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 .
Claims Status
Claims 1, 4-5, 8, 11, 13, 15, 55, and 57 are amended. Claims 2-3, 6-7, 9-10, and 36 are cancelled. Claims 1, 4-5, 8, 11, 13, 15, 55, 57, 61, 67-68, and 80 are pending and are examined on the merits.
Objections Withdrawn
All objections to the specification with regard to the date on which the sequence listing was filed are withdrawn in view of Applicant’s amendments.
Rejections Withdrawn
Claims 2-3, 6-7, 9-10, and 36 are cancelled, rendering all previous rejections moot.
Rejection of claim 5 under 35 U.S.C. 112(b) is withdrawn with applicant amendment of claims.
Rejection of claims 1, 4-5, 8, 13, 55, 57, 61, 67-68 and 80 under 35 U.S.C. 112(a) are withdrawn with applicant amendment of claims.
Rejection of claims 1, 13, 55, 57, 61, and 67 under 35 U.S.C. 102(a)(1) are withdrawn with applicant amendment of claims necessitating new rejections.
Rejection of claims 1, 4-5, 8, 11, 13, 55, 57, 61, 67-68 and 80 under 35 U.S.C. 103 are withdrawn with applicant amendment of claims necessitating new rejections.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
In particular, claim 1 recites the extracellular domain of a CSR comprising a “means for binding.” The claimed extracellular domain of the CSR is modified by functional language (i.e. binding to oligomeric pTau (o-pTau)). The term “means for binding” is not modified by sufficient structure or materials for performing the claimed functions in claim 1, and is thus being interpreted under 35 U.S.C. § 112(f). Claims 4-5, 13, 15, 55, 57, 61, 67, 68, and 80, which depend from or recite the CSR of claim 1 and also do not disclose sufficient structure or materials for performing the claimed function, are similarly interpreted under 35 U.S.C. § 112(f).
With respect to the structure of the “means for binding” that corresponds to the instantly claimed functional properties of the CSR, the specification (pages 2-3) recites that the CSR comprising the “means for binding” comprises an extracellular domain comprising an antigen-specific binding domain, wherein the antigen-specific binding domain comprises an scFv sequence, wherein the scFv sequence has a variable light chain having a sequence at least 95% identical to SEQ ID NO: 6, and wherein the scFv sequence has a heavy chain having a sequence at least 95% identical to SEQ ID NO: 7 (paragraphs [0006]-[0008]). Because this claim limitation is being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it is being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof, which are understood to sufficiently modify the “means for binding” of the CSR of the invention. Accordingly, claim 8, which recite these structural elements, is not being interpreted under 35 U.S.C. § 112(f).
If applicant does not intend to have this/these limitation(s) interpreted under 35
U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the
claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA
35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the
claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s)
sufficient structure to perform the claimed function so as to avoid it/them being
interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
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, 4-5, 13, 15, 55, 57, 61, 67-68, and 80 are rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, because the claim purports to invoke 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, but fails to recite a combination of elements as required by that statutory provision and thus cannot rely on the specification to provide the structure, material or acts to support the claimed function. As such, the claim recites a function that has no limits and covers every conceivable means for achieving the stated function, while the specification discloses at most only those means known to the inventor. Accordingly, the disclosure is not commensurate with the scope of the claim.
Claims 1, 4-5, 13, 15, 55, 57, 61, 67-68, and 80 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.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the 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 applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
Amgen Inc. v. Sanofi, Aventisub LLC, 872 F.3d 1367 (Fed. Cir. 2017) supported previous decisions (Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011); AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285 (Fed. Cir. 2014)) that defining an antibody solely by what it binds does not satisfy the written description requirement, stating that this would allow patentees to “claim antibodies by describing something that is not the invention, i.e., the antigen”. Thus, claiming an antibody by describing the invention by what it does (function) rather than what it is (structure) is invalid. This can be overcome if a relevant number of species with structure/function correlation is known to the art or present in the specification. See also pages 206-208 of Deng (mAbs (2018) 10(2): 204-209).
