Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Continued Examination under 37 CFR 1.114 after Final Rejection
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 20 October 2025 has been entered.
Status of Claims
Claims 1, 5-7, 10-15, 36, 37 and 41-44 are pending.
Claims 1, 5-7, 10-15, 43 and 44 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected Group I. Election is being considered as an election without traverse in the reply filed on 10 February 2025 to the Restriction/Election Office Action mailed 26 November 2024.
Claims 36, 37, 41 and 42 are rejected.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. §119(e) or under 35 U.S.C. §120, §121, or §365(c) is acknowledged. This application discloses and claims only subject matter disclosed in prior application no. 17/122,521, filed 12/15/2020, which is a CON of 15/756,473, 02/28/2018, which is a 371 of PCT/US2016/049205, 08/29/2016, which claims benefit of 62/212,279, 08/31/2015, and names the inventor or at least one joint inventor named in the prior application. (The specifications filed with applications 18/431,638 and 17/122,521 appear to be the same; i.e., instant application 18/431,638 does not appear to include any subject matter which would constitute new matter (MPEP 201.07).) In addition, the patent (No. 11,925,662) issued from parent application 17/122,521 was published after the filing date of the instant application.
Applicant designates the instant application a “DIV" of 17/122,521; however, it is noted that the instantly claimed subject matter, does not represent an invention described in the claimed subject matter of prior application 17/122,521 which had been withdrawn from consideration (and not rejoined), as the result of a Restriction/Election Office Action, during the prosecution of application 17/122,521, leading to issued patent no. 11,925,662. Therefore, the instantly-claimed subject matter is not protected under 35 USC §121 with regard to potential double patenting rejections.
Applicant has declared the instant application as a divisional application (but it appears to be a continuation (CON)). Applicant has claimed the benefit of the filing date of the prior application.
Applicant has complied with all of the conditions for receiving the benefit of an earlier filing date under 35 U.S.C. §120 or §365(c).
Claims 36, 37, 41 and 42 have the effective filing date of 31 August 2015.
Claim Interpretations
Claim 36 recites the term “canonical neutrophil associated molecules”, as well as the term “canonical tumor-associated neutrophil (TAN)”.
An American English dictionary definition of the word ‘canonical’ is: the standard, rule or primary source that is accepted as authoritative for the body of knowledge or literature in that context.
Claim 36 describes, then, that the molecules which are expressed by those white blood cells (leukocytes) which would be considered to be conventional or typical neutrophils are Arg1, MPO, CD66b and CD15. The specification describes canonical TANs as expressing the molecules CD11b+CD66b+CD15+ (clean copy specification filed 22 May 2024, pg. 9, lines 7-9). Therefore, it appears as though tumor associated neutrophils not only express Arg1, MPO, CD66b and CD15 (so-called conventional or typical neutrophil cell markers), but also CD11b+.
One of ordinary skill in the art of immunology and leukocyte cell discrimination would understand that neutrophils have the potential to express other cell surface (or intracellular) molecules that are not described in the instant claims or specification (but which would be considered to be ‘canonical’), depending on the biophysiological or biochemical milieu in which the cells are located. However, for the purpose of compact prosecution, the claims will be interpreted to read:
Claim 36: "..., wherein the hybrid neutrophil co-expresses the neutrophil associated molecules…, and the antigen presenting cell (APC) associated molecules…”; and
“…, wherein the expression of any one of the molecules is increased relative to expression of the molecule on a tumor associated neutrophil (TAN).”
In addition, prior art which shows increased expression of molecules on a TAN which are not CD11b, CD66b or CD15 will be considered to be showing an increased level of any one of the molecules cited in claim 36 relative to a canonical TAN.
Claim Rejections - 35 U.S.C. § 103
The rejection of Claims 36, 37, 39 and 42 under 35 U.S.C. §103 as being unpatentable over Matsushima et al. in view of Glasser, Amsalem et al., Fridlender et al., Edberg et al., and Takashima et al., in the Final Office Action mailed 21 July 2025, is withdrawn in view of Applicants' amendment received 20 October 2025, and further search and consideration of the claimed subject matter.
The rejection of Claim 41 under 35 U.S.C. §103 as being unpatentable over Matsushima et al. in view of Glasser, Amsalem et al., Fridlender et al., and Edberg et al., as applied to claims 36-39 and 42 above, and further in view of Croft et al., Kwon, and Beauvillain et al., in the Final Office Action mailed 21 July 2025, is withdrawn in view of further search and consideration of the claimed subject matter.
