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 .
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, 365(c), or 386(c) is acknowledged. This application is a CON of PCT/US2021/030976 filed 05/05/2021 and claims benefit of Application No. 63/152,769 filed 02/23/2021. Based on the filing receipt, the effective filing date of this application is February 23, 2021 which is the filing date of Application No. 63/152,769.
Information Disclosure Statement
The information disclosure statement filed 10/18/2024 has been considered by the examiner.
Status of Claims
Claims 1, 6-7, 9, 12, 17-22, 24, 28, 30-37, 39-49, and 55-101 are cancelled.
Claims 2-5, 8, 10-11, 13-16, 23, 25-27, 29, 38, 50-54, and 102-107 are pending and examined herein.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 16 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP 2163.
The claim requires a method of identifying an anti-SARS-CoV-2 antibody or antigen binding fragment thereof that binds to an antibody therapeutic or antibody drug conjugate. The specification provides no disclosure of an anti-SARS-CoV-2 antibody that binds to an antibody therapeutic or an antibody drug conjugate. The specification merely recites, “In some embodiments, the antibody or antigen binding fragment thereof is an anti-SARS-CoV-2 antibody or antigen binding fragment thereof” (see para. [0025] of applicant’s specification). The specification also recites, “In some embodiments, said therapeutic antibody or antigen binding fragment thereof is an anti-SARS-CoV-2 antibody or antigen binding fragment thereof” (see para. [0009] of applicant’s specification). However, claim 16 encompasses methods where the anti-SARS-CoV-2 antibody is the antigen binding molecule and an antibody therapeutic or antibody drug conjugate is the antigen, as in para. [0025] of the applicant’s specification. The method recited in para. [0009] is not encompassed in claim 16 because in that embodiment, the anti-SARS-CoV-2 antibody is the antigen, instead of the antigen binding molecule. The specification does not describe the structure of the anti-SARS-CoV-2 antibody or an antigen, wherein the antigen is an antibody therapeutic or antibody drug conjugate, that would bind to the anti-SARS-CoV-2 antibody necessary to practice the claimed method. The art does not provide examples of species to be used. The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1 (IDS, 02/22/2021). Therefore, those of skill in the art would not accept that the inventor had been in possession of the antibodies presently claimed.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
No reduction to practice has been disclosed in the applicant’s specification.
Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus of antibodies nor guidance as to which of the myriad of molecules encompassed by the claimed antibodies would meet the limitations of the claims. Further, given the well-known high level of polymorphism of immunoglobulins and antibodies, the skilled artisan would not have recognized that applicant was in possession of the vast repertoire of antibodies encompassed by the claimed invention.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [they] invented what is claimed.” (See Vas-Cath at page 1116).
The skilled artisan cannot envision the detailed chemical structure of the antibodies used in the claims, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Therefore, the claim does not meet the written description provision of 35 U.S.C. §112 (a).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 2-3, 11, 23, 26, 29, 38, 51-52, and 102-104 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Vigneault (US 20170268056 A1, published 2017-09-21) as evidenced by Kim, et al. (“Adoptive immunotherapy with transient anti-CD4 treatment enhances anti-tumor response by increasing IL-18Rαhi CD8+ T cells”, published 2021-09-07).
With respect to claim 2, Vigneault teaches a method of identifying at least one antigen binding molecule that binds to an antigen (see, e.g., para. [0007]). It is understood that the “cellular DNA or mRNA analysis” will identify at least one antigen binding molecule. Vigneault teaches contacting a cell among a plurality of cells, the cell expressing at least one antigen binding molecule, with a reporter oligonucleotide conjugated antigen, wherein the reporter oligonucleotide comprises a reporter barcode and the antigen is an antibody therapeutic (see, e.g., para. [0007], sheet 12 of 29, under “FIG. 9A”, and sheet 3 of 29, under “FIG. 3A”). Kim provides evidence that the anti-CD4 mAb in “FIG. 3A” of Vigneault is a therapeutic antibody (see, e.g., Kim, p. 2, col. 1, para. 1: “Anti-CD4 monoclonal antibody, a prominent immunomodulatory agent, elicits robust anti-tumor immunity in various cancers by increasing tumor-infiltrating lymphocytes (TILs)”). Vigneault teaches providing a partition among a plurality of partitions comprising the cell and a partition-specific barcode molecule comprising a partition-specific barcode sequence (see, e.g., para. [0007]: “Cells are then encapsulated in vessels, e.g., an emulsion. The cells can be present in the vessels at a single cell per vessel density”). It is understood that the vessels of Vigneault are equivalent to partitions. Vigneault teaches generating a barcode nucleic acid molecule using the reporter oligonucleotide barcode sequence and the partition-specific barcode sequence (see, e.g., para. [0007]: “The method can comprise attaching a vessel-specific DNA sequence (e.g., a unique vessel barcode) to the affinity-conjugated oligonucleotides […] after barcoding the affinity-conjugated oligonucleotide, (e.g., with a DNA barcode)”, and sheet 7 of 29, under “FIG. 4”). Vigneault teaches sequencing the barcoded nucleic acid molecule to identify the cell contacted with the reporter oligonucleotide conjugated antigen (see, e.g., para. [0009]: “A method can comprise sequencing polynucleotide molecules from the vessels that contain both an Antigen ID sequence and droplet-specific barcode sequence”). Vigneault teaches sequencing the at least one antigen binding molecule expressed by the cell (see, e.g., para. [0452]: “To measure target protein levels on each cell custom oligonucleotide DNA labels were conjugated to anti-human CD4 and CD8 antibodies, and incubated the labeled antibodies with an unseparated mixture of CD4+ and CD8+ T-cells […] After sequencing and filtering 3,682 droplet barcodes were identified with high confidence TCR VαVβ pairs. Consistent with the previous experiment, roughly half (52%) of the TCR pairs could be assigned CD4 or CD8 status based on mRNA”). It is understood that CD4 and CD8 are equivalent to antigen binding molecules. It is understood that the mRNA of CD4 and CD8 are sequenced after the cells expressing CD4 and CD8 have been partitioned with antibody-oligonucleotide conjugates.
