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 1-6, 13, 15, 17-18, 21-23, 29, 37, 41-42, 57-58 and 66 are pending.
Claims 22-23, 29, 37, 42 and 66 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1-6, 13, 15, 17-18, 21, 41, 57 and 58, drawn to a particular chimeric receptor and method of treating a subject diagnosed with or at risk of developing a neurodegenerative disease that read on (A) SEQ ID NO: 28 as the species of chimeric receptor, (B) SEQ ID NO: 1 (anti-Aβ scFv) as the species of single-chain variable antibody fragment (scFv), (C) FCERG as the species of first intracellular phagocytic signaling domain, (D) MRC1 as the species of second intracellular phagocytic signaling domain and (E) CD8 as the species of transmembrane domain, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/163,016, filed March 18, 2021, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on August 28, 2026 been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Objection and Rejection Withdrawn
The objection to claims 1-3, 13 is withdrawn in view of the claim amendment.
The rejection of claim 13 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in light of the claim amendment.
The rejection of claims 1, 3-4, 17 on the judicially-created basis that it contains an improper Markush grouping is withdrawn in view of the claim amendment.
The rejection of claims 1, 3-6, 13, 18 and 21 under 35 U.S.C. 103 as being unpatentable over US20200345774 (of record, Getts hereafter, published November 5, 2020, claimed earliest priority to 62/841,190, filed April 30, 2019, PTO 892) in view of US20100104577 (Golde hereafter, published April 29, 2010; PTO 892) and U.S. Patent No. 12,344,662 (filed February 11, 2019, claimed earliest priority to 62/628,632, filed February 9, 2018; PTO 892) is withdrawn in view of the amendment to claims 1 and 3.
The rejection of claim 15 under 35 U.S.C. 103 as being unpatentable over US20200345774 (Getts hereafter, published November 5, 2020, claimed earliest priority to 62/841,190, filed April 30, 2019, PTO 892) in view of US20100104577 (Golde hereafter, published April 29, 2010; PTO 892) and U.S. Patent No. 12,344,662 (filed February 11, 2019, claimed earliest priority to 62/628,632, filed February 9, 2018; PTO 892) as applied to claims 1, 3-6, 13, 18, and 21 mentioned above and further in view of US20200055917 (Corey hereafter, published February 20, 2020; PTO 892) is withdrawn in view of the amendment to claims 1 and 3. The addition of Gorey does not cure the deficiency of Getts, Golde and the ‘662 patent.
The rejection of claims 41, 57 and 58 under 35 U.S.C. 103 as being unpatentable over US20200345774 (Getts hereafter, published November 5, 2020, claimed earliest priority to 62/841,190, filed April 30, 2019, PTO 892) in view of US20100104577 (Golde hereafter, published April 29, 2010; PTO 892) and U.S. Patent No. 12,344,662 (filed February 11, 2019, claimed earliest priority to 62/628,632, filed February 9, 2018; PTO 892) as applied to claims 1, 3-6, 13, 18, and 21 mentioned above and further in view of Rosenthal (US20180186855, published July 5, 2018; PTO 892) is withdrawn in view of the amendment to claims 1 and 3. The addition of Rosenthal does not cure the deficiency of Getts, Golde and the ‘662 patent.
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 1-6, 13, 15, 18, 21, 41, 57 and 58 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Written Description Guidelines for examination of patent applications indicates, “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 by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other 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 applicant was in possession of the claimed genus.” (see MPEP 2163).
Claim 1 encompasses any chimeric receptor comprising:(i) an intracellular phagocytic signaling domain,(ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta peptide and (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, wherein the scFv comprises an amino acid sequence having at least 99% sequence identity to any of SEQ ID NOs: 1-3.
Claim 2 encompasses any chimeric receptor comprising (i) any intracellular phagocytic signaling domain, (ii) any extracellular binding domain comprising any single-chain variable antibody fragment (scFv) having affinity for any amyloid beta peptide, and (iii) any transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, wherein the intracellular phagocytic signaling domain is derived from any TREM2 (triggering receptor expressed on myeloid cells-2) receptor.
Claim 3 encompasses any chimeric receptor comprising:(i) a first intracellular phagocytic signaling domain, (ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta peptide, (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, and (iv) a second intracellular phagocytic signaling domain fused to the first intracellular phagocytic signaling domain, wherein the scFv comprises an amino acid sequence having at least 99% sequence identity to any of SEQ ID NO: 1-3.
Claim 4 encompasses the chimeric receptor of claim 2, wherein the scFv comprises an amino acid sequence having at least 99% sequence identity to any of SEQ ID NOs: 1-3.
Claim 5 encompasses the chimeric receptor of claim 1, wherein the transmembrane domain comprises a hinge domain.
Claim 4 encompasses the chimeric receptor of claim 1, wherein the transmembrane domain is covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain by one or more linkers.