The claimed invention
The nature and scope of the claimed invention at issue, in part, is a chimeric scavenger receptor (CSR) comprising (1) an intracellular signaling domain comprising an intracellular domain of a scavenger receptor; (2) a transmembrane domain comprising a transmembrane domain of the scavenger receptor; and (3) an extracellular domain comprising a means for binding to oligomeric pTau (o-pTau), wherein the scavenger receptor is FcγRIIb, CD163, or CD204 (claim 1), wherein the CSR is defined by its functional properties without reciting a corresponding structure that would be expected to correlate with the claimed functions. In light of the interpretation of the claims under 35 U.S.C. § 112(f) as noted above, the broadest reasonable interpretation of “means for binding to o-pTau” is limited by the description in the specification. With respect to a structure of the “means for binding” that corresponds to the instantly claimed functional properties of the protein binder, the specification recites structural elements, described in pages 2-3 of the specification, that are outlined above in the section on 35 U.S.C. § 112(f). In view of the interpretation of the claims under 35 U.S.C. § 112(f), the claim is also drawn to equivalents thereof of the disclosed structures. However, the Applicant does not possess equivalents thereof to the instantly claimed CSR, and the disclosure does not permit a skilled artisan to determine the corresponding structure of the equivalents thereof that would be expected to be able to perform the instantly claimed functions. Claims 4-5, 13, 15, 55, 57, 61, 67-68, and 80, which depend directly or indirectly from claim 1, do not remedy the written description issues raised by the independent claim.
Claim 15 further defines the CSR of claim 1 to which the means binds comprises an amino acid sequence identical to the sequence of one of SEQ ID NOs:1-5 or 11. These claims further describe the CSR of claim 1 by a unique functional property (binding to a specific epitope of o-pTau) without identifying a corresponding structure expected to perform the claimed function. Because the claims are drawn to a unique binding property that is more specific than the broad limitation of “binding to o-pTau” (e.g., claim 1), claims reciting such a unique binding property require greater disclosure of the corresponding structural elements that confer the specifically claimed function in order to satisfy the written description requirement.
Claims 4 and 5 further recite that the cytoplasmic tail of the intracellular domain of the CSR is replaced by the cytoplasmic tail or a signaling domain of an anti-inflammatory cytokine receptor (as recited in claim 4, examples given in claim 5). Claim 13 recites that the CSR further comprises a hinge sequence positioned between the transmembrane domain and the extracellular domain. Although these claims further define the CSR of the instant application, they do not provide sufficient written description of a structural element (means) that would be expected to perform the claimed functions recited in claim 1.
State of the prior art.
The generic structure of a chimeric antigen receptor is generally considered to comprise an extracellular portion comprising an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. For example, Zhang et al (Zhang et al, Engineering CAR-T cells, Biomark Res, 2017 Jun 24, 5:22) teaches that CAR-T cells generally comprise an extracellular antigen-binding domain comprising an scFv, a spacer, a transmembrane domain, and an intracytoplasmic domain (Figure 1). Zhang et al also teaches that the engineering of CARs has evolved to include costimulatory modules such as CD137 (Fig. 2). Accordingly, second generation CARs added intracellular signaling domains from various co-stimulatory protein receptors to the cytoplasmic tail of the CARs to provide additional signals to the T cell, such as CD28 or CD137, which can improve the proliferation, cytotoxicity, and sustained response and prolong the life of CAR-T cells in vivo [16,17,18]” (See “Second generation” section).
With respect to oligomeric pTau, Sierks et al (US20150266947 A1, Priority to 10/12/2012) teaches that numerous studies have implicated small soluble oligomeric aggregates of Aβ as toxic species in Alzheimer's disease (AD), and increasing evidence also implicated oligomeric forms of tau as having a direct role in disease pathogenesis of AD and other tauopathies such as Frontotemporal Dementia (FTD) (page 32, paragraph [0002]). The microtubule-associating protein tau is a major component of the neurofibrillary tangles associated with AD and tauopathies that are characterized by hyperphosphorylation and aggregation of tau. Tau is a natively unfolded protein, and similar to a number of other natively unfolded proteins, it can aberrantly fold into various aggregate morphologies. The different types of post-translational modifications of tau in AD include phosphorylation, glycosylation, and aggregation among others and excess phosphorylation can interfere with microtubule assembly. Elevated total tau concentration in CSF has been correlated with AD, as has the presence of various phosphorylated tau forms. Reactive nitrogen and oxygen can modify tau, facilitating formation of aggregate forms including oligomeric species. Levels of oligomeric tau have also been implicated as a potential early diagnostic for AD. Therefore, determination of total tau, phosphorylated tau and oligomeric tau concentrations all have potential value as diagnostics for neurodegenerative diseases including tauopathies and AD (page 32, paragraph [0003]). Sierks also teaches that collectively, numerous studies all indicate that aggregated oligomeric species of tau, both intracellular and extracellular, are vitally important in AD and other tauopathies (page 32, paragraph [0007]).