With respect to claim 3, Vigneault teaches generating a plurality of partitions (see, e.g., para. [0007]: “Cells are then encapsulated in vessels, e.g., an emulsion”).
With respect to claim 11, Vigneault teaches the plurality of cells comprise at least one B cell (see, e.g., para. [0004]: “a T cell receptor (TCR) or B cell receptor (BCR) of a single cell that is displayed can be identified from the Antigen ID sequence. In some aspects, the binding affinity of a TCR or BCR displayed on the surface of a cell may be determined using the affinity-oligonucleotide conjugated described herein. One or more of the surface proteins of a single cell can be used to define the single cell's identity, characteristics or relevance”).
With respect to claim 23, Vigneault teaches the antigen is a chimeric antigen receptor (see, e.g., para. [0046]).
With respect to claim 26, Vigneault teaches the reporter oligonucleotide conjugated antigen further comprises a fluorophore tag (see, e.g., sheet 26 of 29, under “FIG. 18”).
With respect to claim 29, Vigneault teaches the reporter oligonucleotide is conjugated to the antigen via direct/non-specific click-chemistry (see, e.g., par-a. [0108], and sheet 23 of 29, under “ FIG. 15”).
With respect to claim 38, Vigneault teaches the reporter oligonucleotide is captured by contacting the reporter nucleotide with the partition-specific barcode molecule (see, e.g., para. [0007]: “The method can comprise attaching a vessel-specific DNA sequence (e.g., a unique vessel barcode) to the affinity-conjugated oligonucleotides”).
With respect to claim 51, Vigneault teaches identifying the plurality of cells binding to the reporter oligonucleotide conjugated antigen using the reporter barcode and using the binding to generate a count matrix for the binding cell counts (see, e.g., para. [0207]: “An antigen molecular barcode (AMB) sequence can be unique for each oligonucleotide molecule of an affinity-oligonucleotide conjugate. An AMB sequence can enable the counting of the number of oligonucleotide molecules of an affinity-oligonucleotide conjugate that are bound to an antigen, such as an antigen of an individual cell in a vessel, e.g., an emulsion droplet”). It is understood that the molecular barcode allows for identification of cells by their surface antigens. It is understood that any digital counting of affinity-oligonucleotide binding will inherently contain a matrix of counts.
With respect to claim 52, Vigneault teaches embedding the count matrix by transforming by applying a log transformation and identifying distinct populations, wherein the distinct populations represent a similar binding profile (see, e.g., sheet 27 of 29, under “FIG. 19”).
With respect to claim 102, Vigneault teaches hybridizing the reporter oligonucleotide to the partition-specific barcode molecule (see, e.g., para. [0039]: “the attaching comprises hybridizing the vessel polynucleotide to the oligonucleotide”).
With respect to claim 103, Vigneault teaches the partition-specific barcode molecule further comprises a unique molecular identifier (see, e.g., para. [0096]: “MB1—molecular barcode 1; MB2—molecular barcode 2”, and sheet 12 of 29, under “FIG. 9A”).
With respect to claim 104, Vigneault teaches isolating the cell to identify the antigen binding molecule (see, e.g., para. [0007]: “Cells are then encapsulated in vessels, e.g., an emulsion. The cells can be present in the vessels at a single cell per vessel density”). It is understood that the cells are isolated in their vessels.
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.