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.
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 of this title, 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.
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 36, 37 and 42 are rejected under 35 U.S.C. §103 as being unpatentable over Takashima et al. ((2015 Jan.) J. Leukoc. Biol. 98: 489-496) in view of Glasser ((1977) Blood 50(6): 1145-1150), Amsalem et al. ((2014) J. Immunol. 193: 3070-3079), Matsushima et al. ((2013) Blood 121(10): 1677-1689), Edberg et al. ((1998) J. Biol. Chem. 237(14): 8071-8079), and Scapini et al. ((2014) Blood 124(5): 710-719).
[All references except Scapini et al. cited in the Final Office Action mailed 21 July 2025.]
Takashima et al. addresses some of the limitations of claim 36.
Regarding claim 36, pertaining to a human hybrid neutrophil,
Takashima et al. teaches that accumulating lines of evidence now demonstrate that neutrophils can participate in adaptive immune responses directly or indirectly. Even more striking is their potential to acquire phenotypic and functional properties that are typically reserved for professional APCs (antigen presenting cells) (pg. 489, column 1, Abstract). Human peripheral blood neutrophils have been shown to acquire various properties of APCs when cultured in the presence of selected cytokines. Many of these features were also observed for the neutrophil-DC (dendritic cell) hybrids (pg. 490, column 1, para. 2).
Further regarding claim 36, pertaining to the hybrid neutrophil co-expresses the canonical neutrophil associated myeloperoxidase (MPO), CD66b, and CD15, and the antigen presenting cell (APC) associated molecules HLA-DR, CD64, and CD89,
Takashima et al. shows a study in which neutrophils isolated from human peripheral blood were cultured in the presence of GM-CSF, IL-4, and TNF-α. Even after prolonged culture (up to 9 days) the neutrophils retained MPO expression (pg. 491, column 1, para. 1). In order to identify a human hybrid neutrophil counterpart, CD15+ band cells were purified from human BM (bone marrow) samples (pg. 490, column 1, para. 1). After cell culture for 7 days in the presence of GM-CSF, TNF-α, and IL-4, band cells retained surface expression of all tested neutrophil markers (e.g., CD15, CD24, CD66b, and CD89). The neutrophil band cells acquired the surface expression of DC (dendritic cell) markers, including MHC II [MHC II is encoded by at least the HLA-DR gene/isotype] (pg. 490, column 1, para. 1). One study showed that circulating neutrophils in sepsis patients showed elevated surface expression of CD40, CD64, and CD86 compared with control neutrophils in healthy individuals (pg. 493, column 2, para. 1).
Further regarding claim 36, pertaining to the expression of any one of the APC associated molecules is increased relative to expression of the molecule on a canonical tumor-associated neutrophil (TAN),
[See Claim Interpretations section above.]
Takashima et al. shows that it appears reasonable to state that human neutrophils can acquire surface expression of many DC markers, full APC capacity, and DC-like morphology after long-term (5–9 days) culturing in the presence of GM-CSF, IL-4, and TNF-α. Importantly, they maintain some of the original features of neutrophils (pg. 491, column 2, lines 9-14).
Takashima et al. also shows that culture conditions which included the reagents GM-CSF, IFN-γ, and TNF-α resulted neutrophils that had the neutrophil properties of, minimally, CD11b (pg. 491, Table 1, entry# 6 [i.e., the marker of a canonical TAN).
That is, because the instant specification describes canonical TANs as expressing the molecules CD11b+CD66b+CD15+, the expression of any (other) APC associated molecule (e.g., HLA-DR, CD64, CD89) on the hybrid neutrophil would be considered to show increased expression relative to a canonical TAN (see Claim Interpretations section above).
Takashima et al. does not show: 1) a non-naturally occurring container [Claim 36]; and 2) arginase-1 (Arg1), CD14 and CD32 [Claim 36].
Glasser addresses some of the limitations of claim 36.
Glasser shows the effect of storage on normal neutrophils (pg. 1145, Title [nexus to Matsushima et al.- neutrophils]).