As the focus of Aβ studies have slowly shifted toward soluble Aβ species and mechanisms, Sierks discloses that new reagents were needed that could specifically identify the variety of different aggregate species present (page 32, paragraph [0002]). Sierks teaches antibodies, antibody fragments and binding agents that specifically recognize oligomeric tau, but do not bind to monomelic tau, fibrillar tau, or non-disease associated forms of tau (page 1, Abstract). Pfeifer et al (US20140294731 A1, Priority to 10/7/2011) teaches methods and compositions for the therapeutic and diagnostic use in the treatment of diseases and disorders which are caused by or associated with neurofibrillary tangles. In particular, Pfeifer et al teaches antibodies which specifically recognize and bind to phosphorylated pathological protein tau-conformers and to methods and compositions involving said antibodies for the therapeutic and diagnostic use in the treatment of tauopathies including AD (page 19, paragraph [0002]). Furthermore, Winderickx et al (WO2013007839 A1) discloses affinity tools for oligomeric forms of tau protein comprising novel tau antibodies and antibody fragments, nucleic acids encoding such antibodies and antibody fragments, cell lines producing such antibodies and antibody fragments, antibody compositions, and kits for the detection of aggregated tau and for the diagnosis of diseases involving aggregated tau. Furthermore, Winderickx provides methods for the detection of aggregated tau, for the diagnosis of diseases involving aggregated tau, and for the identification of compositions interfering with the formation and/or stability of tau aggregates (page 1, Abstract). However, at the time of filing, there is no prior art that explicitly discloses a CAR engineered to recognize and specifically bind to oligomeric phosphorylated Tau.
At the time of filing, with respect to antibody and/or chimeric antigen receptors (CARs), It is well established in the art that the formation of an intact antigen-binding site of all antibodies requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”) (PTO-892). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30). It was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33 (PTO-892) (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Chimeric antibodies comprise the heavy and light chain variable regions of a rodent antibody linked to human constant regions and preserve the entirety of the VH and VL of the parent antibody. Id. at 1619-20. Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4. Almagro provides a detailed discussion regarding various methods of humanization, including rationale design approaches and empirical approaches based on random screening. Almagro, Sections 4 and 5. It has long been established that even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function. In 1982, Rudikoff et al(Proc. Natl. Acad. Sci. USA 1982 Vol. 79: page 1979) (PTO-892) teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. It is unlikely that humanized antibody, humanized scFv and fragments thereof as defined by the claims, which may contain less than the full complement of CDRs from the heavy and light chain variable regions have the required binding function. Pascalis et al (The Journal of Immunology (2002) 169, 3076-3084) (PTO-892) demonstrate that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right col.). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al. (2003) BBRC 307, 198-205 (PTO-892), which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.). More recently, D’Angelo et al, Frontiers in Immunology vol. 9 p. 1 (2018) (PTO-892) shows that antibodies bind their targets using diversified loops (CDRs) and, of the 6CDRs, HCDR3 is the most diverse. D’Angelo et al examined one CDR in depth and concluded that HCDR3 generated many different VDJ rearrangements (abstract and entire reference). They conclude “that a specific HCDR3 will only define a particular binding specificity within a very narrow structurally appropriate context: i.e. HCDRs is necessary, but is insufficient to define specific anti-binding properties unless combined with appropriate VL and VL germline genes” (page 8, second column). Thus, binding is highly specific to HCDR3 and VH and VL combinations. A generic disclosure of “antibody” with only one example, does not provide a representative number of examples to show that applicant had possession of the claimed invention at the time of filing.
Scope of species disclosed in original specification.
The CSR is described solely in terms of function—i.e. binding to oligomeric pTau. The only examples provided in the specification are for CSR comprising SEQ ID NOs:1-5 and 11. However, these 6 sequences do not provide a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of a representative number of species falling within the genus sufficient to distinguish the genus from other materials. Merely describing the antigen provides no information about the CSR.
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Although CSRs comprising amino acid sequences SEQ ID NO:1-5, and 11 have been recited in the disclosure, the examples provided in the disclosure (starting from page 33 of the instant application) only recites “three CSRs that were designed by replacing the natural ligand-binding domain of the scavenger receptors with an anti-o-pTau single-chain variable fragment (ScFv) based on an in vivo validated anti-o-pTau antibody, wherein these three CSR constructs encoding an anti-o-pTau ScFv supported by an FcyRIIb (FIG. 14), CD163 (FIG. 15), or CD204 (FIG. 16) scaffold were cloned into antibiotic selectable retroviral vectors” (page 33, paragraph [00130] of instant specification) without the corresponding amino acid sequences comprising the antigen binding region of the CSR, thus the disclosure does not provide the structure, material or acts to support the claimed function of claim 1.
