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 .
This action is in response to the papers filed on 06/05/2023. Claims 1, 2, 5, 6, 8, 10, 11, 13-25 are currently pending as per claims filed on 06/05/2023. Claims 3, 4, 7, 9, and 12, are cancelled as per claims filed on 06/05/2023. Claims 1, 2 and 18 are independent claims.
Therefore, claims 1, 2, 5, 6, 8, 10, 11, 13-25 are examine in their merits to which the following grounds of rejection are applicable.
Priority
The instant application is a 371 of PCT/US2021/034817 filed on 05/28/2021 which claims benefit of 63/031,184 filed on 05/28/2020. Thus, the earliest possible priority for the instant application is 05/28/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/14/2023, was filed before the mailing date of the non-final office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 1, 2, 6, 10, 14 and 24 are in improper Markush form; a Markush group should be in the form “selected from the group consisting of A, B, and C”. Appropriate correction is requested
Claim 1 is objected to because abbreviations such as NK should be spelled out at their first encounter in the claims. Appropriate correction is required.
Claim 17 is objected to because abbreviations such as FcγR should be spelled out at the first encounter in the claims. Appropriate correction is required.
Claim 19 is objected to because abbreviations such as G-CSF should be spelled out at the first encounter in the claims. Appropriate correction is required.
Claim 20 is objected to because abbreviations such as FcγRI should be spelled out at the first encounter in the claims. Appropriate correction is required.
Claim 24 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 14. Claim 24 is no different in scope than claim 14, in light of the preamble of claim 2. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 706.03(k).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 5, 6, 8, 10, 11, 13-25 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 and 2 are vague and indefinite in the recitation of “direct” (claim 1) and “indirect” (claim 2). It is unclear what constitutes whether the method is direct or indirect as there is no comparative method to determine if the method is direct or indirect. Appropriate correction is required. Claims 8, 10, 11, and 21 are included in the rejection as it directly or indirectly depends on claim 1. Claims 5, 6, 14-17, 20, 22-25 are included in the rejection as it directly or indirectly depends on claim 2.
Claim 1 is indefinite in its recitation of “said immunologically active anti-B cell antibody” in line 8. There is not proper antecedent bases for “said immunologically active anti-B cell antibody” in the claim.
Claims 1, 2, 15, 16, 17, 18 are indefinite in their recitation of “essentially naïve condition” The term " essentially naïve condition " is not defined by the claim”. The specification does not provide any closed definition as to what is meant by “essentially naïve condition”. The term “essentially” is a relative term. Thus the metes and bounds of the claim are indefinite.
Claims 1, 2, 5, 8 and 18 are indefinite in their recitation of “immunologically active” as it is unclear as to “immunologically active” function or functions that are intended as being encompassed by the noted phrase. Antibodies or antibody fragments (e.g., Fab) are known in the prior art to have numerous immune activities, both specific and general. For example, all antibodies are used by the immune system to identify and neutralize antigens. It is suggested that applicant clarify the intended meaning of the noted phrase.
Claim 1 is indefinite in its recitation of “a naive target T cell fraction” in the preamble. The term " naive target T cell fraction " is not defined by the claim”. The specification does not provide any closed definition as to what is meant by “naive target T cell fraction”. Thus, it is unclear how “recovering the target T cell fraction” in step c) of claim 1 results in “a naive target T cell fraction”. Therefore, the metes and bounds of the claim are indefinite.
Claim 1 is indefinite because of its recitation “upon binding” in step a) line 12. The claim refers in step a) line in line 7 to “simultaneously binds to both Fc receptor-bearing cells and epitopes on B cells present in said preparation”. Thus, it is unclear the phrase “upon binding” refers to “simultaneously binds to both Fc receptor-bearing cells and epitopes on B cells” or other binding. As such the metes and bounds of the claim are indefinite.
Claims 1, 11 15, 16, and 17, “a ferrofluid comprising magnetically responsive particles” “a ferrofluid having magnetically responsive particles” “magnetically responsive particles present in ferrofluid; “magnetically responsive particles present in ferrofluid;” “particles present in ferrofluid”, respectively. The Specification discloses in paragraph [0022] of the published application that “PBMC were first incubated with anti-CD3 mAb and subsequently magnetically labeled with common capture versions of our 135-165 nm proprietary highly magnetic nanoparticles (alternatively referred to as ferrofluid or FF)”. In other words, the Specification discloses that ferrofluid is an alternative name for highly magnetic nanoparticles. Thus, it is unclear how a ferrofluid can simultaneously contain magnetic nanoparticles and being itself a nanoparticle. As such the metes and bounds of the claims are indefinite.