Claims 4-5, 8, 10, 13-15, 50, 53-54, and 105-107 are rejected under 35 U.S.C. 103 as being unpatentable over Vigneault (US 20170268056 A1, published US 20170268056 A1) as evidenced by Kim, et al. (“Adoptive immunotherapy with transient anti-CD4 treatment enhances anti-tumor response by increasing IL-18Rαhi CD8+ T cells”, published 2021-09-07), as applied to claims 2-3, 11, 23, 26, 29, 38, 51-52, and 102-104 above, and further in view of Vaisman-Mentesh, et al. (“Molecular Landscape of Anti-Drug Antibodies Reveals the Mechanism of the Immune Response Following Treatment With TNFα Antagonists”, published 2019-12-18).
Vigneault teaches as set forth above, but fails to teach quantifying a subject’s response to the antigen over a time course of about bi-weekly, wherein the cells are obtained from the subject, the antigen is an antibody therapeutic, specifically infliximab (IFX) or adalimumab (ADL), and the antigen binding molecule is an anti-drug antibody (ADA), as in claims 4, 8, 10, 13-14, 50, 53, and 105. Vigneault fails to teach determining diversity of a subject’s immune response to the antibody therapeutic by identifying the at least one antigen binding molecule, as in claims 5 and 15. Vigneault fails to teach identifying an antigen binding site of the antibody therapeutic to which the anti-drug antibody binds, as in claims 54 and 106. Vigneault fails to teach modifying the antigen binding site of the antibody therapeutic to modify the binding of the antibody therapeutic, as in claim 107.
However, in a journal article studying anti-drug antibodies, Vaisman-Mentesh rectifies these deficiencies. Vaisman-Mentesh teaches quantifying a subject’s response to the antigen over a time course of about bi-weekly, wherein the cells are obtained from the subject, the antigen is an antibody therapeutic, specifically infliximab or adalimumab, and the antigen binding molecule is an anti-drug antibody, as in claims 4, 8, 10, 13-14, 50, 53, and 105 (see, e.g., p. 2, col. 2, last paragraph: “To elucidate the nature of the immune response following drug administration we chose to study a patient with IBD who was treated with IFX and who had high ADA levels and neutralization capacity. At 10 days (D10) following IFX infusion, the patient exhibited an ∼13-fold increase in the frequency of plasmablasts (PB) and unchanged frequency of activated memory B cells (mBC), compared with the pre-infusion time point (D0)”). It is understood that IFX is a therapeutic antibody due to being claimed as such in claim 50. It is understood that 10 days is about bi-weekly.
Vaisman-Mentesh teaches determining diversity of a subject’s immune response to the antibody therapeutic by identifying/sequencing the at least one antigen binding molecule, as in claims 5 and 15 (see, e.g., p. 11, under “Antibody Repertoire of ADA Encoding B-Cells”, para. 2: “Next-generation sequencing (NGS) of the antibody variable regions (V-genes) coupled with advanced bioinformatics tools provides the means to elucidate the antigen-specific antibody repertoire’s immense diversity”).
Vaisman-Mentesh teaches identifying an antigen binding site of the antibody therapeutic to which the anti-drug antibody binds, as in claims 54 and 106 (see, e.g., p. 2, col. 2, last paragraph: "Comparative NGS analysis of the antibody heavy chain variable region (VH) from isolated PB at D0 and D10, showed a significant temporal decrease in the level of somatic hypermutation (SHM) and an increase in the length of the complementary determining region 3 of the antibody heavy chain (CDRH3)”). It is understood that the complementary determining region 3 of the antibody heavy chain is the antigen binding site.
Vaisman-Mentesh teaches modifying the antigen binding site of the antibody therapeutic to modify the binding of the antibody therapeutic, as in claim 107 (see, e.g., p. 9, col. 1, para. 1: “We therefore modified our newly developed mAb-F(ab’)2 based bio-immunoassay by blocking the coated IFX-F(ab’)2 binding site with TNFα in order to obtain a differential signal compared to the unblocked assay”).
Vigneault and Vaisman-Mentesh are analogous to the field of the claimed invention because they are both in the field of immunology. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate Vaisman-Mentesh’s quantification of a subject’s immune response to IFX over a time course of about bi-weekly in the assay of Vigneault. An artisan would have been motivated to do so because Vaisman-Mentesh discloses, “a mAb administered to a patient can still induce an immune sensitization as reflected by the production of ADA, which is associated with low trough drug levels and can mediate loss of clinical response to the drug” (see p. 14, col. 1, para. 1). An artisan would have had a reasonable expectation of success.
