3 x CD20 triomabs known in the art. Applicant has yet to define any structural differences that would yield this different functionality (i.e. does not induce selective B cell depletion), thus it is unclear how the instantly claimed invention can comprise the same structure as the genus, yet possess properties not known to that genus.
103; pg 7, para 4
Applicant argues “Indeed, it is an aim of the presently claimed subject matter to induce .. immunization against EBV by only inducing the destruction of the ex vivo involved partly infected B cells by the added trifunctional antibody… After subsequent subcutaneous application … cells such as macrophages or monocytes will then phagocytose the lysed and partly EBV-infected B cells to raise, e.g. a humoral anti-EBV response, as shown in the Examples. Such a mechanism is not described in any of the cited references.”
Applicant did not point to a specific deficiency in the references, or even refer to any of the references by name. The argument appears to affirm the previous conclusion that the triomab depletes the EBV-infected B cells, producing potentially antigenic by-products which can then be used to enhance EBV immunity. Again, the method as claimed amounts to adding an existing triomab which is known to deplete EBV infected cells, and injecting the mixture of triomab and cells back into the patient. Because neither the instant application or the applied art refer to a purification step that excludes the remaining EBV-infected cells or the fragments of destroyed EBV-infected cells, a material difference between the product produced by the method of the references versus that instantly claimed could not be found.
103; pg 8, para 2
Applicant argues the references only teach in vivo injection of the triomab, but then admits that the references teach an ex vivo preparation of depleted B cells for allogenic transplantation back into the patient. The argument appears to circle back to the definition of “depleted” and “enriched” B cells.
Firstly, the references are not limited to in vivo injection of the triomab, as evidenced by the reference of Michael which is drawn purely to ex vivo cell culture studies upon treatment with a triomab. Secondly, the reference of Engelberts teaches that the triomab can be used in conjunction with autologous or allogenic adoptive cell therapies (pg 43, para 0624) and the reference of Wu teaches that treatment of EBV requires depleting the population of EBV-infected B cells and re-activating the T cell’s immune response. In sum, it was known in the prior art that in order to treat EBV-related diseases, the population of EBV-infected B cells needed to be depleted and the patient’s T cells need to be re-activated towards regulating the B cells. Because EBV-predominantly affects B cells, one of skill in the art would have found it obvious to first deplete the EBV-infected B cells and re-activate the patient’s T cells prior to reintroducing these cells back into the patient in order to avoid the life-threatening post-transplant complication of PTLD. The step of adding more PBMCs to the isolated B cells would have been obvious as a means of adding T cells to the therapy, which are taught by Wu and Lacy as critical for regulating B cells.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) 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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/L.A.E./
Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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