Claim 13 encompasses the chimeric receptor of claim 1, wherein the first intracellular phagocytic signaling domain comprises a TREM2 signaling domain, a macrophage mannose receptor 1 (MRC1) signaling domain, a multiple epidermal growth factor-like domains protein 10 (MEGF10) signaling domain, a DAP12 signaling domain, a tyrosine-protein kinase Mer (MERTK) signaling domain, a high-affinity immunoglobulin epsilon receptor subunit gamma (FCERG) signaling domain (elected species), a mannose 6 phosphate receptor (M6PR) signaling domain, or a C-type lectin domain family 4 member L (CLEC4L) signaling domain.
Claim 15 encompasses the chimeric receptor of claim 3, wherein the first intracellular phagocytic signaling domain comprises a TREM2 signaling domain, a MRC1 signaling domain, a MEGF10 signaling domain, a DAP12 signaling domain, a MERTK signaling domain, a FCERG signaling domain (elected species), a M6PR signaling domain, or a CLEC4L signaling domain; and the second intracellular phagocytic signaling domain comprises a TREM2 signaling domain, a MRC1 signaling domain (elected species), a MEGF10 signaling domain, a DAP12 signaling domain, a MERTK signaling domain, a FCERG signaling domain, a M6PR signaling domain, or a CLEC4L signaling domain.
Claim 17 encompasses the chimeric receptor of claim 1, wherein the chimeric receptor comprises an amino acid sequence having at least 98% sequence identity to any of SEQ ID NOs: 26-35, 42 and 43 (SEQ ID NO: 28 as the elected species).
Claim 18 encompasses the chimeric receptor of claim 1, wherein the chimeric receptor comprises a second extracellular binding domain.
Claim 21 encompasses the chimeric receptor of claim 1, wherein the transmembrane domain is a TREM2 transmembrane domain, a MRC1 transmembrane domain, a MEGF10 transmembrane domain, a DAP12 transmembrane domain, a MERTK transmembrane domain, a CD8 transmembrane domain (elected specie), a M6PR transmembrane domain, or a CLEC4L transmembrane domain.
Claim 41 encompasses the chimeric receptor of claim 1, wherein the modified cell is an astrocyte.
Claim 57 encompasses a method of treating any subject diagnosed with an amyloid-related neurodegenerative disease, disorder, or condition, the method comprising: administering to the subject the modified cell of claim 41.
Claim 58 encompasses a method of treating an amyloid-related neurodegenerative disease, disorder, or condition, the method comprising: administering to any subject the modified cell of any one of claim 41.
Regarding antibody, the specification defines as follow:
[0040] An “antibody” refers to an immunoglobulin molecule capable of specific or selective binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule. As used herein, the term “antibody” encompasses not only intact (e.g., full-length) polyclonal or monoclonal antibodies, but also antigen-binding fragments thereof (such as Fab, Fab′, F(ab′)2, Fv), single chain (scFv), mutants thereof, fusion proteins comprising an antibody portion, humanized antibodies, chimeric antibodies, diabodies, linear antibodies, single chain antibodies, multispecific antibodies (e.g., bispecific antibodies) and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity or selectivity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. An antibody includes an antibody of any class, such as IgD, IgE, IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant domain of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
Regarding scFv antibody encompassed by the claimed chimeric receptor that binds to any amyloid beta peptide, the specification discloses just three scFv antibodies. Anti-Aβ9 scFv comprises the amino acid sequence of SEQ ID NO: 1, anti-Aβ2.1.3 scFv comprises the amino acid sequence of SEQ ID NO: 2, anti-Aβ scFv comprises the amino acid sequence of SEQ ID NO: 3.
However, the specification does not describe the structure of any and all possible single-chain variable antibody fragment (scFv) antibodies having affinity for any amyloid beta peptide encompassed by the claimed chimeric receptor (claim 2). The specification does not describe the structure, e.g., amino acid sequences of heavy chain variable domain and light chain variable domain of a sufficient number of species of the genus of scFvs that having affinity for any amyloid beta peptide encompassed by the claimed chimeric receptors. The specification does not describe the structure-identifying information about the claimed chimeric receptor, nor describe a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed chimeric receptor themselves.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. newly cited, Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (newly cited, J Mol Biol. 334(1): 103-118, 2003, PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Even a single CDR substitution can disrupt antigen binding as evidenced by Rudikoff et al. (of record, Proc Natl Acad Sci USA Vol 79 page 1979, 1982; PTO 892). Rudikoff et al. 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.
Ito et al (of record, FEBS Letters 309(1): 85-88, 1992; PTO 892) teaches substitution of histidine at various positions in an anti-lysozyme antibody. The L3A mutant contained a histidine in place of tyrosine in CDR3 of the light chain and the resulting mutant antibody lost its ability to bind to lysozyme antigen in an ELISA assay, see section spanning left and right column of page 86.
Piche-Nicholas et al (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
Regarding any chimeric receptor (claims 1-6, 13, 15, 17-18, 21, 41, 57 and 58), the specification discloses chimeric phagocytic receptors (CPRs), see title, [0005], [0006], [0008], [0093], and throughout the specification. However, the specification does not disclose chimeric receptor. This is new matter.