Regarding claim 36, pertaining to a non-naturally occurring container,
Glasser shows that leukocytes were collected from the blood of healthy donors. Red cells were sedimented out and aliquots of the leukocyte-rich plasma were stored in plastic tubes at 4oC and 6oC (pg. 1145, para. 2, Materials and Methods [neutrophils are a subpopulation of leukocytes or white blood cells]). It is recommended that the storage of normal granulocytes/neutrophils collected by discontinuous-flow centrifugation (DFC) be limited to approximately 24 hr (pg. 1150, lines 2-4).
Amsalem et al. addresses some of the limitations of claim 36.
Amsalem et al. shows the identification of a novel neutrophil population (pg. 3070, Title [nexus to Takashima et al.- hybrid neutrophil]).
Regarding claim 36, pertaining to arginase-1 (Arg-1),
Amsalem et al. shows flow cytometric analyses of human decidual leukocytes. In comparison with peripheral blood neutrophils (PMNs), the decidual neutrophils expressed high levels of neutrophil activation markers and the angiogenesis-related proteins: vascular endothelial growth factor-A, Arginase-1 (ARG1), and CCL2, similarly shown in tumor-associated neutrophils (pg. 3070, Abstract). Decidual and blood neutrophils (dNs and PMNs, respectively) were identified by side and forward scatter and the relative expression of the granulocyte markers CD15 and CD66b in the CD45+ leukocyte population (pg. 3072, column 2, para. 3 [nexus to Takashima et al.- neutrophils express CD15 and CD66b]).
Matsushima et al. addresses some of the limitations of claim 36.
Matsushima et al. teaches that neutrophils have been reported to acquire surface expression of MHC class II and costimulatory molecules as well as T-cell stimulatory activities when cultured with selected cytokines (pg. 1677, Abstract). Matsushima et al. shows that CD15+/CD10-/CD64-/CD14- cells purified from human bone marrow (BM) samples, which were cultured in the presence of GM-CSF, TNFα and IL-4 maintained the expression of all tested neutrophil markers (e.g., minimally, CD15, CD66b and CD89) (pg. 1681, column 2, para. 1). Depending on the cytokine composition (of the culture medium) human neutrophils acquire additional markers of antigen presenting cells (APCs), such as CD14, CD64, CD83, CCR6 (CD196), macrophage colony-stimulating factor (M-CSF) receptor (CD115), and macrophage mannose receptor (CD206) (pg. 1677, column 1, para. 2 thru column 2, lines 1-5 [nexus to Takashima et al.- human hybrid neutrophil expressing APC associated molecules]).
Regarding claim 36, pertaining to CD14,
Matsushima et al. shows that depending on the cytokine composition (of the culture medium) human neutrophils acquire additional markers of antigen presenting cells (APCs), such as, minimally, CD14 (pg. 1677, column 1, para. 2 thru column 2, lines 1-5).
Edberg et al. addresses some of the limitations of claim 36.
Regarding claim 36, pertaining to CD32,
Edberg et al. teaches that human neutrophils express two structurally distinct receptors for the Fc region of IgG, FcγRIIa (CD32) and FcγRIIIb (CD16) (pg. 8071, Title and column 1, Abstract).
Scapini et al. provides information from which one of ordinary skill in the art of producing human hybrid neutrophils, as shown by Takashima et al., would have understood that routine optimization could have been used to determine the culture conditions required to produce a human hybrid neutrophil expressing the neutrophil- and APC- associated molecules cited in claim 36, by way of addressing the limitations of claim 36.
Regarding claim 36, Scapini et al. teaches that the concept that neutrophils may display a previously unanticipated plasticity derives from observations on their ability, under inflammatory settings, to differentiate into other myeloid cell types. Accordingly, the fact that neutrophils can acquire antigen presenting (APC)-like properties and dendritic cell (DC) characteristics on long-term incubation with discrete cytokine combinations, or be reprogrammed into macrophages, has been known for a long time. Both immature and mature mouse neutrophils have been shown to differentiate into hybrid populations showing dual phenotypes and properties of both neutrophils and DCs, either when cultured in vitro with granulocyte macrophage-colony-stimulating factor (GM-CSF) or when transferred to inflammatory settings in vivo. This study has been corroborated in humans (pg. 712, column 1, para. 1).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have stored or held the human hybrid neutrophil, shown by Takashima et al., in a non-naturally occurring container [Claim 36], as shown by Glasser, with a reasonable expectation of success, because Glasser shows that a leukocyte blood sample (which comprises neutrophils) can be stored in a plastic tube for up to 24hr (under the isolation and storage conditions described) (MPEP 2143 (I)(G)).
