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
This application is a U.S. national phase of International Application No. PCT/CN2021/106404, filed on 07/15/2021. This application claims priority to International Application No. PCT/CN2020/102367, filed 07/16/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status
The amendment, filed on 07/16/2023, in which claims 22-23, 26, 28, and 30-35 are amended; and claim 36 is new, is acknowledged. Claims 1-36 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/16/2023 has been considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
Page 2, lines 13, 17, 21, and 25 - “identify thereof” should read “identity thereof”
Page 8, line 19 - “a region…that elicit” should read “a region…that elicits”
Page 17, line 23 - “zata” should read “zeta”
Page 20, line 21 - “polynuleotide” should read “polynucleotide”
Page 21, line 5 - “disclsoure" should read “disclosure”
Page 23, line 18 - “entanercept” should read “etanercept”
Appropriate correction is required.
The use of the terms “Lipofectamine” (page 25, line 13), “Dynabeads” (page 25, line 17), “cytoflex” (page 25, line 22; page 26, line 8), and “eFlour” (page 26, lines 6, 7, 10, and 11), which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1-3 and 5-8 are objected to because of the following informalities:
Regarding claim 1, “An polynucleotide…” should read “A polynucleotide…” (line 1)
Regarding claims 2-3 and 5-8, “identify thereof” should read “identity thereof” (Claim 2, line 4; Claim 3, line 5; Claim 5, line 3; Claim 6, line 3 of (a)-(e), respectively; Claim 7, line 2 of (b); Claim 8, line 2 of (b)).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 7 and 8 are 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.
Claims 7 and 8 recite reference to tables within the specification (Table 2 and 3, respectively). Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) - See MPEP § 2173.05(s).
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2 and 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 2, the instant claim recites the polynucleotide of claim 1, wherein the immunogenic fragment comprises a heavy chain variable region or a light chain variable region of the therapeutic anti-TNF alpha, a sequence having 90% identity thereof, or a sequence having 1-5 amino acid mutations. The instant specification defines “immunogenic fragment” in the context of a therapeutic antibody as a region of the antibody that elicit the immune response of the host (¶ [0050]). This implies that the immunogenic fragment as recited in the base claim 1 would share identity with a specific sequence within a therapeutic anti-TNFα antibody, and therefore dependent claim which recites variability in sequence identity of the desired “epitope” broadens the scope of the base claim (i.e. increases the number of potential immunogenic sequences) and therefore does not further limit the subject matter.
Regarding claim 5, base claim 4 recites sequences of immunogenic fragments (VH/VL amino acid sequences) targeting TNFα and Claim 5 recites said sequences with up to 10% variance or having 1-5 amino acid residue differences from said sequences, which broadens the scope of the base claim. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-36 are 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(s) 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.
Claim 1 is drawn to a polynucleotide encoding a chimeric anti-drug antibody receptor (CADAR), comprising an extracellular domain (ECD) comprising an immunogenic fragment of a therapeutic anti-TNFα monoclonal antibody, a transmembrane domain and an intracellular signaling domain (ICD), wherein the immunogenic fragment (i.e. the ECD) binds to a B cell receptor (BCR) expressed on a B-cell, wherein a cell expressing the CADAR binds the BCR expressed on the B-cell or induces the killing of the B cell expressing the antibody. Dependent claims 2-8 further claim the polynucleotide of base claim 1, wherein the sequences of anti-TNFα antibodies or immunogenic sequences within share identity to the recited SEQ ID NOs, or have at least 90% identity or 1-5 amino acid residue differences therefrom.
Instant claim 1 contains functional language by claiming a genus of CADAR by what they do (function), rather than by what they are (structure). MPEP 2173.05(g) teaches that "Unlimited functional claim limitations that extend to all means or methods of resolving a problem may not be adequately supported by the written description or may not be commensurate in scope with the enabling disclosure, both of which are required by 35 U.S.C. 112(a) and pre-AIA 35 U.S.C. 112, first paragraph. In re Hyatt, 708 F.2d 712, 714, 218 USPQ 195, 197 (Fed. Cir. 1983); Ariad, 598 F.3d at 1340, 94 USPQ2d at 1167. For instance, a single means claim covering every conceivable means for achieving the stated result was held to be invalid under 35 U.S.C.112, first paragraph because the court recognized that the specification, which disclosed only those means known to the inventor, was not commensurate in scope with the claim. Hyatt, 708 F.2d at 714-715, 218 USPQ at 197." In this case, the CADARs claimed are based on the potential epitopes derived from any monoclonal anti-TNFα antibody, not the structure of the antibody that would result in the claimed epitope binding.