Claim 5 recites the term “and, or” in line 2. It is unclear what the metes and bounds of this term, as “and” could be interpreted as the capture agent includes both biotinylated antibody and an immunologically active fragment, or, “or” would imply that the capture agents are in the alternative. Appropriate correction is required. Claims 6 is included in the rejection as it directly or indirectly depends on claim 5.
Claim 10 which depends on claim 1 is indefinite because of the recitation of “said binding pair members”. There is not proper antecedent bases for “said binding pair members” in the claim or parent claim 1.
Claim 13 depends from cancelled claim 12, thereby rendering it indefinite and is therefore “incomplete”. See MPEP § 608.01(n)(V). The claim 13 limitation (“each antibody…” ) lacks antecedent basis from canceled base claim 12. See MPEP § 2173.05(e). It appears claim 13 should depend from 2. For purposes of compact prosecution, for the remainder of examination, claim 13 will be considered as if it depended on 2.
Claim 17 is vague and indefinite in the recitation of “under conditions suitable for high affinity FcγR binding”. It is unclear what constitutes “high affinity FcγR binding” as “high” is relative terminology. The specification fails to further describe the relativeness of “high affinity FcγR binding” and what conditions would be required to achieve binding.
Claim 18 is indefinite in the recitation of “an essentially naïve”. Neither the Specification nor claims define “CD34+ stem cells in an essentially naïve condition”. It is unclear in reference to what the selection of CD34+ stem cells is completed as naïve. Claim 20, is vague and indefinite in the recitation of “concentrations which promote interactions”. It is unclear what constitutes “promote interactions”. The specification fails to further describe what concentration would promote interactions and how one would know if interactions were promoted sufficiently.
Claim 21 and 25 are indefinite in their recitation of “ferrofluid comprises ….monoclonal antibodies per particle.” The Specification discloses in paragraph [0022] that ferrofluid is an alternative name for highly magnetic nanoparticles. Thus, it is unclear if the claimed antibodies per particle refer to antibodies per ferrofluid or magnetic nanoparticles or to a different type of particle. For consistency in the claims, it is recommended to use the same term, e.g., either ferrofluid or magnetic nanoparticles.
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.
Claim(s) 1, 2, 5-6, 8, 10-11, 13-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liberti et al (WO Publication No. 2018/022694 Al, Date of Publication February 1, 2018; Citations are from the National Stage U.S. Patent Application No. US 2020/0010826 Al.) and further in view of Fowler et al (US Application Publication No. 20060159667 A1), Robak et al (BioDrugs, 2011, page 13-25), Martinex et al (Ann Hematol, 1996, Page 269-272), Saha et al (Analytical Chemistry, 2014, Page 8158-66), Boesch (mAbs, 2014, Page 915-927), and Arce Vargas et al (Cancer Cell, 2018, page 649-663).
The applied Liberti reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). The publication dated for Liberti is 1 February 2018. The earliest effective filing date of the instant application is May 28 2020.
Therefore rejection under 35 U.S.C. 103 CANNOT be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02. Because the reference qualifies as prior art under 102(a)(1), the provisions of MPEP 717.02 do not apply.
Regarding claim 1, Liberti teaches negative selection of T cells by a method of separating and activating a population of T cells (page 14, para 0084) comprising:
incubating a sample comprising a blood product, wherein the blood product comprises mononuclear cells obtained from peripheral blood” (page 15, para 0086, column 2) and “the PBMC layer was removed and washed by centrifugation with Mg- and Ca-free DPBS containing 1 % HSA to pellet the cells. The cell pellet was re-suspended and re-centrifuged at 300 ref two more times to remove platelets” (i.e. removing endogenous or added IgG) (page 11, para 0073), rendering obvious a direct method (i.e. negative selection) of isolating a naïve target T cell fraction from a peripheral blood mononuclear cell (PBMC) preparation comprising at least T and B cells said preparation substantially lacking endogenous or added IgG;
and “a population of magnetic particles bound to at least one second antibody that binds to a cell surface protein of a cell in the blood product that is not a T cell” (claim 40 of US 2020/0010826). The examiner notes in paragraph [0012] an “antibody” is defined as full-length antibodies and antibody fragments. One of ordinary skill in the art would readily appreciate that a full-length antibody comprises a Fc fragment that would bind Fc receptors on the cell surface of cells of a blood product that is not a T cell. Binding to Fc receptors on the cell surface of cells would lead to clustering of Fc receptor-bearing cells when the antibody is linked to a nanoparticle, rendering obvious introducing into said PBMC preparation, a capture agent (e.g., anti-mouse IgG or streptavidin; para 0016) comprising a single immunologically active antibody and a functional fragment thereof operably linked to a ferrofluid comprising magnetically and non-magnetically responsive particles-which forms a magnetic cluster of Fc receptor-bearing cells.