Even in the absence of Glasser, it would have been obvious to one of ordinary skill in the art of blood cell handling and storage to have understood that any of the component cells of a blood sample (i.e., red blood cells or white blood cells (leukocytes) (which, in turn, comprise neutrophils, eosinophils, basophils, lymphocytes and monocytes), could be stored and held and/or incubated in a non-naturally occurring container (such as the plastic tube shown by Glasser), as a well known common container for such biological samples when performing experiments or transporting said cells (MPEP 2144 (I)).
It would have been further obvious to have expected that the human hybrid neutrophil, shown by Takashima et al., would also have expressed the neutrophil associated molecule Arg-1, and the APC associated molecules CD14 and CD32 [Claim 36], as shown by Amsalem et al., Matsushima et al., and Edberg et al., with a reasonable expectation of success, because Amsalem et al., Matsushima et al., and/or Edberg et al. show that these expression molecules can be detected in/on native neutrophils or detected on a subpopulation of neutrophils considered to be novel or different from native or naïve neutrophils (e.g., the hybrid neutrophil shown by Takashima et al., and the tumor associated neutrophil (TAN) shown by Amsalem et al.) under specific biological or culture conditions (MPEP 2143 (I)(G)).
For example, Matsushima et al. shows that when cultured with granulocyte macrophage-colony-stimulating factor (GM-CSF) and interferon-γ (IFNγ), human neutrophils begin to express MHC II molecules and to function as accessory cells by promoting superantigen-induced T-cell activation (Matsushima et al., pg. 1677, column 1, para. 2). Compare to one embodiment of Applicant’s method of preparing hybrid neutrophils in which peripheral blood neutrophils are contacted with IFNγ and GM-CSF (clean copy specification filed 22 May 2024, pg. 3, lines 22-25).
One of ordinary skill in the art would have been motivated to have made those modifications, because Scapini et al. teaches that a growing amount of evidence suggests that neutrophils play critical roles in chronic inflammatory conditions, such as atherosclerosis, type 2 diabetes, vascular, liver, and intestinal inflammation, and local and systemic allergic reactions (pg. 715, column 2, para. 2). Inducing the conversion of neutrophils from protumor to antitumor cells may represent a new form of immunotherapy for cancer. In this context, because neutrophils are the most abundant population of circulating white blood cells expressing FcγR and FcαR able to execute potent cytotoxic functions, the possibility of exploiting neutrophils for antibody-based cancer immunotherapy holds significant promise and deserves further investigation (pg. 717, column 1, lines 19-25). That is, the ability of researchers to determine the biological characteristics of neutrophils via specific culture conditions therefor promote the development of hybrid neutrophils which can target specific disease disorders.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Takashima et al. further addresses the limitations of claim 37.
Regarding claim 37, pertaining to the hybrid neutrophil further expresses at least one molecule selected from a group which includes MHC class II,
Takashima et al. shows that the neutrophil band cells acquired the surface expression of DC (dendritic cell) markers, including MHC II (pg. 490, column 1, para. 1).
Matsushima et al. further addresses the limitations of claim 42.
Regarding claim 42, pertaining to CD64,
Matsushima et al. teaches that depending upon the cytokine composition, neutrophils acquire additional markers of antigen presenting cells (APCs), such as CD14, CD64, CD83, CCR6 (CD196), macrophage colony-stimulating factor (M-CSF) receptor (CD115), and macrophage mannose receptor (CD206) (pg. 1677, column 2, lines 1-5).
Therefore, it would have been obvious to have selected a hybrid neutrophil with a high expression level of CD64 compared to its expression level in/on normal or naïve neutrophils or on a canonical tumor-associated neutrophil (TAN).
[See Claim Interpretations section above.]
Claim 41 is rejected under 35 U.S.C. §103 as being unpatentable over Takashima et al. in view of Glasser, Amsalem et al., Matsushima et al., Edberg et al., and Scapini et al., as applied to claims 36, 37 and 42 above, and further in view of Fridlender et al. ((2012) Carcinogen. 33(5): 949-955), Croft et al. ((2009) Immunol. Rev. 229: 173-191), Kwon ((2009) Immune Network 9(3): 84-89), and Beauvillain et al. ((2011) Blood 117(4): 1196-1204).
[Fridlender et al., Croft et al., Kwon, and Beauvillain et al. cited in the Final Office Action mailed 21 July 2025.]
Matsushima et al. further addresses some of the limitations of claim 41.