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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 applicant was in possession of the claimed genus. As illustrated by the state of the art, the CDR structures in the VH and VL of conventional antibodies and/or CARs are a critical determinant of functional antigen-binding properties. Additionally, as recited above, the disclosure does not provide sufficient written description of the structural element (means) that would be expected to perform the claimed function (binding to oligomeric pTau).
Conclusion.
Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, the Applicant did not possess the full genus of protein binders comprising a means for binding to oligomeric pTau as broadly claimed at the time the application was filed.
New Rejections Necessitated by Claim Amendments
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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, 8, 13, 55, 57, 61, 67-68 and 80 are rejected under 35 U.S.C. 103 as being unpatentable over Gill and Klichinsky (WO 2019152781A1, Priority to 2/2/2018; hereinafter Gill), and further in view of Kam et al (eLife, 2016, 5(e18691): 1-25; hereinafter Kam).
Regarding instant claims 1, 8, 13, 55, 57, 61, 67-68, and 80, Gill teaches compositions and methods for treating diseases or disorders associated with protein aggregates, wherein the protein aggregate is aggregates of the tau protein (page 1, Abstract; page 26, lines 19-28). Gill discloses a chimeric antigen receptor (CAR) comprising (i) an extracellular domain comprising an antigen binding domain, wherein the antigen binding domain comprises an antibody agent selected from a group consisting of a monoclonal antibody, polyclonal antibody, synthetic antibody, humanized antibody, single chain variable fragment (scFv), and antigen-binding fragments thereof, wherein the antibody agent comprises a Tau antibody or an scFv of a Tau antibody (page 6, lines 21-31; page 17, line 31-page 18, line 6; page 44, lines 1-10); (ii) a transmembrane domain wherein the domain may be derived from any membrane-bound or transmembrane protein (page 45, “Transmembrane Domain” Section); and (iii) an intracellular domain comprising a scavenger receptor, wherein the intracellular domain comprises common FcR gamma (page 6, line 32 – page 7, line 5; page 46-47, “Intracellular Domain” Section). Gill also discloses a “spacer domain” between the antigen binding domain and the transmembrane domain of the provided CAR, wherein a spacer domain generally means any oligo- or polypeptide linker that may comprise up to 300 amino acids, preferably 10-100 amino acids (page 47, lines 1-10).
Additionally, Gill teaches an isolated nucleic acid sequence encoding the CAR, wherein the isolated nucleic acid sequence comprises a nucleic acid sequence encoding an antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the antigen binding domain is capable of binding to an antigen of a protein aggregate (page 6, lines 14-20). Gill further discloses a vector comprising the DNA of the CAR, wherein the vector is a viral vector (page 51-54, “Vectors” section), wherein the vector comprising the nucleic acid sequence encoding the CAR is used to introduce the nucleic acid sequence to a monocyte, macrophage, or dendritic cell (page 54-56, “Introduction of Nucleic Acids” section).
Furthermore, Gill teaches a pharmaceutical composition comprising the modified immune cells included in a composition for treatment of a subject and further include a pharmaceutically accepted carrier (claim 19), wherein the pharmaceutical composition is used in a method of treating a disease/disorder related to protein aggregation, wherein the disease/disorder comprises tauopathy, Alzheimer’s disease or frontotemporal dementia (page 66-68, “Therapy” section; page 69-71, “Pharmaceutical Compounds” section), wherein the modified immune cell is a monocyte, macrophage, or dendritic cell comprising the CAR (page 54-56, “Introduction of Nucleic Acids” section) wherein the CAR comprises an antigen binding domain wherein the antigen binding domain comprises an antibody agent selected from a group consisting of a monoclonal antibody, polyclonal antibody, synthetic antibody, humanized antibody, single chain variable fragment (scFv), and antigen-binding fragments thereof, wherein the antibody agent comprises a Tau antibody or an scFv of a Tau antibody (page 6, lines 21-31; page 17, line 31-page 18, line 6; page 44, lines 1-10), a transmembrane domain, and an intracellular domain (page 17, line 26 – page 18, line 6). Gill also discloses that the cells that are administered are autologous with respect to the subject undergoing the therapy (page 69, lines 9-11, “Therapy” section).