MPEP 2163.I1.A.3.a.ii. states that the written description requirement for claimed genus may be satisfied through a sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus.
The instant disclosure discloses five distinct species of anti-TNFα antibodies with defined VH/VL sequences (Table 1) recited in instant claim 4, and discloses specific immunogenic fragments for two species adalimumab and infliximab (Tables 2 and 3). Examiner notes that content with sufficient written description would be sequences comprising known immunogenic fragments (i.e. adalimumab and infliximab; Table 2 and 3). However, there is no description of a structure that would allow an ordinarily skilled artisan to envision all epitopes recognized by BCR within an anti-TNFα monoclonal antibody beyond the disclosed immunogenic sequences (e.g. Table 2 and 3), nor would an ordinarily skilled artisan be able to envision variance in the recited antibody sequences (i.e. up to 10% variance or 1-5 residue mutations) that would predictably maintain (1) identity to an anti-TNFα antibody and (2) BCR binding.
Regarding (1) TNFα binding, the state of the art near the effective filing date of the claimed invention demonstrates that antibody functionality (i.e. antigen binding) is dependent on amino acid structure, particularly regarding complementarity of the six CDRs. It is understood by one of ordinary skill in the art that mutations to CDRs is unpredictable and that each construct requires function testing.
Rabia (Biochem Eng J. 2018 Sep 15;137:365-374.) teaches that antibody-antigen binding specificity is primarily mediated by their CDRs within the sequences of variable heavy and variable light chains (Introduction, ¶ 1). Given the chemical diversity possible within combined CDRs alone (~20 different amino acids at ~60 sites), not all combinations can result in viable antibodies suitable for therapeutic applications. Rabia et al. teaches that natural antibody maturation relies on random somatic mutations followed by clonal selection for antibodies with improved affinity and/or with mutations that compensate for destabilizing affinity enhancing mutations (page 366, column 2, ¶ 2). However, it is expected that most somatic mutations that increase affinity, such as those that increase hydrophobicity or charge, can also reduce specificity. For instance arginine in CDRs was identified as the greatest risk factor for non-specific interactions (page 368, column 1, ¶ 5). Based on these teachings, introducing mutations in antibody structure, particularly in the CDR regions, requires thorough testing to ensure suitable binding specificity and antibody stability.
Koenig (PNAS USA. 2017;114(4):E486-E495) teaches that single amino acid mutations across both VL and VH can alter stability and antibody-antigen binding. In generating a single mutation library in VL and VH chains (Figure 1), Koenig et al. identified mutations distal to CDRs can improve anti-VEGF antibody G6.31 stability (anti-gD tag; enriched in red) and affinity (VEGF; enriched in red), but conserved framework positions including the hydrophobic core and interface residues in addition to a few CDR positions, particularly in HCDR3, exhibited low tolerance to mutation (depleted in blue/ strongly depleted in black). Furthermore, single cysteine mutations or single residue deletions in nearly all residues across VL and VH chains resulted in reduced stability and binding. Therefore, a single mutation, let alone up to 10% variance in sequences including CDR domains encompassed by the instant claims, could therefore potentially result in loss of antibody stability and/or binding.
Regarding (2) BCR binding, the state of the art even several years after the effective filing date of the claimed invention demonstrates that the prediction of B-cell epitope binding based on epitope was still not fully understood.