Liberti also teaches “applying a magnetic force to the sample and separating the cells that are bound to the magnetic particles from the cells that are not bound to the magnetic particles, wherein the labeled magnetic particles are labeled with a common-capture reagent” capable of binding the at least one separation antibody (e.g, one antibody that binds to a T cell surface protein for isolation of the magnetically labeled T-cells; para 0063), rendering obvious isolating said magnetic cluster from said preparation in a magnetic separator; and recovering the target T cell fraction not bound by either the capture agent of step a) or ferrofluid in an essentially naïve condition.
However, Liberti does not teach that the immunologically active antibody is an anti-B cell antibody which can simultaneously bind to both Fc receptor-bearing cells and to epitopes on B cells.
Fowler teaches a lymphocyte fraction is depleted of B cells by incubation with an anti-B cell antibody and sheep anti-mouse magnetic beads (page 18, para 0190) and that T cells from C57Bl/6 mice were purified by negative selection using anti-B cell antibodies (page 17, para 0187). Furthermore, Robak teaches that rituximab (i.e. an anti-B cell antibody which binds to CD20 epitope on B cells) also activates FC receptors that are expressed on NK cells, macrophages, and dendritic cells (Page 14, col 2, para 2) and compared to rituximab, new antibodies have increased Fc binding affinity for the low-affinity variants of the FcγRIIIa receptor on immune effector cells (abstract, Page 13).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of using a negative selection process for isolating naïve T cells from PBMC with a separation antibody (common capture agent) on a magnetic particle from Liberti with a second immunological active agent that is an anti-B cell antibody that binds to both: B cell epitopes and Fc receptors according to Robak where the capture agent can be functionally linked to magnetic beads as contemplated by Fowler to ultimately achieve a method of isolating a T cell fraction not bound to a single immunologically active anti-B cell antibody which simultaneously binds to both Fc receptor-bearing cells and to B cell epitopes using said anti-B cell antibody linked to magnetic particles. One would be motivated to do so to selectively isolate T cells that are not affected by binding to a magnetic particle comprising an anti-B cell antibody as a capture agent for subsequent use of T cells in immunotherapy. A skilled artisan would have had a reasonable expectation of success as separating a cell fraction from a sample that binds to an antibody attached to magnetic nanoparticles to remove/separate them from an unattached cell fraction was known in the art at before the effective filing date of the claimed of the invention.
Regarding claim 2, Liberti teaches negative selection of T cells by a method of separating and activating a population of T cells (page 14, para 0084) comprising:
incubating a sample comprising a blood product, wherein the blood product comprises mononuclear cells obtained from peripheral blood (claim 1 of US2020/0010826) and “the PBMC layer was removed and washed by centrifugation with Mg- and Ca-free DPBS containing 1 % HSA to pellet the cells. The cell pellet was re-suspended and re-centrifuged at 300 ref two more times to remove platelets (i.e. removing endogenous or added IgG) (page 11, para 0073), rendering obvious a direct method (i.e. negative selection) of isolating a naive target T cell fraction from a peripheral blood mononuclear cell (PBMC) preparation comprising at least T and B cells said preparation substantially lacking endogenous or added IgG;
and “a population of magnetic particles bound to at least one second antibody that binds to a cell surface protein of a cell in the blood product that is not a T cell” (claim 49 of US2020/0010826) and the second antibody which can be a biotinylated antibody (i.e. first member of binding pair (biotin) operably linked to capture agent) (page 9, para 0065), rendering obvious introducing into said PBMC preparation, a capture agent comprising a single immunologically active antibody and said capture agent being operably linked to a first member of a specific binding pair.