However, Gill does not teach a transmembrane domain comprising a transmembrane domain of the scavenger receptor, wherein the scavenger receptor is FcγRIIb.
The deficiency is resolved by Kam et al.
Kam teaches that the FcγRIIb-SHIP2 axis is critical in Aβ1-42-induced tau pathology, wherein Fcgr2b knockout or antagonistic FcγRIIb antibody inhibited Aβ1-42-induced tau hyperphosphorylation and rescued memory impairments in AD mouse models (page 1, abstract). Additionally, Kam teaches that amyloid beta (Aβ) binds to many different receptor proteins – including FcγRIIb – on the surface of neurons, wherein adding amyloid beta to mouse neurons caused tau proteins to become hyperphosphorylated while removing FcγRIIb from the neurons or preventing it from binding to amyloid beta abolished this effect (page 2, “eLife digest” section; page 3, 2nd paragraph; page 7, “FcγRIIb ITIM phosphorylation found in AD brains is essential for Aβ neurotoxicity and tau phosphorylation” section). Kam also teaches that given that FcγRIIb was initially reported as a hematopoietic receptor which is mainly expressed in B cells, macrophages, and neutrophils, FcγRIIb deficiency not only reduced microglia activation in the cortex and hippocampus, but also prevented Aβ-induced tau phosphorylation (page 15, 2nd paragraph). Furthermore, Kam teaches that preventing phosphorylation of FcγRIIb by the knockdown of Lyn kinase blocked Aβ-induced FcγRIIb phosphorylation and neurotoxicity (page 15, 3rd paragraph). Kam also teaches nucleic acid sequences of FCGR2B (FcγRIIb) that were amplified and subcloned into a vector for in vitro studies (page 18, “DNA constructs” section).
Regarding instant claims 1 and 13, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the CAR comprising (i) an extracellular domain comprising an antigen binding domain, wherein the antigen binding domain comprises a Tau antibody or an scFv of a Tau antibody; (ii) a transmembrane domain wherein the domain may be derived from any membrane-bound or transmembrane protein; (iii) an intracellular domain comprising a scavenger receptor; and (iv) a “spacer domain” between the antigen binding domain and the transmembrane domain as taught by Gill and modify it to include that the intracellular domain and transmembrane domain comprise FcγRIIb as taught by Kam to halt the progression of Alzheimer’s disease by protecting neurons from o-pTau-mediated neurotoxicity as disclosed in the instant specification. This is obvious because, Gill teaches a chimeric antigen receptor (CAR) comprising (i) an extracellular domain comprising an antigen binding domain comprising a Tau antibody or an scFv of a Tau antibody; (ii) a transmembrane domain comprising any membrane-bound or transmembrane protein; (iii) an intracellular domain comprising a scavenger receptor; and (iv) a “spacer domain” between the antigen binding domain and the transmembrane domain of the provided CAR, wherein a spacer domain comprises any polypeptide linker that comprise up to 300 amino acids, Kam teaches that FcγRIIb deficiency reduced microglia activation in the cortex and the hippocampus and blocked Aβ-induced FcγRIIb phosphorylation and neurotoxicity, and the instant specification discloses that scavenger receptors such as FcγRIIb was used to harness anti-inflammatory properties to reprogram the inherent inflammatory myeloid response to o-pTau in Alzheimer’s disease (AD), resulting in monocytes engineered to bind and internalize o-pTau via antibody-redirected chimeric scavenger receptors (CSR) to halt the progression of AD by protecting neurons from o-pTau-mediated neurotoxicity while dampening proinflammatory cytokine release (instant specification, page 33, paragraph [00130], Example 1). Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the CAR comprising (i) an extracellular domain comprising an antigen binding domain, wherein the antigen binding domain comprises a Tau antibody or an scFv of a Tau antibody; (ii) a transmembrane domain wherein the domain may be derived from any membrane-bound or transmembrane protein; (iii) an intracellular domain comprising a scavenger receptor; and (iv) a “spacer domain” between the antigen binding domain and the transmembrane domain as taught by Gill and modify it to include that the intracellular domain and transmembrane domain comprise FcγRIIb as taught by Kam to halt the progression of Alzheimer’s disease by protecting neurons from o-pTau-mediated neurotoxicity as disclosed in the instant specification to form the instant chimeric scavenger receptor (CSR) comprising (1) an intracellular signaling domain, wherein the instant intracellular domain comprises an intracellular domain of a scavenger receptor; (2) a transmembrane domain comprising a transmembrane domain of the scavenger receptor; (3) an extracellular domain, wherein the extracellular domain comprises a means for an antigen-specific binding to oligomeric pTau (o-pTau) domains; and (4) a hinge sequence positioned between the instant transmembrane domain and the instant extracellular domain, wherein the instant scavenger receptor is FcγRIIb.