Yu (Drug Discov Today. 2025;30(11):104489) teaches 90% of B-cell epitopes are discontinuous (or conformational), rather than sequential, and may comprise otherwise distant residues brought together by three-dimensional folding (pg 2, column spanning ¶). Yu teaches benchmarked conformational B-cell epitope prediction web servers published before 2022, including both antibody agnostic and antibody specific methods, revealed that overall performance of existing prediction methods was low, and that the commonly used consensus strategies performed only marginally better than random predictions (pg 3, column spanning ¶). While machine learning models have since improved epitope prediction accuracy (pg 14, left column), it is generally understood that the accuracy of predicted B-cell epitopes is still not sufficient to eliminate the need for experimental validation (pg 10, right column).
Overall, neither the disclosure nor the prior art recognize a fully mapped structure- function relationship that would allow a priori determination of antibody immunogenic sequence within the breadth of the claimed genus that fulfills claimed function of BCR binding and TNFα binding with reasonable expectation of success. Therefore, claims 1-8, and subsequent dependent claims 9-36 that do not rectify these issues, were determined not to meet the written description requirement of 35 USC 112(a).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-7, 9-28, and 30-35 are rejected under 35 U.S.C. 103 as being unpatentable over US 11,407,803 B2 (herein Payne) and Homann (Theranostics. 2017;7(19):4699-4709) and Rafiq (Nat Rev Clin Oncol. 2020;17(3):147-167).
Payne teaches a nucleic acid encoding a chimeric autoantigen receptor (CAAR) comprising an autoantigen derived extracellular domain (from desmoglein) that binds to an autoantibody expressed on a B-cells, a transmembrane domain, and intracellular domains (ICDs), wherein when the CAAR is present on the surface of a cell, it will bind the autoantibody expressed on the B-cell or induce killing of the B-cell expressing the auto antibody (claim 1; Figure 4). Payne teaches targeting autoreactive B-cells as a means to avoid side effects related to general immune suppression (i.e. infection and secondary cancers) (column 1-2 spanning ¶). Payne teaches a construct with a CD8α signaling peptide (SEQ ID NO:1 identical to instant SEQ ID NO:20), a CD8α hinge and transmembrane (SEQ ID NO:13 identical to fusion of instant SEQ ID NOs: 22 and 21), a CD137 intracellular domain (ICD) (SEQ ID NO:15 identical to instant SEQ ID NO: 23) and a CD3ζ ICD (SEQ ID NO:16 identical to instant SEQ ID NO: 24) (Figures 4 and 36; claims 1 and 6, 9-10, 14-18). Payne also teaches the nucleic acid encoding the CAAR in a vector, where the vector is a lentiviral vectors or an RNA vector expressed on cells including T cells and natural killer cells (claims 2 and 20-21). Payne further teaches that based on ex vivo procedures well known in the art, the engineered immune cells can be autologous or allogenic (column 32, lines 48-51) and can be administered to a patient in conjunction with other components (e.g. IL-2 or other cytokines - i.e. agents that induce proliferation/persistence as evidenced by Rafiq (pg 149, left column)) or treatment modalities (column 33, lines 18-22; column 34, ¶ 3).
Payne does not teach an ECD that is derived from an immunogenic fragment of an anti-TNFα antibody.
Homann teaches adalimumab (ADL - variable heavy and variable light domains (VH and VL, respectively) identical to instant SEQ ID NO:1 and 2) and infliximab (IFX - VH and VL identical to instant SEQ ID NO:3 and 4) treatments induce anti-drug antibody production in at least 5% of applications, resulting in associated loss-of-drug effects from enhanced clearance of therapeutics and/or hypersensitivity reactions and inflammation (4700, left column). Homann further teaches exact immunogenic peptide sequences (e.g. ADL sequences identical to instant SEQ ID NOs: 11-15 within Table 2; i.e. having at least 90% identity of an ant-TNFα monoclonal sequence) derived from epitope mapping of serum IgG (i.e. produced by B-cells) from patients treated with ADL, which may result in loss-of drug effects during therapy (Figure 3B). Of these epitopes, four were located in the TNFα binding pocket: two in the VH and two in the VL; and individual epitope immunogenicity varied in the patients tested (Figure 3A-3B).