Liberti also teaches magnetic nanoparticles that are a solid, HSA-coated ferrofluid nanoparticle and “the first common-capture agent immobilized on the magnetic nanoparticle is streptavidin” (i.e. second binding pair) (page 10, para 0066), that various common capture agents (e.g. anti-mouse IgG or streptavidin) can be covalently coupled (page 2, para 0016), and at least one antibody binds to the common-capture reagent bound to the magnetic particle and the antibody is labeled with biotin (page 4, para 0028), rendering obvious contacting the preparation of step (a) with a ferrofluid comprising magnetically responsive particles operably linked to a second binding member, under conditions where a specific binding pair forms between said first and second binding pair members forming a magnetic cluster.
Liberti further teaches the cocktail of antibodies and nanoparticles are rapidly combined, mixed with cells containing the desired T cell subset or subsets, and a magnetic force is employed to separate magnetically labeled cells (page 10, para 0066), rendering obvious isolating said magnetic cluster from said preparation in a magnetic separator and recovering the target T cell fraction not bound by either immunologically active capture agent or ferrofluid in an essentially naïve condition.
However, Liberti does not teach that the immunologically active antibody is an anti-B cell antibody. Fowler teaches a lymphocyte fraction is depleted of B cells by incubation with an anti-B cell antibody and sheep anti-mouse magnetic beads (page 18, para 0190) and that T cells from C57Bl/6 mice were purified by negative selection using anti-B cell antibodies (page 17, para 0187). Furthermore, Robak teaches that rituximab (i.e. an anti-B cell antibody which binds to CD20 epitope on B cells) also activates FC receptors that are expressed on NK cells, macrophages, and dendritic cells (Page 14, col 2, para 2) and compared to rituximab, new antibodies have increased Fc binding affinity for the low-affinity variants of the FcγRIIIa receptor on immune effector cells (abstract, page 13).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of using a negative selection process for isolating a fraction of T cells from PBMC with a second immunological active agent that is an anti-B cell antibody that binds to both: B cell epitopes and Fc receptors according to Robak and wherein the immunological active agent (anti-B cell antibody) is biotinylated and where a capture agent (streptavidin from Liberti) can be functionally linked to magnetic beads as contemplated by Liberti to ultimately achieve a method of isolating a T cell fraction not bound to a single immunologically active anti-B cell antibody which simultaneously binds to both Fc receptor-bearing cells and to B cell epitopes using said anti-B cell antibody linked to a first member binding member (biotin) and can form binding pairs with streptavidin-bound magnetic particles. One would be motivated to do so to selectively isolate T cells that are not affected by binding to a magnetic particle comprising an anti-B cell antibody capture agent for subsequent use. A skilled artisan would have had a reasonable expectation of success as separating a cell fraction from a sample that binds to an antibody attached to magnetic nanoparticles to remove/separate them from an unattached cell fraction was known in the art at before the effective filing date of the claimed of the invention. Regarding claim 5, the teachings of Liberti, Fowler, and Robak render obvious claim 2. Moreover, Liberti teaches combining with at least one separation antibody that is selected from the group comprising biotinylated mouse-derived anti-human CD4 of the lgG2a subclass, biotinylated mouse-derived antihuman CD8 of the lgG2a subclass, or combinations thereof (page 10, para 0066). Moreover, Liberti teaches “the separation antibody can be any antibody that one of skill in the art wants to use to separate cells” (page 10, para 0066) and “the magnetic nanoparticle can be a solid, HSA-coated ferrofluid nanoparticle, and the first common-capture agent immobilized on the magnetic nanoparticle is streptavidin” (page 9, para 0065), rendering obvious capture agent of step a) i) is an a biotinylated antibody and,or immunologically active fragment thereof, and said second binding pair member is a biotin binding streptavidin ferrofluid. Liberti exemplifies in example 5 (para [0083]) positive selection of a T Cell Subset (i.e., CD4+ T Cells) by using two antibodies, a separation antibody that is biotinylated and an activation antibody, e.g, a mouse-derived anti-human CD3 of the IgG1 subclass that are combined with two nanoparticles, a) a streptavidin-coated ferrofluid and b) a non-magnetic nanoparticle. Regarding claim 6, the teachings of Liberti, Fowler, and Robak render obvious claim 5 and 2. Moreover, Liberti teaches that separation antibodies include, but are not limited to, anti-CD11b, anti-CD16, anti-CD19 (page 10, para 0066), rendering obvious wherein the Fab region binds a B cell epitope CD19.