Regarding instant claims 55, 57, and 61, it would have been obvious for a person having ordinary skill in the art at the time of filing to take an isolated nucleic acid sequence encoding the modified CAR of Gill and Kam, wherein the vector is a viral vector that is introduced to a monocyte, macrophage, or dendritic cell, as taught by Gill and modify it so that the CAR comprises (i) an extracellular domain comprising an antigen binding domain comprising a Tau antibody; (ii) a transmembrane domain comprising the transmembrane domain of FcγRIIb and (iii) an intracellular domain comprising the intracellular domain of FcγRIIb as taught by the combined teachings of Gill and Kam. This is obvious because, Gill teaches an isolated nucleic acid sequence encoding a CAR and a vector comprising the DNA of a CAR, wherein the vector is a viral vector that is introduced to a monocyte, macrophage, or dendritic cell, and the combined teachings of Gill and Kam teach a CAR comprising (i) an extracellular domain comprising an antigen binding domain comprising a Tau antibody ; (ii) a transmembrane domain comprising the transmembrane domain of FcγRIIb and (iii) an intracellular domain comprising the intracellular domain of FcγRIIb. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take an isolated nucleic acid sequence encoding the CAR discussed above and a vector comprising the DNA of the CAR, wherein the vector is a viral vector that is introduced to a monocyte, macrophage, or dendritic cell, as taught by Gill and modify it so that the CAR comprises (i) an extracellular domain comprising an antigen binding domain comprising a Tau antibody ; (ii) a transmembrane domain comprising the transmembrane domain of FcγRIIb and (iii) an intracellular domain comprising the intracellular domain of FcγRIIb as taught by the combined teachings of Gill and Kam to form the instant nucleic acid encoding the instant CSR, the instant viral vector comprising the instant nucleic acid encoding the instant CSR, and the instant engineered immune effector cell comprising the instant nucleic acid encoding the instant CSR, wherein the instant CSR comprises (1) an intracellular signaling domain comprising an intracellular domain of a scavenger receptor; (2) a transmembrane domain comprising a transmembrane domain of the scavenger receptor; and (3) an extracellular domain, wherein the instant extracellular domain comprises a means for an antigen-specific binding to o-pTau domains, wherein the instant scavenger receptor is FcγRIIb.
Regarding instant claims 67-68, and 80, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the pharmaceutical composition comprising modified immune cells wherein the cells that are administered are autologous with respect to the subject undergoing the therapy, and a pharmaceutically accepted carrier, wherein the pharmaceutical composition is used in a method of treating a disease/disorder related to protein aggregation, wherein the disease/disorder comprises tauopathy, Alzheimer’s disease or frontotemporal dementia, wherein the modified immune cell is a monocyte, macrophage, or dendritic cell of Gill to comprise the modified CAR of Gill and Kam, to form a pharmaceutical composition comprising an immune cell (including monocyte, macrophage, or dendritic cell) to express the modified CAR comprising (i) an extracellular domain comprising an antigen binding domain comprising a Tau antibody ; (ii) a transmembrane domain comprising the transmembrane domain of FcγRIIb and (iii) an intracellular domain comprising the intracellular domain of FcγRIIb as taught by the combined teachings of Gill and Kam. This is obvious because, Gill teaches pharmaceutical composition comprising modified immune cells, wherein the cells that are administered are autologous with respect to the subject undergoing the therapy, and a pharmaceutically accepted carrier, wherein the pharmaceutical composition is used in a method of treating a disease/disorder related to protein aggregation, wherein the disease/disorder comprises tauopathy, Alzheimer’s disease or frontotemporal dementia, wherein the modified immune cell is a monocyte, macrophage, or dendritic cell comprising the CAR, and the combined teachings of Gill and Kam teach a CAR comprising (i) an extracellular domain comprising an antigen binding domain comprising a Tau antibody ; (ii) a transmembrane domain comprising the transmembrane domain of FcγRIIb and (iii) an intracellular domain comprising the intracellular domain of FcγRIIb. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant pharmaceutical formulation comprising the engineered cells comprising the instant CSR and a pharmaceutically acceptable carrier to use in the instant method of treating Alzheimer’s disease comprising administering an effective amount of the instant pharmaceutical formulation comprising the instant engineered cells to the patient, wherein the engineered cell is autologous to the patient, the instant CSR comprises (1) an intracellular signaling domain, wherein the instant intracellular domain comprises an intracellular domain of a scavenger receptor; (2) a transmembrane domain comprising a transmembrane domain of the scavenger receptor; and (3) an extracellular domain, wherein the extracellular domain comprises an antigen-specific binding to a Tau protein, wherein the instant scavenger receptor is FcγRIIb as taught in Gill and Kam.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Gill and Klichinsky (WO 2019152781A1, Priority to 2/2/2018; hereinafter Gill) and Kam et al (eLife, 2016, 5(e18691): 1-25; hereinafter Kam), as applied to claim 1 above, and further in view of Bluestone et al (WO 2019/178518, IDS entered on 1/23/24; hereinafter Bluestone) and Suri et al (WO 2018/231729; hereinafter Suri).