Regarding intracellular phagocytic signaling domain (claims 1, 3, 4, 5, 6, 21), the specification discloses human FCERG comprises the amino acid sequence of SEQ ID NO: 11, human MRC1 comprises the amino acid sequence of SEQ ID NO: 12, mouse FCERG comprises the amino acid sequence of SEQ ID NO: 18, mouse MRC1 comprises the amino acid sequence of SEQ ID NO: 19, dual human FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 15, dual human MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 16, mouse dual FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 24 and mouse MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 25.
However, the specification does not describe the structure-identifying information about the claimed intracellular phagocytic signaling domain (claims 1, 3, 4, 5, 6, 21); the specification does not disclose a representative number of species falling within the scope of the genus or structure common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed intracellular phagocytic signaling domain.
Even assuming the intracellular phagocytic signaling domain is derived from TREM2 (triggering receptor expressed on myeloid cells 2) receptor, the term “derived” encompasses addition, substitution, deletion or a combination thereof (claim 2 in the event of rejoinder). The specification discloses just human TREM2.
However, the specification does not describe where and what amino acid within the full-length sequence of any TREM2 (triggering receptor expressed on myeloid cells 2) receptor to be deleted, added, substituted or a combination thereof such that the derivative still maintains intracellular phagocytic signaling.
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Regarding chimeric phagocytic receptor (CPR), the specification discloses chimeric receptors that bind to amyloid beta and comprise the amino acid sequence of SEQ ID NO: 26-35, 42-43, see para. [0100].
Regarding treatment, the specification discloses:
[0035] The terms “ameliorate” and “treat” are used interchangeably and include both therapeutic and prophylactic treatment. Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a neurodegenerative disease or disorder described herein).
Regarding “disease”, the specification discloses:
[0045] “Disease” means any condition or disorder that damages or interferes with the normal function of a cell, tissue, organ or organism. Exemplary diseases of the disclosure are neurodegenerative diseases.
Regarding “subject”, the specification discloses:
[0049] The term “subject” includes organisms which are capable of suffering from a disorder as described herein or who could otherwise benefit from the administration of a compound of the present disclosure, such as human and non-human animals. Preferred humans include human patients suffering from or prone to suffering from diseases or disorders as discussed above, as described herein. Mammalian species that may benefit from the disclosed methods of treatment include, but are not limited to, apes; chimpanzees; orangutans; humans; monkeys; domesticated animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and other animals such as mice, rats, guinea pigs, and hamsters. A “subject in need of treatment” includes a subject diagnosed, e.g., by a medical or veterinary professional, as suffering from or susceptible to a neurodegenerative disease, disorder or condition described herein.
The specification exemplifies:
[0205] In vivo CPR prevention and clearance assessment. To evaluate the ability of CPR to prevent amyloid pathology, astrocytes are selectively transduced using rAAV-PHP.eB-GFAP-CPR and evaluate effects on amyloid pathology in CRND8 mice, a transgenic model that overexpresses mutant human amyloid protein precursor (APP) at levels approximately 5-fold higher than endogenous murine APP (see Chakrabarty, et al. Neuron 85, 519-533 (2015), incorporated herein by reference). For the prevention paradigm newborn CRND8 are injected with rAAV-PHP.eB-GFAP-CPR (with FCER1G, MRC1, MERTK, and CLEC4L with a non-specific CPR, anti-pan Aβ scFv alone, and GFP used as controls) (ICV, 4×10.sup.10 viral genomes/pup) and assess Aβ levels and plaque burden at 3 months. Each construct is delivered to 4-5 litters, resulting in −20 transgenic mice, of whom half will reach 3 months of age. Based on extensive experience with this strain, this cohort size allows to detect significant changes of 25% in amyloid levels. Small sub-cohorts on non-transgenic littermates at 4 weeks old are harvested to evaluate transduction and tropism.
[0206] At 3 months, the age at which substantial plaque formation is typically observed in these mice, one hemibrain is fixed and stained for amyloid immunoreactivity burden with anti-pan-Aβ antibody, Aβ5-biotin, and Thio-S. The other hemibrain is fractionated and Aβ levels are quantified by ELISA from RIPA-soluble fraction, SDS-soluble, and SDS-insoluble, formic acid-soluble fractions. Astrogliosis and microgliosis are evaluated using glial fibrillary acid protein (GFAP) and ionized calcium-binding molecule-1 (IBA-1) antibodies, respectively. Image analysis is done following scanning whole slides with the Aperio System and analysis of immunoreactivity burden by ImageScope program (Aperio, CA). Neuron counts in specific areas of the hippocampus and cortex where neurodegenerative may be observed by gross H&E analysis are also assessed quantitatively using NeuN antibody and determined by double-blinded quantification. Detailed calculations of mouse numbers are presented in the Vertebrate animals section. Control groups were injected with a non-specific CPR, anti-pan Aβ alone, and GFP. It is expected that each CPR has a differential effect on Aβ.