Regarding claim 8, the teachings of Liberti, Fowler, and Robak render obvious claim 1. Moreover, Fowler teaches a lymphocyte fraction is depleted of B cells by incubation with an anti-B cell antibody and sheep anti-mouse magnetic beads (page 18, para 0190) and that T cells from C57Bl/6 mice were purified by negative selection using anti-B cell antibodies (page 17, para 0187). Furthermore, Robak teaches that rituximab (i.e. an anti-B cell antibody which binds to CD20 epitope on B cells) also activates FC receptors that are expressed on NK cells, macrophages, and dendritic cells (Page 14, col 2, para 2) and compared to rituximab, new antibodies have increased Fc binding affinity for the low-affinity variants of the FcγRIIIa receptor on immune effector cells (abstract, page 13), rendering obvious the capture agent of step a) is a monoclonal IgG antibody of mouse or human origin and comprises Fc regions which are bound by human FcγR.
Regarding claim 10, 14, and 24, the teachings of Liberti, Fowler, and Robak render obvious claim 1 and 2. Moreover, Liberti teaches an activation antibody is biotinylated mouse-derived anti-human CD3 and the second common-capture agent immobilized on the solid non-magnetic particle is streptavidin (page 10, 0069), rendering obvious wherein said binding pair members are selected from biotin-streptavidin, receptor-ligand, agonist- antagonist, lectin-carbohydrate, avidin-biotin, biotin analog-avidin, desthiobiotin- streptavidin, desthiobiotin-avidin, iminobiotin-streptavidin, and iminobiotin-avidin.
Regarding claim 11, the teachings of Liberti, Fowler, and Robak render obvious claim 1. Moreover, Liberti teaches the magnetic nanoparticle is a solid, HSA-coated ferrofluid nanoparticle, and the first common-capture agent immobilized on the magnetic nanoparticle is rat-derived anti-mouse lgGl (page 10, para 0069), rendering obvious wherein the capture agent comprises a ferrofluid having magnetically responsive particles operably linked to a rat-anti-mouse IgG antibody or a mouse anti-human IgG antibody.
Regarding claim 13, while Liberti does not disclose that each antibody comprises between 3-7 biotin molecules.
However, Apexbt discloses that biotinylating of proteins “ordinarily will yield incorporation of 3-5 biotins per molecule of protein. Antibodies, which are large proteins, often will label with ~8-12 biotin molecules per molecule of IgG, especially when greater molar excesses of biotin reagent are used. The molar ratio of biotin reagent to protein may be adjusted to obtain the level of incorporation desired.” (Page 1, Procedure for Biotinylating Proteins, downloaded on 02/04/2026).
Therefore, in the view of determining the proper number of biotin molecules for each antibody, it would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to combine the teachings of Liberti of using biotinylated antibodies to isolate target T cell fraction, the teachings of Fowler and Robak where antibodies binding to both Fc receptor–bearing cells and B cells can be attached to magnetic particles with the teachings of Apexbt to determine the number of biotin molecules per antibody to achieve the correct concentration of biotin-to-antibody. One would be motivated to do so to achieve ideal binding efficiency of second binding member streptavidin to the biotin on the antibodies and thus optimal isolation of cells of interest.
Applicant is reminded that differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson,315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). See MPEP § 2144.
Regarding claim 15 and 16, the teachings Liberti, Fowler, and Robak render obvious claim 2. Moreover, Liberti teaches separating and activating of a sub-population of T cells using a population of magnetic particles bound to at least one first antibody that binds to the cells not in a desired sub-populations of T cells in the blood product and “if one desired to collect CD8+ cells, but not the CD4+ cells, then the at least one first antibody would not comprise an anti-CD8 antibody, but would have an anti-CD4 antibody” and vice versa (page 8, para 0057), rendering obvious isolation of CD3+, CD8+ T cells wherein step a) i) or step a) ii) comprise a second capture agent which binds to CD4+ T cells, each of said first and second agents being operably linked to magnetically responsive particles present in ferrofluid, isolating said capture agent-bound Fc receptor-bearing cells, B cells and CD8+ cells from said preparation in a magnetic separator; and recovering CD3+, CD4+ T cells not bound by either capture agent or ferrofluid in an essentially naive condition (claim 15) and a second capture agent which binds to CD4+ T cells, each of said first and second agents being operably linked to magnetically responsive particles present in ferrofluid, isolating said capture agent-bound Fc receptor-bearing cells, B cells and CD4+ cells from said preparation in a magnetic separator; and recovering CD8+ T cells not bound by either capture agent or ferrofluid in an essentially naive condition.