Regarding claim 41, pertaining to CD86 and CD40,
Matsushima et al. further shows that the resulting hybrid cells express markers of both neutrophils (Ly6G, CXCR2, and 7/4) and DCs (CD11c, MHC II, CD80, and CD86) (pg. 1677, Abstract). All tested TLR (toll-like receptor) agonists elevated surface expression of CD40 by the hybrids (pg. 1684, column 1, para. 1).
Takashima et al. in view of Glasser, Amsalem et al., Matsushima et al., Edberg et al., and Scapini et al., as applied to claims 36, 37 and 42 above, do not show: 1) the hybrid neutrophil further expresses MHC class I, OX40L, 4-1BBL and CCR7 [Claim 41].
Fridlender et al. addresses some of the limitations of claim 41.
Regarding claim 41, pertaining to MHC class I,
Fridlender et al. teaches that accumulating data shows that neutrophils can participate in major histocompatibility complex (MHC) class I and class II restricted antigen presentation (pg. 951, column 1, para. 4).
Fridlender et al. further shows in Table I that APC genes are expressed to a low level in naïve neutrophils and high in G-MDSC (granulocytic myeloid-derived suppressor cells) and TAN (tumor associated neutrophils) (pg. 952, column 1, Table I). TAN show increased expression of gene pathways needed to present antigens that are not expressed in NN (naïve neutrophils), suggesting an enhanced capability of functioning as antigen-presenting cells (pg. 951, column 2, lines 3-6).
Croft et al. addresses some of the limitations of claim 41.
Regarding claim 41, pertaining to OX40L,
Croft et al. teaches that although it was thought for a long time that OX40 expression was restricted to activated conventional T cells, it has now been visualized on, minimally, activated regulatory T cells, and neutrophils (pg. 173, column 2, para. 2). OX40L can be induced on professional antigen-presenting cells (APCs) such as, minimally, dendritic cells (DCs), in line with its action in controlling the extent of T-cell priming following recognition of antigen (pg. 174, column 1, para. 1 [nexus to Matsushima et al.- hybrid neutrophil expresses DC expression molecules]).
Kwon addresses some of the limitations of claim 41.
Regarding claim 41, pertaining to 4-1BBL,
Kwon teaches that among amyloid cells, neutrophils seem to constitutively express CD137, even though its levels are low on the cell surface. CD137 expression also is induced on other granulocytes (pg. 85, column 1, lines 1-6). CD137 is also known as 4-1BB; CD137 ligand is also known as CD137L and 4-1BBL (pg. 84, column 1, para. 2). CD137L is constitutively expressed on professional antigen-presenting cells (dendritic cells, monocyte/macrophages, and B cells) and upregulated by their respective activation stimuli. Data have shown that CD137L expression is observed on various cell types, including neutrophils and fibroblasts (pg. 85, column 1, para. 1 [nexus to Matsushima et al.- hybrid neutrophil expresses DC expression molecules]).
Beauvillain et al. addresses some of the limitations of claim 41.
Regarding claim 41, pertaining to CCR7,
Beauvillain et al. teaches that increasing evidence suggests that neutrophils may participate in the regulation of adaptive immune responses, and can reach draining lymph nodes and cross prime naive T cells. Beauvillain et al. shows a study to identify the mechanism(s) involved in the migration of neutrophils to draining lymph nodes. The presented data demonstrate that a subpopulation of human and mouse neutrophils express CCR7. Stimulated human neutrophils migrate in response to the CCR7 ligands CCL19 and CCL21 (pg. 1196, Abstract).
Beauvillain et al. also teaches that the expression of CCR7 by DCs (dendritic cells) is induced, among other stimuli, by microbes and microbial moieties, and characterizes a mature phenotype (pg. 1196, column 2, para. 1 [nexus to Matsushima et al.- hybrid neutrophil expresses DC expression molecules]). Intradermally injected interleukin-17– and granulocyte-macrophage colony stimulating factor (GM-CSF) –stimulated neutrophils from wild-type mice migrate to the draining lymph nodes (pg. 1196, Abstract [nexus to Matsushima et al.- induction of DC expression molecules on neutrophils by culturing them in GM-CSF]).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the human hybrid neutrophil which co-expresses the neutrophil associated molecules Arg-1, MPO, CD66b, CD15, and the APC associated molecules CD14, HLA-DR, CD32, CD64 and C89, as shown by Takashima et al. in view of Glasser, Amsalem et al., Matsushima et al., Edberg et al., and Scapini et al., as applied to claims 36, 37 and 42 above, by selecting hybrid neutrophils that further express MHC class I, OX40L, 4-1BBL and CCR7 molecules [Claim 41], with a reasonable expectation of success, because Fridlender et al., Croft et al., Kwon, and Beauvillain et al. show that neutrophils express these molecules (either natively or under inducible conditions) (MPEP 2143 (I)(G)).