[0207] Based on these results the most effective anti-AβCPR agent can be pinpointed. To test whether CPRs are functional in a therapeutic paradigm, one or two of the most promising CPR from prevention study, and the appropriate controls, are administered intraocularly or into the tail vein into 4 month old CRND8 mice. At 4 months of age CRND8 mice have moderate levels of deposits, by 6 months they have significant amyloid accumulation. Amyloid burden and Aβ levels are assessed at 2 months post injection and compared to the non-specific CPR control group. These controls are designed to test whether non-specific activation of astrocytes is beneficial in targeting amyloid pathology. Additionally, control groups are injected with scFv's alone and GFP.
[0208] Given the above-described positive preliminary results and the demonstrated success in performing all the methods, experiments to assess the effect on prevention of aggregation and clearance of existing pathology are ongoing. CPRs activate astrocytes and microglia and it is possible that the non-specific CPR may have an effect on amyloid pathology. Nevertheless, the role of phagocytosis in amyloid clearance and the specific CPR domain may become better understood. Experiments are ongoing to optimize the CPRs of the disclosure to induce minimal off-target effects.
Example 2
[0209] CPRs May Bind AD or Tau when Expressed in Microglia or Monocytes and Alter the Proteinopathy in Ex Vivo Brain Slice Culture Models or In Vivo Following Transplantation of the CPR Expressing Microglia/Monocytes into the Brain of the Appropriate Proteinopathy Mouse Model.
[0210] This experiment evaluated whether the CPRs enhance microglial phagocytosis of amyloid plaques and tau aggregates. Multiple genetic association studies have identified numerous loci that harbor genes that encode proteins of known immune function that alter the risk of developing AD and other neurodegenerative proteinopathies (35). Microglial cells are the primary immune cells of the central nervous system and function as macrophages. They respond to foreign material or cellular debris by changing their morphology, becoming activated, migrating to the site of damage, clearing the foreign material and cellular debris through phagocytosis, and secreting signals to increase response to the insult (36). Activated microglia have been described as a common feature of many neurodegenerative diseases (37-39). To enhance microglial activity, microglia are transduced with CPRs (i.e., by AAV vectors encoding the CPRs). Transducing microglia in vivo remains a technical challenge, but a novel mutant capsid has been developed that transduces microglial cells in culture and ex vivo brain slices (FIGS. 9A and 9B). This allows testing of the approach of CPRs in a BSC model of model of tauopathy and to engineer microglial cells ex vivo and transplant into AD mouse model to increase phagocytic clearance of amyloid.
However, there are no objective evidences of administering astrocyte expressing any chimeric receptor wherein the claimed method can prevent any and all subject that include, but are not limited to, apes; chimpanzees; orangutans; humans; monkeys; domesticated animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and other animals such as mice, rats, guinea pigs, and hamsters having diagnosed with any and all possible amyloid-related neurodegenerative disease, disorder or condition.
Chen et al (of record, Science 391: 1006-1018, 2026; PTO 892) teaches that astrocytes are known to play essential roles in regulating neuronal activity and, like microglia, may contribute to synaptic pruning through their phagocytic function. However, owing to limitations of the current disease model, it remains unclear whether direct manipulation of astrocytes using our CAR system could lead to adverse effects from enhanced phagocytic activity. Despite clear reductions inamyloid pathology, behavioral outcomes—particularly in the late-stage Adu-Dectin1 cohort—did not show corresponding improvement. It re-mains unclear whether signaling from CAR intracellular domains, especially Dectin1, further amplifies activation of amyloid-primed glia, thereby disrupting synapse maintenance and neuronal function and offsetting the benefits of plaque reduction. Consistent with this possibility, CAR-A treatment in this cohort failed to rescue amyloid-associated synapse loss to the same extent observed in the early-intervention group. Together, these findings indicate that optimization of CAR-A signaling design, dosing strategies, and treatment timing will be essential to achieve cognitive benefit and underscore the need for systematic evaluation of potential side effects across multiple disease models and with more comprehensive behavioral testing. Future work should also assess how CAR-A compares with other gene- and cell-based approaches and whether combination strategies, including astrocyte-targeted metabolic therapies, can further enhance functional recovery, see p. 11, left col, in particular. Thus a skilled artisan would reasonably conclude that Applicant were not possession of the claimed invention at the time the application was filed.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear 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 [he or she] invented what is claimed.” (See Vas-Cath at page 1116.).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
Therefore, only (1) a chimeric phagocytic receptor comprising: (i) an intracellular phagocytic signaling domain, (ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta, and (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, wherein the scFv comprises the amino acid sequence selected from the group consisting of SEQ ID NOs: 1-3, wherein the intracellular phagocytic signaling domain is selected from the group consisting of a human FCERG comprises the amino acid sequence of SEQ ID NO: 11, a human MRC1 comprises the amino acid sequence of SEQ ID NO: 12, a mouse FCERG comprises the amino acid sequence of SEQ ID NO: 18, a mouse MRC1 comprises the amino acid sequence of SEQ ID NO: 19, a dual human FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 15, a dual human MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 16, a mouse dual FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 24 and a mouse MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 25, (2) the chimeric phagocytic receptor above wherein the chimeric phagocytic receptor comprises an amino acid sequence having at least 98% sequence identity to any of SEQ ID NO: 26-35, 42 and 43, (2) a modified astrocyte comprising a chimeric phagocytic receptor wherein the chimeric phagocytic receptor comprises an amino acid sequence having at least 98% sequence identity to any of SEQ ID NO: 26-35, 42 and 43, (3) a method of reducing or clearing protein aggregates in a subject diagnosed with an amyloid-related neurogenerative disease, the method comprising administering to the subject a modified astrocyte comprising a chimeric phagocytic receptor wherein the chimeric phagocytic receptor comprises an amino acid sequence having at least 98% sequence identity to any one of SEQ ID NO: 26-35, 42 and 43, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph.