Regarding claim 17, the teachings of Liberti and Fowler render obvious claim 2. Moreover, Liberti teaches separating and activating of a sub-population of T cells using a population of magnetic particles bound to at least one first antibody that binds to the cells not in a desired sub-populations of T cells in the blood product and if one desired to collect CD8+ cells, but not the CD4+ cells, then the at least one first antibody would not comprise an anti-CD8 antibody, but would have an anti-CD4 antibody (page 8, para 0057). Liberti also teaches “the separation antibody can also be referred to as the first antibody. Whether or not an antibody or a plurality of antibodies is referred to as a first or second antibody is not critical. Additionally, this list of antibodies is non-limiting and any other antibody could be used to separate cells from a population being processed based upon the preference of the user” (page 5, para 0032), rendering obvious a second immunologically active capture agent (first or second antibody) which binds to CD3+ T cells each of said first and second capture agents being operably linked to magnetically responsive particles present in ferrofluid, such that NK cells are isolated.
However, Liberti does not teach that the conditions are suitable for high affinity FcγR binding. It would have been prima facie obvious to one of ordinary skill in the art to optimize the conditions to permit high affinity FcγR binding as required by claim 17 with a reasonable expectation of success since where the general conditions of a claim are disclosed in the prior art, the conducting of routine experimentation in order to discover or determine optimum or workable ranges is not inventive.
Therefore, a person of ordinary skill would have been motivated to optimize the conditions to permit high affinity FcγR binding to ensure the capture agent properly binds its respective antigen. It is not inventive to find optimal workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding independent claim 18, Liberti teaches selection of T cells by a method of separating and activating a population of T cells (page 14, para 0084) comprising:
incubating a sample comprising a blood product, wherein the blood product comprises mononuclear cells obtained from peripheral blood” (page 15, para 0086, column 2) and “the PBMC layer was removed and washed by centrifugation with Mg- and Ca-free DPBS containing 1 % HSA to pellet the cells. The cell pellet was re-suspended and re-centrifuged at 300 ref two more times to remove platelets” (i.e. removing endogenous or added IgG) (page 11, para 0073), rendering obvious a method of isolating a cell fraction from a peripheral blood mononuclear cell (PBMC) preparation comprising at least T and B cells said preparation substantially lacking endogenous or added IgG;
and “a population of magnetic particles bound to at least one first antibody that binds to a cell surface protein of a desired sub-population of cells” (claim 59 of US 2020/0010826). The examiner notes in paragraph [0012] an “antibody” is defined as full-length antibodies and antibody fragments. One of ordinary skill in the art would readily appreciate that a full length antibody comprises a Fc fragment that would bind Fcγ receptors on the cell surface of cells of a blood product that would lead to clustering of Fcγ receptor-bearing cells, rendering obvious introducing into said PBMC preparation, a capture agent (e.g., anti-mouse IgG or streptavidin; para 0016) which binds to Fcγ-receptor bearing cells and operably linked to a ferrofluid comprising magnetically and non-magnetically responsive particles-which forms a magnetic cluster of Fcγ receptor-bearing cells.
Liberti also teaches “applying a magnetic force to the sample and separating the cells that are bound to the magnetic particles from the cells that are not bound to the magnetic particles, wherein the labeled magnetic particles are labeled with a common-capture reagent” capable of binding the at least one separation antibody, rendering obvious isolating said capture agent-bound Fc receptor-bearing cells from said preparation in a magnetic separator.
However, Liberti does not teach that the method is for isolating naïve CD34+ stem cells and the capture agent binds to T cells epitopes and simultaneously to Fcγ receptor-bearing cells.