Therefore, it would have been obvious to one of ordinary skill in the art of cell sorting to have established a flow cytometry protocol in order to isolate hybrid neutrophils which also express MHC class I, OX40L, 4-1BBL, CD86, CD40, and CCR7, because the prior art references either show that neutrophils can express these molecules or show that one of ordinary skill in the art would have expected that neutrophils could express said molecules because they are expressed on APCs- and the prior art shows that expression of such APC molecules are able to be induced in/on neutrophils (MPEP 2143 (I)(G)).
Fridlender et al. shows in Table I that APC genes are expressed to a low level in naïve neutrophils and high in G-MDSC (granulocytic myeloid-derived suppressor cells) and TAN (tumor associated neutrophils) (pg. 952, column 1, Table I). TAN show increased expression of gene pathways needed to present antigens that are not expressed in NN (naïve neutrophils), suggesting an enhanced capability of functioning as antigen-presenting cells (pg. 951, column 2, lines 3-6).
One of ordinary skill in the art would have been motivated to have made those modifications, because Fridlender et al. teaches that recent evidence shows that TANs can be altered to assume antitumor roles (N1 TAN) (pg. 953, column 2, para. 1). Beauvillain et al. shows that simulated (hybrid) neutrophils express CCR7 which is involved in neutrophil migration to lymph nodes (pg. 1196, Abstract). Kwon teaches that CD137/CD137L interactions are involved in inflammation, and that the interactions regulate inflammation by forming a complex network connecting various immune cells and non-immune cells (pg. 84, column 2, para. 1). That is, the various APC molecules or markers play distinctive roles in supporting a variety of immune responses, and, therefore, one of ordinary skill in the art would have been motivated to have screened “activated” neutrophils in order to collect those that express as many neutrophil and APC molecules as possible.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP 2159. See MPEP 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/ patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/ patents/apply/applying-online/eterminal-disclaimer.
Claims 36, 37 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 16 of Patent No. 11,925,662 B2.
The claimed subject matter of instant Application No. 18/431,638 is:
Claim 36. A human hybrid neutrophil in a non-naturally occurring container. The hybrid neutrophil co-expresses the canonical neutrophil associated molecules arginase-1 (Arg1), myeloperoxidase (MPO), CD66b, and CD15, and the antigen presenting cell (APC) associated molecules CD14, HLA-DR, CD32, CD64, and CD89. The expression of any one of the APC associated molecules is increased relative to expression of the molecule on a canonical tumor-associated neutrophil (TAN).
Claim 37. The human hybrid neutrophil further expresses molecules at least one molecule selected from the group consisting of: MHC class I, MHC class II, OX40L, 4-1BBL, CD86, CD40, and CCR7.
Claim 41. The human hybrid neutrophil further expresses molecules MHC class I, OX40L, 4-1BBL, CD86, CD40, and CCR7.
The claimed subject matter of Patent No. 11,925,662 is:
Claim 1. A method of inhibiting tumor growth in a human subject. The method comprises: (a) administering to the subject an effective amount of an anti-tumor antibody or an antigen-binding fragment thereof; and
(b) administering to the subject an effective amount of a human hybrid neutrophil, wherein the hybrid neutrophil co-expresses the canonical neutrophil associated molecules arginase-1 (Arg1), myeloperoxidase (MPO), CD66b, and CD15, and the antigen presenting cell (APC) associated molecules CD14, HLA-DR, CD32, CD64, and CD89, thereby inhibiting tumor growth in the subject.
Claim 2. The human hybrid neutrophil further expresses molecules at least one molecule selected from the group consisting of: MHC class I, MHC class II, OX40L, 4-1BBL, CD86, CD40, and CCR7.
Claim 3. The expression of any one of the molecules is increased relative to expression of the molecule on a canonical neutrophil.