Applicant's arguments filed on August 28, 2026 have been fully considered but they are not persuasive.
Applicant has amended claims 1, 3, 17, 57, and 58. Claims 1 and 3 have been amended to recite, in relevant part, that the extracellular binding domain comprises a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta peptide wherein the scFv comprises an amino acid sequence with at least 99% sequence identity to any of SEQ ID NOs: 1-3. Claim 17 has been amended to recite that the chimeric receptor comprises an amino acid sequence having at least 98% sequence identity to any of SEQ ID NOs: 26-35, 42, and 43. Claims 57 and 58 have been amended to recite that the neurodegenerative disease, disorder or condition is an amyloid-related neurodegenerative disease, disorder, or condition and to be directed solely toward treating a subject (claim 58). Applicant submits that the instant specification provides adequate written description for the amended claims.
Accordingly, withdrawal of the rejections of claims 1, 3-6, 13, 15, 17, 18, 21, 41, 57, and 58 under 35 U.S.C. § 112 is respectfully requested.
In response, the amendment to claims 1, 3, 17, 57, and 58 is acknowledged.
However, amended claims 1 and 3 still recite any and all intracellular phagocytic signaling domain.
Regarding intracellular phagocytic signaling domain (claims 1, 3, 4, 5, 6, 21), the specification discloses human FCERG comprises the amino acid sequence of SEQ ID NO: 11, human MRC1 comprises the amino acid sequence of SEQ ID NO: 12, mouse FCERG comprises the amino acid sequence of SEQ ID NO: 18, mouse MRC1 comprises the amino acid sequence of SEQ ID NO: 19, dual human FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 15, dual human MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 16, mouse dual FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 24 and mouse MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 25.
However, the specification does not describe the structure-identifying information about the claimed intracellular phagocytic signaling domain (claims 1, 3, 4, 5, 6, 21); the specification does not disclose a representative number of species falling within the scope of the genus or structure common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed intracellular phagocytic signaling domain.
Even assuming the intracellular phagocytic signaling domain is derived from TREM2 (triggering receptor expressed on myeloid cells 2) receptor, the term “derived” encompasses addition, substitution, deletion or a combination thereof (claim 2 in the event of rejoinder). The specification discloses just human TREM2.
However, the specification does not describe where and what amino acid within the full-length sequence of any TREM2 (triggering receptor expressed on myeloid cells 2) receptor to be deleted, added, substituted or a combination thereof such that the derivative still maintains intracellular phagocytic signaling.
Regarding any chimeric receptor (claims 1-6, 13, 15, 17-18, 21, 41, 57 and 58), the specification discloses chimeric phagocytic receptors (CPRs), see title, [0005], [0006], [0008], [0093], and throughout the specification. However, the specification does not disclose chimeric receptor. This is new matter.
Regarding scFv antibody encompassed by the claimed chimeric receptor that binds to any amyloid beta peptide, the specification discloses just three scFv antibodies. Anti-Aβ9 scFv comprises the amino acid sequence of SEQ ID NO: 1, anti-Aβ2.1.3 scFv comprises the amino acid sequence of SEQ ID NO: 2, anti-Aβ scFv comprises the amino acid sequence of SEQ ID NO: 3.
However, the specification does not describe the structure of any and all possible single-chain variable antibody fragment (scFv) antibodies having affinity for any amyloid beta peptide encompassed by the claimed chimeric receptor (claim 2). The specification does not describe the structure, e.g., amino acid sequences of heavy chain variable domain and light chain variable domain of a sufficient number of species of the genus of scFvs that having affinity for any amyloid beta peptide encompassed by the claimed chimeric receptors. The specification does not describe the structure-identifying information about the claimed chimeric receptor, nor describe a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed chimeric receptor themselves.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. newly cited, Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (newly cited, J Mol Biol. 2003 Nov 14;334(1): 103-118, PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Even a single CDR substitution can disrupt antigen binding as evidenced by Rudikoff et al. (of record, Proc Natl Acad Sci USA Vol 79 page 1979, 1982; PTO 892). Rudikoff et al. 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.