One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate Vaisman-Mentesh’s determination of the diversity of a subject’s immune response to the antibody therapeutic by identifying/sequencing the at least one antigen binding molecule in the assay of Vigneault. An artisan would have been motivated to do so to “provide a molecular level characterization of the ADA: (i) V(D)J family usage; (ii) CDR3 length distribution; (iii) SHM levels, and, (iv) isotype distribution” (see, Vaisman-Mentesh, p. 11, col. 2, para. 2). An artisan would have had a reasonable expectation of success.
One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate Vaisman-Mentesh’s identification of an antigen binding site of the antibody therapeutic to which the anti-drug antibody binds into the assay of Vigneault. An artisan would have been motivated to do so because the identification allows an artisan “[to] elucidate the nature of the immune response following drug administration” (see Vaisman-Mentesh, p. 2, col. 2, last paragraph). An artisan would have had a reasonable expectation of success.
One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate Vaisman-Mentesh’s modification of the antigen binding site of the antibody therapeutic to modify the binding of the antibody therapeutic into the assay of Vigneault. An artisan would have been motivated to do so because Vaisman-Mentesh discloses, “Due to high clinical relevance and different mechanism of action of bADA [(binding anti-drug antibody)] and ntADA [(neutralizing ADA)], identifying their relative abundances in serum can provide valuable insights regarding the nature of the immune response following mAb administration”. The modification of the antigen binding site allows for the insight into relative abundances of neutralizing and non-neutralizing anti-drug antibodies. An artisan would have had a reasonable expectation of success.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Vigneault (US 20170268056 A1, published US 20170268056 A1) as evidenced by Kim, et al. (“Adoptive immunotherapy with transient anti-CD4 treatment enhances anti-tumor response by increasing IL-18Rαhi CD8+ T cells”, published 2021-09-07) and Vaisman-Mentesh, et al. (“Molecular Landscape of Anti-Drug Antibodies Reveals the Mechanism of the Immune Response Following Treatment With TNFα Antagonists”, published 2019-12-18), as applied to claims 4-5, 8, 10, 13-15, 50, 53-54, and 105-107 above, and further in view of Vernaite, et al. (“Expansion of SARS-CoV-2–Specific Antibody-Secreting Cells and Generation of Neutralizing Antibodies in Hospitalized COVID-19 Patients”, published 2020-09-02).
Vigneault and Vaisman-Mentesh teach as set forth above, but fail to teach the antibody is an anti-SARS-CoV-2 antibody, as in claim 16. However, in a journal article on SARS-CoV-2 specific antibody-secreting cells, Vernaite rectifies this deficiency. Vernaite teaches measuring the SARS-CoV-2 specific antibodies, as in claim 16 (see, e.g., p. 2348, col. 2, under “FluoroSpot Assay for ASCs”: “The number of SARS-CoV-2 nucleocapsid (N) protein–specific IgA, IgG, and IgM ASCs, as well as the total number of IgA–, IgG–, and IgM–ASCs in freshly isolated PBMCs, were measured using a multicolor B cell FluoroSpot kit with modification”).
Vigneault, Vaisman-Mentesh, and Vernaite are analogous to the field of the claimed invention because they are both in the field of cell-based immunoassays. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use the SARS-CoV-2 specific antibodies of Vernaite as the antibody in the Vigneault and Vaisman-Mentesh assay. An artisan would have been motivated to do so because Vernaite discloses, “extensive longitudinal studies in humans are required to investigate if recovered COVID-19 patients are protected from reinfection with SARS-CoV-2”. An artisan would have had a reasonable expectation of success based on the given disclosures.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Vigneault (US 20170268056 A1, published US 20170268056 A1) as evidenced by Kim, et al. (“Adoptive immunotherapy with transient anti-CD4 treatment enhances anti-tumor response by increasing IL-18Rαhi CD8+ T cells”, published 2021-09-07), as applied to claims 2-3, 11, 23, 26, 29, 38, 51-52, and 102-104 above, and further in view of Potthoff, et al. (“A cell-based immunogenicity assay to detect antibodies against chimeric antigen receptor expressed by tisagenlecleucel”, published 2019-11-01).
Vigneault teaches as set forth above, including chimeric antigen receptors, but fails to teach the antigen is a chimeric antigen receptor, specifically tisagenlecleucel, as in claim 25. However, in a journal article on a cell-based assay to detect antibodies against tisagenlecleucel, Potthoff rectifies this deficiency. Potthoff teaches the antigen is a chimeric antigen receptor, specifically tisagenlecleucel, as in claim 25 (see, e.g., p. 1, under “ABSTRACT”: “T-cell lines expressing the CAR offer the opportunity to measure anti-drug antibodies to the CAR in its natural cell environment, as an alternative to ligand-binding assays. Here we describe a novel, flow cytometry-based humoral immunogenicity assay for tisagenlecleucel (CTL019, Kymriah®) using a human T-cell line that expresses murine CAR19”).