Claim 4. The human hybrid neutrophil co-expresses Arg1, MPO, CD66b, CD15, CD14, HLA-DR, MHC class I, OX40L, 4-1BBL, CD86, CD40, CCR7, CD32, CD64 and CD89.
Claim 16. A method of treating a tumor in a human subject. The method comprises: (a) administering to the subject an effective amount of an anti-tumor antibody or an antigen-binding fragment thereof; and
(b) administering to the subject an effective amount of a human hybrid neutrophil, wherein the hybrid neutrophil co-expresses the canonical neutrophil associated molecules arginase-1 (Arg1), myeloperoxidase (MPO), CD66b, and CD15, and the antigen presenting cell (APC) associated molecules CD14, HLA-DR, CD32, CD64, and CD89, thereby treating the tumor in the subject.
Although the claims are not identical, they are not patentably distinct from each other because, as demonstrated above in the claim sets from each application, the method of inhibiting tumor growth and the method of treating a tumor comprising administering a human hybrid neutrophil, described in Patent No. 11,925,662 B2 anticipates the hybrid neutrophil, described in instant Application No. 18/431,638.
Response to Arguments
Applicant’s arguments, pp. 6-12, filed 20 October 2025, with respect to the prior art references cited in the 35 U.S.C. §103 rejections, have been fully considered but they are either not persuasive or are moot because the arguments do not apply to the references as they are applied in the context of the current rejection, or as new grounds necessitated by Applicant’s amendment, in which claim 36 was amended.
1. Applicant remarks (pg. 7, para. 5 thru pg. 10) that Matsushima identified analogous population of cells in tumor-free mice, which they termed hybrid neutrophils. A substantial body of evidence has demonstrated striking phenotypic and functional differences between murine and human neutrophils. The alleged murine hybrid neutrophils of Matsushima differ fundamentally from the hybrid neutrophils disclosed and claimed in the instant application for at least the following key reasons (see pp. 7 thru 10).
However, in response to Applicant, Matsushima et al. is not the primary reference in the 103 rejection above; Takashima et al. has been cited to show human hybrid neutrophils. On the other hand, although Matsushima et al. does show studies exemplifying murine neutrophils, Matsushima et al. also shows studies conducted to identify a human counterpart (to murine hybrid neutrophils): "To identify a human counterpart, we cultured D15+/CD10-/CD64-/CD14- band cells purified from human BM samples in the presence of GM-CSF, TNFα, and IL-4...they maintained the expression of all tested neutrophil markers (e.g., CD15, CD24, CD66b, and CD89),...[and] expressed all tested DC markers (HLA-DR, CD1c, and CD11c)... Thus, human neutrophils can also differentiate into a hybrid population characterized by dual expression of both neutrophil and DC markers" (Matsushima et al., pg. 1681, column 2, para. 1).
2. Applicant remarks (pg. 10, para. 1) that given the unpredictability in the art of immunotherapy and the key differences between murine and human neutrophils, a person of ordinary skill would not have been motivated to combine Matsushima with the additional references cited by the Examiner to arrive at the claimed invention with a reasonable expectation of success. The cited references would not have suggested to those of ordinary skill in the art that they should make the claimed composition; nor would the references have revealed that in so making or carrying out, those of ordinary skill would have a reasonable expectation of success.
However, in response to Applicant, again, the differences between murine and human neutrophils cited by Applicant are irrelevant with regard to the current prior art rejections. Both Takashima et al., and Matsushima et al. shows human hybrid neutrophils.
3. Applicant remarks (pg. 10, para. 2 thru pg. 11) that Glasser, Amsalem, Fridlender, Edberg, and Takashima fail to overcome the deficiencies of Matsushima because nowhere in the cited references is the teaching or suggestion of a human hybrid neutrophil, much less a human hybrid neutrophil that co-expresses Arg1, MPO, CD66b, CD15, CD14, HLA-DR, CD32, CD64, and CD89. Edberg only describes a native canonical human neutrophil and demonstrated that canonical neutrophils can express FcγRIIa (CD32) and FcγRIIIb (CD16) and become activated through their engagement. Amsalem only describes the presence of canonical neutrophil associated molecules (i.e., Arg1). Fridlender only discusses the use of a tumor-associated neutrophil (TAN) in mice, which according to the instant specification, is different from a hybrid neutrophil. A canonical TAN usually expresses classic neutrophil markers.