Ito et al (of record, FEBS Letters 309(1): 85-88, 1992; PTO 892) teaches substitution of histidine at various positions in an anti-lysozyme antibody. The L3A mutant contained a histidine in place of tyrosine in CDR3 of the light chain and the resulting mutant antibody lost its ability to bind to lysozyme antigen in an ELISA assay, see section spanning left and right column of page 86.
Piche-Nicholas et al (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
Regarding treating a subject diagnosed with an amyloid-related neurodegenerative disease or disorder or condition, the specification defines the term “treat” to include prophylactic treatment:
[0035] The terms “ameliorate” and “treat” are used interchangeably and include both therapeutic and prophylactic treatment. Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a neurodegenerative disease or disorder described herein).
Regarding “subject”, the specification discloses:
[0049] The term “subject” includes organisms which are capable of suffering from a disorder as described herein or who could otherwise benefit from the administration of a compound of the present disclosure, such as human and non-human animals. Preferred humans include human patients suffering from or prone to suffering from diseases or disorders as discussed above, as described herein. Mammalian species that may benefit from the disclosed methods of treatment include, but are not limited to, apes; chimpanzees; orangutans; humans; monkeys; domesticated animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and other animals such as mice, rats, guinea pigs, and hamsters. A “subject in need of treatment” includes a subject diagnosed, e.g., by a medical or veterinary professional, as suffering from or susceptible to a neurodegenerative disease, disorder or condition described herein.
However, there are no objective evidences of administering modified astrocyte expressing any chimeric receptor wherein the claimed method can prevent any and all subject that include, but are not limited to, apes; chimpanzees; orangutans; humans; monkeys; domesticated animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and other animals such as mice, rats, guinea pigs, and hamsters having diagnosed with any and all possible amyloid-related neurodegenerative disease, disorder or condition.
Chen et al (of record, Science 391: 1006-1018, 2026; PTO 892) teaches that astrocytes are known to play essential roles in regulating neuronal activity and, like microglia, may contribute to synaptic pruning through their phagocytic function. However, owing to limitations of the current disease model, it remains unclear whether direct manipulation of astrocytes using our CAR system could lead to adverse effects from enhanced phagocytic activity. Despite clear reductions inamyloid pathology, behavioral outcomes—particularly in the late-stage Adu-Dectin1 cohort—did not show corresponding improvement. It re-mains unclear whether signaling from CAR intracellular domains, especially Dectin1, further amplifies activation of amyloid-primed glia, thereby disrupting synapse maintenance and neuronal function and offsetting the benefits of plaque reduction. Consistent with this possibility, CAR-A treatment in this cohort failed to rescue amyloid-associated synapse loss to the same extent observed in the early-intervention group. Together, these findings indicate that optimization of CAR-A signaling design, dosing strategies, and treatment timing will be essential to achieve cognitive benefit and underscore the need for systematic evaluation of potential side effects across multiple disease models and with more comprehensive behavioral testing. Future work should also assess how CAR-A compares with other gene- and cell-based approaches and whether combination strategies, including astrocyte-targeted metabolic therapies, can further enhance functional recovery, see p. 11, left col, in particular. Thus a skilled artisan would reasonably conclude that Applicant were not possession of the claimed invention at the time the application was filed.
For these reasons, the rejection is maintained.
Claims 1-6, 13, 15, 18, 21, 41, 57 and 58 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for only (1) a chimeric phagocytic receptor comprising: (i) an intracellular phagocytic signaling domain, (ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta, and (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, wherein the scFv comprises the amino acid sequence selected from the group consisting of SEQ ID NOs: 1-3, wherein the intracellular phagocytic signaling domain is selected from the group consisting of a human FCERG comprises the amino acid sequence of SEQ ID NO: 11, a human MRC1 comprises the amino acid sequence of SEQ ID NO: 12, a mouse FCERG comprises the amino acid sequence of SEQ ID NO: 18, a mouse MRC1 comprises the amino acid sequence of SEQ ID NO: 19, a dual human FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 15, a dual human MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 16, a mouse dual FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 24 and a mouse MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 25, (2) the chimeric phagocytic receptor above wherein the chimeric phagocytic receptor comprises an amino acid sequence having at least 98% sequence identity to any of SEQ ID NO: 26-35, 42 and 43, (2) a modified astrocyte comprising a chimeric phagocytic receptor wherein the chimeric phagocytic receptor comprises an amino acid sequence having at least 98% sequence identity to any of SEQ ID NO: 26-35, 42 and 43, (3) a method of reducing protein aggregates in a subject diagnosed with an amyloid-related neurogenerative disease, the method comprising administering to the subject a modified astrocyte comprising a chimeric phagocytic receptor wherein the chimeric phagocytic receptor comprises an amino acid sequence having at least 98% sequence identity to any one of SEQ ID NO: 26-35, 42 and 43, does not reasonably provide enablement for any chimeric receptor as set forth in claims 1-6, 13, 15, 17-18, 21 for treating that include prevention of a subject diagnosed with any and all possible amyloid-related neurodegenerative disease as set forth in claims 57-58. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 encompasses any chimeric receptor comprising:(i) an intracellular phagocytic signaling domain,(ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta peptide and (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, wherein the scFv comprises an amino acid sequence having at least 99% sequence identity to any of SEQ ID NOs: 1-3.