Vigneault and Potthoff are analogous to the field of the claimed invention because they are both in the field of cell-based immunoassays. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use tisagenlecleucel from Potthoff as the chimeric antigen receptor of Vigneault. An artisan would have been motivated to do so because Potthoff discloses, “The nature of tisagenlecleucel treatment requires an immunogenicity assay strategy that is taking into account the high prevalence of pre-existing ADAs” (see, p. 7, col. 2, last paragraph). An artisan would have had a reasonable expectation of success based on the given disclosures.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Vigneault (US 20170268056 A1, published US 20170268056 A1) as evidenced by Kim, et al. (“Adoptive immunotherapy with transient anti-CD4 treatment enhances anti-tumor response by increasing IL-18Rαhi CD8+ T cells”, published 2021-09-07), as applied to claims 2-3, 11, 23, 26, 29, 38, 51-52, and 102-104 above, and further in view of Schwartz (US 8846875 B2, published 2014-09-30).
Vigneault teaches as set forth above, but fails to teach the reporter oligonucleotide conjugated antigen further comprises a peptide tag selected from a Flag tag, a myc tag, or an S-tag, as in claim 27. However, in a U.S. patent on the preparation and purification of oligonucleotide conjugates, Schwartz rectifies this deficiency. Schwartz teaches the reporter oligonucleotide conjugated antigen further comprises a peptide tag selected from a Flag tag, a Myc tag, or an S-tag, as in claim 27 (see, e.g., Schwartz, claim 19).
Vigneault and Schwartz are analogous to the field of the claimed invention because they are both in the field of antibody-oligonucleotide conjugates. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the peptide tag of Schwartz into the assay of Vigneault. An artisan would have been motivated to do so because Schwartz discloses the conjugate tag is useful for “isolating the antibody-oligonucleotide conjugates from the conjugation solution” (see, e.g., Schwartz, claim 19). An artisan would have had reasonable expectation of success.
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.
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Claims 2-3, 26, and 104 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 16, and 18 of U.S. Patent No. 12,298,314 (referred to as ‘314 hereto). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With respect to claim 2, ‘314 teaches a method of identifying at least one antigen binding molecule that binds to an antigen (see claims 1-2 of ‘314). ‘314 teaches contacting a cell among a plurality of cells, the cell expressing at least one antigen binding molecule, with a reporter oligonucleotide conjugated antigen, wherein the reporter oligonucleotide comprises a reporter barcode and the antigen is an antibody therapeutic (see claims 1-2 of ‘314). ‘314 teaches providing a partition among a plurality of partitions comprising the cell and a partition-specific barcode molecule comprising a partition-specific barcode sequence (see claims 1-2 of ‘314). ‘314 teaches generating a barcode nucleic acid molecule using the reporter oligonucleotide barcode sequence and the partition-specific barcode sequence (see claims 1-2 of ‘314). ‘314 teaches sequencing the barcoded nucleic acid molecule to identify the cell contacted with the reporter oligonucleotide conjugated antigen (see claims 1-2 of ‘314). ‘314 teaches sequencing the at least one antigen binding molecule expressed by the cell (see claims 1-2 of ‘314).
With respect to claim 3, ‘314 teaches generating a plurality of partitions (see claim 1 of ‘314).
With respect to claim 26, ‘314 teaches the reporter oligonucleotide conjugated antigen further comprises a fluorophore tag (see claim 18 of ‘314)
With respect to claim 104, ‘314 teaches isolating the cell to identify the antigen binding molecule (see claim 16 of ‘314).
Claims 11, 23, 29, 38, 51-52, and 102-103 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 16, and 18 of U.S. Patent No. 12,298,314 (referred to as ‘314 hereto), as applied to claims 2-3, 26, and 104 above, and further in view of Vigneault (US 20170268056 A1, published 2017-09-21).
‘314 teaches as set forth above, but fails to teach generating a plurality of partitions, as in claim 3. ‘314 fails to teach the plurality of cells comprise at least one B cell, as in claim 11. ‘314 fails to teach the antigen is a chimeric antigen receptor, as in claim 23. ‘314 fails to teach the reporter oligonucleotide is conjugated to the antigen via direct/non-specific click-chemistry, as in claim 29. ‘314 fails to teach the reporter oligonucleotide is captured by contacting the reporter nucleotide with the partition-specific barcode molecule, as in claim 38. ‘314 fails to teach identifying the plurality of cells binding to the reporter oligonucleotide conjugated antigen using the reporter barcode and using the binding to generate a count matrix for the binding cell counts, as in claim 51. ‘314 fails to teach embedding the count matrix by transforming by applying a log transformation and identifying distinct populations, wherein the distinct populations represent a similar binding profile, as in claim 52. ‘314 fails to teach hybridizing the reporter oligonucleotide to the partition-specific barcode molecule, as in claim 102. ‘314 fails to teach the partition-specific barcode molecule further comprises a unique molecular identifier, as in claim 103.