The teachings of Gill and Kam are discussed above.
The teachings of Gill and Kam do not teach a CSR wherein the cytoplasmic tail of the intracellular domain is replaced by the cytoplasmic tail or a signaling domain of an anti-inflammatory cytokine receptor, wherein the anti-inflammatory cytokine receptor is an IL-10 receptor.
The deficiency is resolved by Bluestone and Suri.
Bluestone discloses modified CAR comprising anti antigen binding domain, a spaced domain, a transmembrane domain and an intracellular signaling domain (summary and entire reference). The reference discloses that the intracellular domain is CD28 and that incorporating the IL-2 signaling ability into the cytoplasmic end of the CD28 would trigger CAR Treg vitality and function and thus, IL2R gamma was incorporated downstream of the CD28 (para 71 and 190).
Suri discloses CAR molecules wherein the intracellular domains are modified with cytokine receptors that have been fused to the intracellular domain and these cytokine receptors include IL2R and IL10R (summary, para 622 and entire reference).
Regarding instant claims 4 and 5, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the CAR comprising (i) an extracellular domain comprising an antigen binding domain comprising a Tau antibody ; (ii) a transmembrane domain comprising the transmembrane domain of FcγRIIb and (iii) an intracellular domain comprising the intracellular domain of FcγRIIb as taught by the combined teachings of Gill and Kam and modify it to replace the cytoplasmic tail of the intracellular domain with an anti-inflammatory cytokine receptor as taught by Bluestone, wherein the anti-inflammatory cytokine receptor is an IL4 receptor as taught by Suri. This is obvious because, the combined teachings of Gill and Kam teach a CAR comprising (i) an extracellular domain comprising an antigen binding domain comprising a Tau antibody ; (ii) a transmembrane domain comprising the transmembrane domain of FcγRIIb and (iii) an intracellular domain comprising the intracellular domain of FcγRIIb as taught by the combined teachings of Gill and Kam, Bluestone teaches modified CAR comprising an antigen binding domain, a spaced domain, a transmembrane domain and an intracellular signaling domain wherein the cytoplasmic tail of the intracellular domain comprising CD28 was replaced by the IL-2 signaling ability to trigger CAR Treg vitality and function, and Suri teaches CAR molecules wherein the intracellular domains were modified with cytokine receptors that have been fused to the intracellular domain, wherein these cytokine receptors include IL2R and IL10R. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the CAR comprising (i) an extracellular domain comprising an antigen binding domain comprising a Tau antibody ; (ii) a transmembrane domain comprising the transmembrane domain of FcγRIIb and (iii) an intracellular domain comprising the intracellular domain of FcγRIIb as taught by the combined teachings of Gill and Kam and modify it to replace the cytoplasmic tail of the intracellular domain with an anti-inflammatory cytokine receptor as taught by Bluestone, wherein the anti-inflammatory cytokine receptor is an IL10 receptor as taught by Suri to form the instant chimeric scavenger receptor (CSR) comprising (1) an intracellular signaling domain, wherein the instant intracellular domain comprising FcγRIIb, wherein the instant cytoplasmic tail of the instant intracellular domain is replaced by the a signaling domain of an anti-inflammatory cytokine receptor wherein the anti-inflammatory cytokine receptor is an IL-10 receptor; (2) a transmembrane domain comprising a transmembrane domain of FcγRIIb; and (3) an extracellular domain, wherein the extracellular domain comprises a means for an antigen-specific binding to oligomeric pTau (o-pTau) domains wherein the instant scavenger receptor is FcγRIIb.