Claim 2 encompasses any chimeric receptor comprising (i) any intracellular phagocytic signaling domain, (ii) any extracellular binding domain comprising any single-chain variable antibody fragment (scFv) having affinity for any amyloid beta peptide, and (iii) any transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, wherein the intracellular phagocytic signaling domain is derived from any TREM2 (triggering receptor expressed on myeloid cells-2) receptor.
Claim 3 encompasses any chimeric receptor comprising:(i) a first intracellular phagocytic signaling domain, (ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta peptide, (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, and (iv) a second intracellular phagocytic signaling domain fused to the first intracellular phagocytic signaling domain, wherein the scFv comprises an amino acid sequence having at least 99% sequence identity to any of SEQ ID NO: 1-3.
Claim 4 encompasses the chimeric receptor of claim 2, wherein the scFv comprises an amino acid sequence having at least 99% sequence identity to any of SEQ ID NOs: 1-3.
Claim 5 encompasses the chimeric receptor of claim 1, wherein the transmembrane domain comprises a hinge domain.
Claim 4 encompasses the chimeric receptor of claim 1, wherein the transmembrane domain is covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain by one or more linkers.
Claim 13 encompasses the chimeric receptor of claim 1, wherein the first intracellular phagocytic signaling domain comprises a TREM2 signaling domain, a macrophage mannose receptor 1 (MRC1) signaling domain, a multiple epidermal growth factor-like domains protein 10 (MEGF10) signaling domain, a DAP12 signaling domain, a tyrosine-protein kinase Mer (MERTK) signaling domain, a high-affinity immunoglobulin epsilon receptor subunit gamma (FCERG) signaling domain (elected species), a mannose 6 phosphate receptor (M6PR) signaling domain, or a C-type lectin domain family 4 member L (CLEC4L) signaling domain.
Claim 15 encompasses the chimeric receptor of claim 3, wherein the first intracellular phagocytic signaling domain comprises a TREM2 signaling domain, a MRC1 signaling domain, a MEGF10 signaling domain, a DAP12 signaling domain, a MERTK signaling domain, a FCERG signaling domain (elected species), a M6PR signaling domain, or a CLEC4L signaling domain; and the second intracellular phagocytic signaling domain comprises a TREM2 signaling domain, a MRC1 signaling domain (elected species), a MEGF10 signaling domain, a DAP12 signaling domain, a MERTK signaling domain, a FCERG signaling domain, a M6PR signaling domain, or a CLEC4L signaling domain.
Claim 17 encompasses the chimeric receptor of claim 1, wherein the chimeric receptor comprises an amino acid sequence having at least 98% sequence identity to any of SEQ ID NOs: 26-35, 42 and 43 (SEQ ID NO: 28 as the elected species).
Claim 18 encompasses the chimeric receptor of claim 1, wherein the chimeric receptor comprises a second extracellular binding domain.
Claim 21 encompasses the chimeric receptor of claim 1, wherein the transmembrane domain is a TREM2 transmembrane domain, a MRC1 transmembrane domain, a MEGF10 transmembrane domain, a DAP12 transmembrane domain, a MERTK transmembrane domain, a CD8 transmembrane domain (elected specie), a M6PR transmembrane domain, or a CLEC4L transmembrane domain.
Claim 41 encompasses the chimeric receptor of claim 1, wherein the modified cell is an astrocyte.
Claim 57 encompasses a method of treating a subject diagnosed with an amyloid-related neurodegenerative disease, disorder, or condition, the method comprising: administering to the subject the modified cell of claim 41.
Claim 58 encompasses a method of treating an amyloid-related neurodegenerative disease, disorder, or condition, the method comprising: administering to a subject the modified cell of any one of claim 41.
Regarding antibody, the specification defines as follow:
[0040] An “antibody” refers to an immunoglobulin molecule capable of specific or selective binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule. As used herein, the term “antibody” encompasses not only intact (e.g., full-length) polyclonal or monoclonal antibodies, but also antigen-binding fragments thereof (such as Fab, Fab′, F(ab′)2, Fv), single chain (scFv), mutants thereof, fusion proteins comprising an antibody portion, humanized antibodies, chimeric antibodies, diabodies, linear antibodies, single chain antibodies, multispecific antibodies (e.g., bispecific antibodies) and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity or selectivity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. An antibody includes an antibody of any class, such as IgD, IgE, IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant domain of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
Regarding scFv antibody encompassed by the claimed chimeric receptor that binds to any amyloid beta peptide, the specification discloses just three scFv antibodies. Anti-Aβ9 scFv comprises the amino acid sequence of SEQ ID NO: 1, anti-Aβ2.1.3 scFv comprises the amino acid sequence of SEQ ID NO: 2, anti-Aβ scFv comprises the amino acid sequence of SEQ ID NO: 3.