However, in a patent application publication on affinity-oligonucleotide conjugates, Vigneault rectifies these deficiencies. Vigneault teaches the plurality of cells comprise at least one B cell, as in claim 11 (see, e.g., para. [0004]: “a T cell receptor (TCR) or B cell receptor (BCR) of a single cell that is displayed can be identified from the Antigen ID sequence. In some aspects, the binding affinity of a TCR or BCR displayed on the surface of a cell may be determined using the affinity-oligonucleotide conjugated described herein. One or more of the surface proteins of a single cell can be used to define the single cell's identity, characteristics or relevance”). Vigneault teaches the antigen is a chimeric antigen receptor, as in claim 23 (see, e.g., para. [0046]). Vigneault teaches the reporter oligonucleotide is conjugated to the antigen via direct/non-specific click-chemistry, as in claim 29 (see, e.g., par-a. [0108], and sheet 23 of 29, under “ FIG. 15”). Vigneault teaches the reporter oligonucleotide is captured by contacting the reporter nucleotide with the partition-specific barcode molecule, as in claim 38 (see, e.g., para. [0007]: “The method can comprise attaching a vessel-specific DNA sequence (e.g., a unique vessel barcode) to the affinity-conjugated oligonucleotides”). Vigneault teaches identifying the plurality of cells binding to the reporter oligonucleotide conjugated antigen using the reporter barcode and using the binding to generate a count matrix for the binding cell counts, as in claim 51 (see, e.g., para. [0207]: “An antigen molecular barcode (AMB) sequence can be unique for each oligonucleotide molecule of an affinity-oligonucleotide conjugate. An AMB sequence can enable the counting of the number of oligonucleotide molecules of an affinity-oligonucleotide conjugate that are bound to an antigen, such as an antigen of an individual cell in a vessel, e.g., an emulsion droplet”). It is understood that the molecular barcode allows for identification of cells by their surface antigens. It is understood that any digital counting of affinity-oligonucleotide binding will inherently contain a matrix of counts. Vigneault teaches embedding the count matrix by transforming by applying a log transformation and identifying distinct populations, wherein the distinct populations represent a similar binding profile, as in claim 52 (see, e.g., sheet 27 of 29, under “FIG. 19”). Vigneault teaches hybridizing the reporter oligonucleotide to the partition-specific barcode molecule, as in claim 102 (see, e.g., para. [0039]: “the attaching comprises hybridizing the vessel polynucleotide to the oligonucleotide”). Vigneault teaches the partition-specific barcode molecule further comprises a unique molecular identifier, as in claim 103 (see, e.g., para. [0096]: “MB1—molecular barcode 1; MB2—molecular barcode 2”, and sheet 12 of 29, under “FIG. 9A”).
‘314 and Vigneault are analogous to the field of the claimed invention because they are both in the field of affinity-oligonucleotide conjugates. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use the disclosure of Vigneault in the assay of ‘314, particularly the B cells. An artisan would have been motivated to do so because Vigneault discloses, “B cells, such as small populations of B cells or B cell subsets, can recognize antigens via B-cell receptors (BCRs) […] a B-cell receptor antigen can be an antigen that has been used to immunize a subject” (see para. [0190]). An artisan would have had a reasonable expectation of success based on the given disclosures.
Claims 4-5, 8, 10, 13-15, 50, 53-54, and 105-107 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 16, and 18 of U.S. Patent No. 12,298,314 (referred to as ‘314 hereto), as applied to claims 2-3, 26, and 104 above, in further view of Vaisman-Mentesh, et al. (“Molecular Landscape of Anti-Drug Antibodies Reveals the Mechanism of the Immune Response Following Treatment With TNFα Antagonists”, published 2019-12-18).
‘314 teaches as set forth above, but fails to teach quantifying a subject’s response to the antigen over a time course of about bi-weekly, wherein the cells are obtained from the subject, the antigen is an antibody therapeutic, specifically infliximab (IFX) or adalimumab (ADL), and the antigen binding molecule is an anti-drug antibody (ADA), as in claims 4, 8, 10, 13-14, 50, 53, and 105. ‘314 fails to teach determining diversity of a subject’s immune response to the antibody therapeutic by identifying the at least one antigen binding molecule, as in claims 5 and 15. ‘314 fails to teach identifying an antigen binding site of the antibody therapeutic to which the anti-drug antibody binds, as in claims 54 and 106. ‘314 fails to teach modifying the antigen binding site of the antibody therapeutic to modify the binding of the antibody therapeutic, as in claim 107.