Arce Vargas teaches that “antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion” (i.e. bind to T cell epitopes) and have “improved FcγR binding” (Summary, page 1).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of using a selection process for isolating naïve T cells from PBMC with a separation antibody (common capture agent) on a magnetic particle from Liberti with a second immunological active agent that is an anti-T cell antibody that binds to both: T cell epitopes and Fcγ receptors according to Arce Vargas where the capture agent can be functionally linked to magnetic beads as contemplated by Liberti to ultimately achieve a method of isolating a CD34+ cell fraction not bound to the magnetic particle. One would be motivated to do so to selectively isolate CD34+ cells that are not affected by binding to a magnetic particle. A skilled artisan would have had a reasonable expectation of success as separating a cell fraction from a sample that binds to an antibody attached to magnetic nanoparticles to remove/separate them from an unattached cell fraction was known in the art at before the effective filing date of the claimed of the invention.
Regarding claim 19, the teachings of Liberti, Fowler, and Arce Vargas render obvious claim 18. However, the combined teachings do not teach wherein said PBMC are isolated from a donor treated with G-CSF to cause hematopoietic stem cells to migrate from the bone marrow into peripheral blood.
Martinex teaches “G-CSF administration results in a significant increase in the number of CD34+ cells in peripheral blood. Possible mechanisms include the release of preexisting marrow progenitor cells, an increased production of hematopoietic progenitors, or both” (Discussion, page 271, col 2, para 3).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of isolating CD34+ cells using magnetic particles operably linked to a capture agent from Liberti, Fowler, and Arce Vargas with the teachings of administering G-CSF from Martinex to a donor to get a higher yield of PBMCs. One would be motivated to do so to maximize the number of cells used for the isolation method with a reasonable expectation of success as administering G-CSF to increase PBMCs by being released from bone marrow and thus in circulation was known in the art before the effective filing date of the claimed invention.
Regarding claim 20, the teachings of Liberti, Fowler, and Robak render obvious claim 2 and 17. Moreover, Liberti teaches a “ferrofluid (nanoparticle) coated with rat-derived anti-mouse lgGl is combined with a streptavidin-coated poly(lactic-co-glycolic acid) nanoparticle wherein both nanoparticles are at a final concentration of 8 μg/ml” (page 14, para 0084) and “the resulting mixture is immediately combined with an equal volume of leukapheresis product (i.e. cells which comprise FcγRI)” (page 14, para 0084).
However, Liberti does not teach that the concentrations promote interactions with FcγRI. It would have been prima facie obvious to one of ordinary skill in the art to optimize the conditions to promote interactions as required by claim 20 with a reasonable expectation of success since where the general conditions of a claim are disclosed in the prior art, the conducting of routine experimentation in order to discover or determine optimum or workable ranges is not inventive.
Therefore, a person of ordinary skill would have been motivated to optimize the conditions to promote interactions with FcγRI to ensure the mixture correctly binds to cells expressing FcγRI. It is not inventive to find optimal workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 21 and 25, the teachings of Liberti, Fowler, and Robak render obvious claim 1. However, combined teachings do not teach the ferrofluid comprises 4000-7000 monoclonal antibodies per particle.
Saha teaches an antibody surface density of 51 × 102 (i.e. 5,100) antibodies per magnetic nanoparticle for a monolayer of side-on oriented antibodies, and 173 × 102 (i.e. 17,300) antibodies per magnetic nanoparticle for a monolayer of end-on oriented antibodies (page 8161, para 1). Saha further teaches this calculation is based on the molecular dimension of an antibody molecule being (14.5 × 8.5 × 4 nm3) (page 8160-8161, para 5-1).
Therefore, in the view of calculating the proper concentration of antibody per particle, it would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to combine the teachings of Liberti of using a magnetic particle with an operably linked antibody to isolate target T cell fraction with the teachings of Saha to calculate the number of antibodies per magnetic particle to achieve the correct concentration of antibody-to-particle. One would be motivated to do so to achieve ideal binding efficiency of antibody to the cells and thus optimal isolation of cells of interest.
Applicant is reminded that differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson,315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). See MPEP § 2144.
Regarding claim 22, the teachings of Liberti, Fowler, and Robak render obvious claim 2 and 17.
However, Liberti does not teach where high affinity FcyR binding conditions are promoted by reducing the concentration of monoclonal antibody to about 0.2 pg/ml.
Boesch teaches “As expected, the high affinity FcγRI receptor exhibited signal (i.e. binding) at significantly lower antibody concentrations than the lower affinity FcγR.” (Results, page 916, col 2, para 2).