Claims 8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Gill and Klichinsky (WO 2019152781A1, Priority to 2/2/2018; hereinafter Gill), and Kam et al (eLife, 2016, 5(e18691): 1-25; hereinafter Kam), as applied to claim 1 above, and further in view of Ayalon et al (US 2016/0024193, IDS entered on 1/23/2024; hereinafter Ayalon) and Xiao et al (US2019/0216851, IDS entered on 1/23/2024; hereinafter Xiao).
The teachings of Gill and Kam are discussed above.
The teachings of Gill and Kam do not teach a CSR wherein the variable light chain and variable heavy chain are separated by a linker sequence. Furthermore, the teachings of Gill, Vickers, and Kam do not teach the scFv of anti-tau antibodies with a VH comprising amino acid sequence SEQ ID NO:7 and a VL comprising amino acid sequence SEQ ID NO:6.
The deficiency is resolved by Ayalon et al and Xiao et al.
Ayalon discloses anti-tau antibodies or fragments thereof comprising SEQ ID NO. 55 or 57 (applicant’s SEQ ID NO. 6) and SEQ ID NO. 58 (applicant’s SEQ ID NO. 7) (summary, para 15-16, 104-129 and entire reference). The reference defines fragments as including scFv (para 43, 135-138). The reference also discloses nucleic acids and recombinant methods of making these antibodies and fragments (para 196-203). The reference discloses the use of the antibodies in pharmaceutical compositions for the treatment of Alzheimer's disease, frontotemporal dementia, a tauopathy, or a Tau protein-associated impairment in or loss of cognitive function in a patient in need thereof (para 28-29, 226-263 and entire reference).
Xiao discloses CAR molecules comprising an extracellular antigen binding domain which is an scFv with a linker between the VH and VL (summary, para 96 and entire reference).
Regarding instant claims 8 and 11, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the CAR comprising (i) an extracellular domain comprising an antigen binding domain comprising a scFv of a Tau antibody; (ii) a transmembrane domain comprising the transmembrane domain of FcγRIIb and (iii) an intracellular domain comprising the intracellular domain of FcγRIIb as taught by the combined teachings of Gill and Kam, and modify it to include that the scFv of comprises a VH comprising amino acid sequence SEQ ID NO:7 and a VL comprising amino acid sequence SEQ ID NO:6 as taught by Ayalon, wherein the variable light chain and variable heavy chain are separated by a linker sequence as taught by Xiao. This is obvious because, the combined teachings of Gill and Kam teach a CAR comprising (i) an extracellular domain comprising an antigen binding domain comprising a scFv of a Tau antibody; (ii) a transmembrane domain comprising the transmembrane domain of FcγRIIb and (iii) an intracellular domain comprising the intracellular domain of FcγRIIb, Ayalon teaches anti-tau antibodies or fragments thereof comprising SEQ ID NO. 55 or 57 (identical to instant SEQ ID NO:6) and SEQ ID NO. 58 (identical to instant SEQ ID NO:7), and Xiao teaches CAR molecules comprising an extracellular antigen binding domain which is an scFv with a linker between the VH and VL. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the CAR comprising (i) an extracellular domain comprising an antigen binding domain comprising a scFv of a Tau antibody; (ii) a transmembrane domain comprising the transmembrane domain of FcγRIIb and (iii) an intracellular domain comprising the intracellular domain of FcγRIIb as taught by the combined teachings of Gill and Kam and modify it to include that the scFv of comprises a VH comprising amino acid sequence SEQ ID NO:7 and a VL comprising amino acid sequence SEQ ID NO:6 as taught by Ayalon, wherein the variable light chain and variable heavy chain are separated by a linker sequence as taught by Xiao to form the instant CSR comprising (1) an intracellular signaling domain, wherein the instant intracellular domain comprises an intracellular domain of a scavenger receptor; (2) a transmembrane domain comprising a transmembrane domain of the scavenger receptor; and (3) an extracellular domain, wherein the extracellular domain comprises an antigen-specific binding comprising a single chain monoclonal antibody to oligomeric pTau (o-pTau) whereby the instant single chain monoclonal antibody comprises a variable light chain comprising amino acid sequence instant SEQ ID NO:6 and a variable heavy chain comprising amino acid sequence instant SEQ ID NO:7 wherein the instant variable light chain and instant variable heavy chain are separated by a linker sequence, and wherein the instant scavenger receptor is FcγRIIb.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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