However, in a journal article studying anti-drug antibodies, Vaisman-Mentesh rectifies these deficiencies. Vaisman-Mentesh teaches quantifying a subject’s response to the antigen over a time course of about bi-weekly, wherein the cells are obtained from the subject, the antigen is an antibody therapeutic, specifically infliximab or adalimumab, and the antigen binding molecule is an anti-drug antibody, as in claims 4, 8, 10, 13-14, 50, 53, and 105 (see, e.g., p. 2, col. 2, last paragraph: “To elucidate the nature of the immune response following drug administration we chose to study a patient with IBD who was treated with IFX and who had high ADA levels and neutralization capacity. At 10 days (D10) following IFX infusion, the patient exhibited an ∼13-fold increase in the frequency of plasmablasts (PB) and unchanged frequency of activated memory B cells (mBC), compared with the pre-infusion time point (D0)”). It is understood that IFX is a therapeutic antibody due to being claimed as such in claim 50. It is understood that 10 days is about bi-weekly.
Vaisman-Mentesh teaches determining diversity of a subject’s immune response to the antibody therapeutic by identifying/sequencing the at least one antigen binding molecule, as in claims 5 and 15 (see, e.g., p. 11, under “Antibody Repertoire of ADA Encoding B-Cells”, para. 2: “Next-generation sequencing (NGS) of the antibody variable regions (V-genes) coupled with advanced bioinformatics tools provides the means to elucidate the antigen-specific antibody repertoire’s immense diversity”).
Vaisman-Mentesh teaches identifying an antigen binding site of the antibody therapeutic to which the anti-drug antibody binds, as in claims 54 and 106 (see, e.g., p. 2, col. 2, last paragraph: "Comparative NGS analysis of the antibody heavy chain variable region (VH) from isolated PB at D0 and D10, showed a significant temporal decrease in the level of somatic hypermutation (SHM) and an increase in the length of the complementary determining region 3 of the antibody heavy chain (CDRH3)”). It is understood that the complementary determining region 3 of the antibody heavy chain is the antigen binding site.
Vaisman-Mentesh teaches modifying the antigen binding site of the antibody therapeutic to modify the binding of the antibody therapeutic, as in claim 107 (see, e.g., p. 9, col. 1, para. 1: “We therefore modified our newly developed mAb-F(ab’)2 based bio-immunoassay by blocking the coated IFX-F(ab’)2 binding site with TNFα in order to obtain a differential signal compared to the unblocked assay”).
‘314 and Vaisman-Mentesh are analogous to the field of the claimed invention because they are both in the field of immunology. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate Vaisman-Mentesh’s quantification of a subject’s immune response to IFX over a time course of about bi-weekly in the assay of ‘314. An artisan would have been motivated to do so because Vaisman-Mentesh discloses, “a mAb administered to a patient can still induce an immune sensitization as reflected by the production of ADA, which is associated with low trough drug levels and can mediate loss of clinical response to the drug” (see p. 14, col. 1, para. 1). An artisan would have had a reasonable expectation of success.
One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate Vaisman-Mentesh’s determination of the diversity of a subject’s immune response to the antibody therapeutic by identifying/sequencing the at least one antigen binding molecule in the assay of ‘314. An artisan would have been motivated to do so to “provide a molecular level characterization of the ADA: (i) V(D)J family usage; (ii) CDR3 length distribution; (iii) SHM levels, and, (iv) isotype distribution” (see, Vaisman-Mentesh, p. 11, col. 2, para. 2). An artisan would have had a reasonable expectation of success.
One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate Vaisman-Mentesh’s identification of an antigen binding site of the antibody therapeutic to which the anti-drug antibody binds into the assay of ‘314. An artisan would have been motivated to do so because the identification allows an artisan “[to] elucidate the nature of the immune response following drug administration” (see Vaisman-Mentesh, p. 2, col. 2, last paragraph). An artisan would have had a reasonable expectation of success.
One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate Vaisman-Mentesh’s modification of the antigen binding site of the antibody therapeutic to modify the binding of the antibody therapeutic into the assay of ‘314. An artisan would have been motivated to do so because Vaisman-Mentesh discloses, “Due to high clinical relevance and different mechanism of action of bADA [(binding anti-drug antibody)] and ntADA [(neutralizing ADA)], identifying their relative abundances in serum can provide valuable insights regarding the nature of the immune response following mAb administration”. The modification of the antigen binding site allows for the insight into relative abundances of neutralizing and non-neutralizing anti-drug antibodies. An artisan would have had a reasonable expectation of success.