However, in response to Applicant, Takashima et al. and Matsushima et al. show that hybrid neutrophils maintained the expression of all tested neutrophil markers (e.g., CD15, CD24, CD66b, and CD89). Therefore, it would have been obvious to one of ordinary skill in the art of identifying (e.g., by flow cytometry) cell markers expressed on a cell surface to have understood that all of the canonical or classic "neutrophil markers" (e.g., those shown by Amsalem et al., Matsushima et al., and Edberg et al.) would have also been expressed on the hybrid neutrophils as well (unless shown to the contrary by Applicant), although some of these canonical neutrophil markers were not explicitly tested by Takashima et al. or Matsushima et al.
Further in response to Applicant, a rejection under 35 USC §102/103 can be made when the prior art product seems to be identical except that the prior art is silent as to an inherent characteristic…This same rationale should also apply to product, apparatus, and process claims claimed in terms of function, property or characteristic MPEP 2112 (III). The PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on 'inherency' under 35 USC 102, on 'prima facie obviousness' under 35 USC 103, jointly or alternatively, the burden of proof is the same In re Best, 562 F .2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977) (MPEP 2112 (V)). Here, the inherent characteristic is/are the canonical neutrophil markers untested by Takashima et al. and Matsushima et al.
4. Applicant remarks (pg. 11, para. 3) that the rejection combines elements from work on mouse and human neutrophils without regard to the well documented differences between the neutrophils of the two species that would dissuade a skilled person from relying on work on mouse neutrophils when working on human neutrophils and that would therefore destroy any reasonable expectation of success. Furthermore, the rejection assumes that because expression of variously Arg1, MPO, and CD32, are mentioned in the supporting references that it can be assumed that they are expressed under the conditions that allegedly produced expression of CD66b, CD15, CD14, HLA-DR, CD32, CD64, and CD89 as performed in Matsushima. A person of ordinary skill in the art would not make this assumption and therefore there is no motivation to combine the teachings of the secondary references with those of Matsushima.
However, in response to Applicant, as taught by Scapini et al. (cited above in the 103 rejection), the concept that neutrophils may display a previously unanticipated plasticity derives from observations on their ability, under inflammatory settings, to differentiate into other myeloid cell types. The fact that neutrophils can acquire antigen presenting (APC)-like properties and dendritic cell (DC) characteristics upon long-term incubation with discrete cytokine combinations, or be reprogrammed into macrophages, has been known for a long time (Scapini et al., pg. 712, column 1, para. 1). That is, in view of the extant prior art literature identifying detectable (hybrid) neutrophil cell surface markers, it would have been obvious to one of ordinary skill in the art to have designed a neutrophil cell culture protocol so that the resulting neutrophils would have been induced to express desired cell surface markers, including those indicative of APCs and/or DCs, as well as canonical or classic neutrophil markers (e.g., those cited in instant claims 36, 37 and 41).
5. Applicant remarks (pg. 12), with regard to the rejection of dependent claim 41, that MPEP 2143.01 provides: "The mere fact that references can be combined or modified does not render the resultant combination obvious unless the prior art also suggests the desirability of the combination." Croft is, at best, a review article that discusses OX40 and OX40L in the context of conventional T cell and regulatory T cells. Kwon describes CD137L is expressed on neutrophils. Beauvillain describes that human neutrophils express CCR7. Nowhere in the cited references is the teaching or suggestion of a human hybrid neutrophil, much less a human hybrid neutrophil that co-expresses both the canonical neutrophil associated molecules and the antigen presenting cell associate molecules, which include Arg1, MPO, CD66b, CD15, CD14, HLA-DR, CD32, CD64, CD89, MHC class I, MHC class II, OX40L, 4-1BBL, CD86, CD40, and CCR7.
However, in response to Applicant, as stated above, it would be obvious to one of ordinary skill in the art of neutrophil cell identification and selection to devise a neutrophil cell culture protocol (possibly mimicking inflammatory settings, as taught by Scapini et al.) which would induce the neutrophils to take on a hybrid neutrophil phenotype exhibited by the presentation of specific cell surface markers representing canonical neutrophils, APCs (antigen presenting cells), and/or DCs (dendritic cells), depending on the desired hybrid neutrophil phenotype.
Conclusion
No claims are allowed.
This Office action is a Non-Final action. A shortened statutory period for reply to this action is set to expire THREE MONTHS from the mailing date of this action.
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/SMP/ Examiner, Art Unit 1651
/MELENIE L GORDON/ Supervisory Patent Examiner, Art Unit 1651