Therefore, in the view of determining the ideal concentration of monoclonal antibody to promote high affinity FcyR binding conditions, it would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to combine the teachings of Liberti of using capture agents against FcγR with Boesch teaching that lower antibody concentration is better for high affinity FcγRI receptor binding to achieve the correct concentration of monoclonal antibody. One would be motivated to do so to achieve ideal binding efficiency of between the capture agent (i.e. antibody) and cells and thus optimal isolation of cells of interest. Moreover, one would optimize the conditions to permit high affinity FcγR binding as required by claim 17 and 22 with a reasonable expectation of success since where the general conditions of a claim are disclosed in the prior art, the conducting of routine experimentation in order to discover or determine optimum or workable ranges is not inventive. It is not inventive to find optimal workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 23, the teachings of Liberti, Fowler, and Robak render obvious claim 2. Moreover, Liberti teaches “the magnetic particles are separating (i.e. with separating antibody of one’s choosing) the non-desired cells, those that are not being activated and expanded. Thus, the magnetic force is separating away the non-desired cells and the cells left over, thus negatively selected, are the cells that are being activated and expanded” (page 5, para 0032) and “the separation antibody can be chosen based upon the desired purpose”, rendering obvious the target cells being isolated based on claim 2, are CD3+ T cells.
Provisional Rejection, Obviousness Type 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 1, 2, 5, 6, 8, 10, 11, 13-25 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1 and 17 of copending Application No. 16/320,531 as per claims filed on 6/10/2025 in view of Fowler et al (US Patent Application No. 2006/0159667 A1). Although the conflicting claims are not identical, they are not patentably distinct from each other because the instant claims are obvious over the cited claims of Application 16/320,531.
The claims of copending Application No. 16/320,531 are drawn to (i) a method of separating and activating a population of T cells comprising a) incubating a sample (i.e. mononuclear cells obtained from peripheral blood as stated in claim 17), comprising CD3+ T cells with a biotinylated anti-CD3+ antibody, b) contacting the sample with magnetic particles linked to a common capture agent comprising streptavidin, thus linking CD3+ T cells with magnetic particles, c) applying a magnetic force to the sample, separating CD3+ T cells bound to the magnetic particles from cells that are not bound to the particle, and d) culturing and f) expanding the separated CD3+ T cells.
The instant claims are drawn to a direct (claim 1) or indirect (claim 2) method of isolating naïve T cells from peripheral blood mononuclear cells (PBMC) by introducing a capture agent comprising an anti-B cell antibody and a function fragment thereof either without (claim 1) or with (claim 2) an operably linked first member specific binding pair. In claim 1, the anti-B antibody is operably linked to a magnetic particle thus binding the anti-B antibody to the magnetic particle, whereas in claim 2, first member binding pair (biotin) on the anti-B antibody binds to a second binding pair (streptavidin) that operably linked to a magnetic particle. Additionally, the claims recite isolating cells bound to the capture agents bound to magnetic particles and recovering the T cell fraction that is not bound to the capture agent/magnetic particle.
All methods require the preparation of incubating PBMC containing B and T cells with an antibody that can be biotinylated (first binding member) and said preparation being contacted with magnetic particles that can comprise streptavidin (second binding member). Furthermore, the magnetic particles containing bound cells (via binding to antibody) are separated from unbound magnetic particles and the target T, NK, or CD34+ cell fraction is isolated.
The instant claims differ from claims 1 and 17 by using an anti-B cell antibody for separation of T or NK cell fraction or immunologically active capture agent for separation of CD34+ stem cells.
However, at the time the invention was made, Fowler teaches a lymphocyte fraction is depleted of B cells by incubation with an anti-B cell antibody and an anti-CD8 antibody and sheep anti-mouse magnetic beads (page 18, para 0190) and that T cells from C57Bl/6 mice were purified by negative selection using anti-B cell antibodies (page 17, para 0187).
Therefore, in view of the benefits of purifying T cells using an anti-B cell antibody linked to magnetic nanoparticles where linked cells are removed leaving non-linked cells, it would have been prima facie obvious for one of ordinary skill in the art, to modify the instantly claimed method to use an anti-B cell antibody by Fowler, optionally biotinylate the anti-B cell antibody, and operably link it to a magnetic particle, to purify the non-linked T cell population using negative selection.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
Claims 1, 2, 5, 6, 8, 10, 11, 13-25 are rejected.
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/JULIANA IRENE CANDELARIA/ Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634