Claim 16 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 16, and 18 of U.S. Patent No. 12,298,314 (referred to as ‘314 hereto) and Vaisman-Mentesh, et al. (“Molecular Landscape of Anti-Drug Antibodies Reveals the Mechanism of the Immune Response Following Treatment With TNFα Antagonists”, published 2019-12-18), as applied to claims 4-5, 8, 10, 13-15, 50, 53-54, and 105-107 above, and further in view of Vernaite, et al. (“Expansion of SARS-CoV-2–Specific Antibody-Secreting Cells and Generation of Neutralizing Antibodies in Hospitalized COVID-19 Patients”, published 2020-09-02).
‘314 and Vaisman-Mentesh teach as set forth above, but fail to teach the antibody is an anti-SARS-CoV-2 antibody, as in claim 16. However, in a journal article on SARS-CoV-2 specific antibody-secreting cells, Vernaite rectifies this deficiency. Vernaite teaches measuring the SARS-CoV-2 specific antibodies, as in claim 16 (see, e.g., p. 2348, col. 2, under “FluoroSpot Assay for ASCs”: “The number of SARS-CoV-2 nucleocapsid (N) protein–specific IgA, IgG, and IgM ASCs, as well as the total number of IgA–, IgG–, and IgM–ASCs in freshly isolated PBMCs, were measured using a multicolor B cell FluoroSpot kit with modification”).
‘314, Vaisman-Mentesh, and Vernaite are analogous to the field of the claimed invention because they are both in the field of cell-based immunoassays. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use the SARS-CoV-2 specific antibodies of Vernaite as the antibody in the ‘314 and Vaisman-Mentesh assay. An artisan would have been motivated to do so because Vernaite discloses, “extensive longitudinal studies in humans are required to investigate if recovered COVID-19 patients are protected from reinfection with SARS-CoV-2”. An artisan would have had a reasonable expectation of success based on the given disclosures.
Claim 25 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 16, and 18 of U.S. Patent No. 12,298,314 (referred to as ‘314 hereto) and Vigneault (US 20170268056 A1, published 2017-09-21), as applied to claims 11, 23, 29, 38, 51-52, and 102-103 above, in further view of Potthoff, et al. (“A cell-based immunogenicity assay to detect antibodies against chimeric antigen receptor expressed by tisagenlecleucel”, published 2019-11-01).
‘314 and Vigneault teaches as set forth above, including chimeric antigen receptors, but fails to teach the antigen is a chimeric antigen receptor, specifically tisagenlecleucel, as in claim 25. However, in a journal article on a cell-based assay to detect antibodies against tisagenlecleucel, Potthoff rectifies this deficiency. Potthoff teaches the antigen is a chimeric antigen receptor, specifically tisagenlecleucel, as in claim 25 (see, e.g., p. 1, under “ABSTRACT”: “T-cell lines expressing the CAR offer the opportunity to measure anti-drug antibodies to the CAR in its natural cell environment, as an alternative to ligand-binding assays. Here we describe a novel, flow cytometry-based humoral immunogenicity assay for tisagenlecleucel (CTL019, Kymriah®) using a human T-cell line that expresses murine CAR19”).
‘314, Vigneault, and Potthoff are analogous to the field of the claimed invention because they are both in the field of cell-based immunoassays. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use tisagenlecleucel from Potthoff as the chimeric antigen receptor of ‘314 and Vigneault. An artisan would have been motivated to do so because Potthoff discloses, “The nature of tisagenlecleucel treatment requires an immunogenicity assay strategy that is taking into account the high prevalence of pre-existing ADAs” (see, p. 7, col. 2, last paragraph). An artisan would have had a reasonable expectation of success based on the given disclosures.
Claim 27 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 16, and 18 of U.S. Patent No. 12,298,314 (referred to as ‘314 hereto), as applied to claims 2-3, 26, and 104 above, in further view of Schwartz (US 8846875 B2, published 2014-09-30).
‘314 teaches as set forth above, but fails to teach the reporter oligonucleotide conjugated antigen further comprises a peptide tag selected from a Flag tag, a myc tag, or an S-tag, as in claim 27. However, in a U.S. patent on the preparation and purification of oligonucleotide conjugates, Schwartz rectifies this deficiency. Schwartz teaches the reporter oligonucleotide conjugated antigen further comprises a peptide tag selected from a Flag tag, a Myc tag, or an S-tag, as in claim 27 (see, e.g., Schwartz, claim 19).
‘314 and Schwartz are analogous to the field of the claimed invention because they are both in the field of antibody-oligonucleotide conjugates. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the peptide tag of Schwartz into the assay of ‘314. An artisan would have been motivated to do so because Schwartz discloses the conjugate tag is useful for “isolating the antibody-oligonucleotide conjugates from the conjugation solution” (see, e.g., Schwartz, claim 19). An artisan would have had reasonable expectation of success.
Conclusion
No claims are allowed.
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/MICHAEL CAMERON SVEIVEN/ Examiner, Art Unit 1678
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678