Rafiq teaches the CARs have a modular design and extracellular domain of CARs can include various antigen binding domains including peptides, ligands, cytokines, nanobodies, and traditionally comprise a single-chain variable domain with the VH and VL of a monoclonal antibody connected by a flexible linker (Figure 1; pg 147, right column, ¶ 2). Rafiq teaches CAR-T cell therapies can have adverse treatment-related toxicities either from general toxicities related to T cell activation and subsequent systemic release of high levels of cytokines (i.e. cytokine release syndrome; CRS) or from toxicities resulting from specific interactions between the CAR and its target expressed by non-target cells (pg 150, left column, ¶ 1). Rafiq teaches that CRS is often responsive to treatment with IL-6 signaling inhibitors (e.g. anti-IL6 receptor antibody, anti-IL6 antibody, or corticosteroids).
A skilled artisan would recognize the modular nature of chimeric antigen receptors and would have a reasonable expectation of success in swapping receptor domains (e.g. antigenic domain) as taught by Rafiq. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that the desmoglein antigenic domain within a CAAR used to target specific autoreactive B-cells as taught by Payne could be substituted with an anti-TNFα antibody antigenic sequence (i.e. VH and/or VL or specific epitopes within) that similarly induces antibody production by B cells as taught by Homann. A skilled artisan would be motivated to do so as a means to prevent loss-of-drug effects (i.e. boosting treatment response) and/or hypersensitivity from anti-TNFα antibodies with known immunogenicity and to avoid side effects from general immune or B-cell suppression. Moreover, as patients may be reactive to any one or more of the identified immunogenic domains found within the VH/VL as taught by Homann, a skilled artisan would be motivated to modify a B-cell targeting CAR as taught by Payne with traditional CAR construction methods of using an scFv antigen binding domain as taught by Rafiq comprising a fusion of both immunogenic VH and VL domains as taught by Homann to capture a heterogeneous population of antibody reactive B-cells. Furthermore, a skilled artisan would be motivated to include additional agents such as IL-2 as taught by Payne and/or IL-6 as taught by Rafiq to a CAR-T cell therapy to aid in cell persistence (i.e. increases therapeutic efficacy) while mitigating general toxicities/side effects (i.e. CRS) associated with T cell activation as taught by Rafiq.
Claim 8, 29, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Payne, Homann, and Rafiq as applied to claims 4 and 28 above, and further in view of Homann-2 (J Transl Med. 2015;13:339).
Regarding claims 8 and 36, the combined teachings of Payne and Homann teach claim 4 as discussed above. While Homann teaches that IFX has immunogenicity, Homann does not disclose specific immunogenic sequences.
Homann-2 teaches immunogenic fragments within antigen binding domain (VH and VL regions) of IFX sequences (Figure 3 - identical to instant SEQ ID NOs: 16-19 within Table 3).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that an ADL fragment as taught by Homann could be substituted for an IFX immunogenic domain (i.e. fragment as taught by Homann-2) within a B-cell targeting CAR as taught by Payne because Homann-2 teaches the respective IFX domains also induce ADA antibody production (i.e. there are specific populations of B cells that recognize the epitopes), and therefore a skilled artisan would be motivated to generate a IFX-specific B cell targeting CAR to mitigate ADA production in patient treated with IFX.
Regarding claim 29, the combined teachings of Payne, Homann, and Rafiq teach claim 28 as discussed above. While Homann teaches therapeutic antibodies are a key option for the treatment of various cancers or inflammatory disorders (pg 4699, left column), Homann does not explicitly disclose conditions of a subject within scope of those instantly claimed (i.e. patients that would typically receive anti-TNFα alpha antibody treatment).
Homann-2 teaches that diseases including autoimmune disorders such as inflammatory bowel disease and rheumatoid arthritis are typically treated with TNFα inhibitors, though monoclonal antibody therapy was observed to have adverse reactions such as hypersensitivity or reduced efficacy caused by ADA production (pg 1).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that the method as taught by the combined teachings of Payne, Homann, and Rafiq would be applicable to any condition (e.g. rheumatoid arthritis as taught by Homann-2) typically treated with anti-TNFα blockade antibodies that cause ADA production.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647