However, the specification does not teach the structure of any and all possible single-chain variable antibody fragment (scFv) antibodies having affinity for any amyloid beta peptide encompassed by the claimed chimeric receptor (claim 2). The specification does not teach the structure, e.g., amino acid sequences of heavy chain variable domain and light chain variable domain of a sufficient number of species of the genus of scFvs that having affinity for any amyloid beta peptide encompassed by the claimed chimeric receptors. The specification does not disclose the structure-identifying information about the claimed chimeric receptor, nor describe a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can make and use the actual claimed chimeric receptor themselves without undue experimentation.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. newly cited, Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (newly cited, J Mol Biol. 2003 Nov 14;334(1): 103-118, PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Even a single CDR substitution can disrupt antigen binding as evidenced by Rudikoff et al. (of record, Proc Natl Acad Sci USA Vol 79 page 1979, 1982; PTO 892). Rudikoff et al. 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.
Ito et al (of record, FEBS Letters 309(1): 85-88, 1992; PTO 892) teaches substitution of histidine at various positions in an anti-lysozyme antibody. The L3A mutant contained a histidine in place of tyrosine in CDR3 of the light chain and the resulting mutant antibody lost its ability to bind to lysozyme antigen in an ELISA assay, see section spanning left and right column of page 86.
Piche-Nicholas et al (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Regarding intracellular phagocytic signaling domain (claims 1, 3, 4, 5, 6, 21), the specification discloses human FCERG comprises the amino acid sequence of SEQ ID NO: 11, human MRC1 comprises the amino acid sequence of SEQ ID NO: 12, mouse FCERG comprises the amino acid sequence of SEQ ID NO: 18, mouse MRC1 comprises the amino acid sequence of SEQ ID NO: 19, dual human FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 15, dual human MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 16, mouse dual FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 24 and mouse MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 25.
Other than the particular intracellular phagocytic signaling domains above, the specification does not teach the structure-identifying information about the claimed intracellular phagocytic signaling domain (claims 1, 3, 4, 5, 6, 21); the specification does not teach a representative number of species falling within the scope of the genus or structure common to the members of the genus so the one of skill in the art can make and use the claimed chimeric receptor for treating neurodegenerative disease or disorder.
Even assuming the intracellular phagocytic signaling domain is derived from TREM2 (triggering receptor expressed on myeloid cells 2) receptor, the term “derived” encompasses addition, substitution, deletion or a combination thereof (claim 2 in the event of rejoinder). The specification discloses just human TREM2.
However, the specification does not teach where and what amino acid within the full-length sequence of any TREM2 (triggering receptor expressed on myeloid cells 2) receptor to be deleted, added, substituted or a combination thereof such that the derivative still maintains intracellular phagocytic signaling.
Regarding chimeric phagocytic receptor (CPR), the specification discloses chimeric receptors that bind to amyloid beta peptide 9 and comprise the amino acid sequence of SEQ ID NO: 26-35, 42-43, see para. [0100].
Regarding treatment, the specification discloses:
[0035] The terms “ameliorate” and “treat” are used interchangeably and include both therapeutic and prophylactic treatment. Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a neurodegenerative disease or disorder described herein).
Regarding “disease”, the specification discloses:
[0045] “Disease” means any condition or disorder that damages or interferes with the normal function of a cell, tissue, organ or organism. Exemplary diseases of the disclosure are neurodegenerative diseases.
Regarding “subject”, the specification discloses:
[0049] The term “subject” includes organisms which are capable of suffering from a disorder as described herein or who could otherwise benefit from the administration of a compound of the present disclosure, such as human and non-human animals. Preferred humans include human patients suffering from or prone to suffering from diseases or disorders as discussed above, as described herein. Mammalian species that may benefit from the disclosed methods of treatment include, but are not limited to, apes; chimpanzees; orangutans; humans; monkeys; domesticated animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and other animals such as mice, rats, guinea pigs, and hamsters. A “subject in need of treatment” includes a subject diagnosed, e.g., by a medical or veterinary professional, as suffering from or susceptible to a neurodegenerative disease, disorder or condition described herein.
The specification exemplifies:
Example 1
[0205] In vivo CPR prevention and clearance assessment. To evaluate the ability of CPR to prevent amyloid pathology, astrocytes are selectively transduced using rAAV-PHP.eB-GFAP-CPR and evaluate effects on amyloid pathology in CRND8 mice, a transgenic model that overexpresses mutant human amyloid protein precursor (APP) at levels approximately 5-fold higher than endogenous murine APP (see Chakrabarty, et al. Neuron 85, 519-533 (2015), incorporated herein by reference). For the prevention paradigm newborn CRND8 are injected with rAAV-PHP.eB-GFAP-CPR (with FCER1G, MRC1, MERTK, and CLEC4L with a non-specific CPR, anti-pan Aβ scFv alone, and GFP used as controls) (ICV, 4×10.sup.10 viral genomes/pup) and assess Aβ levels and plaque burden at 3 months. Each construct is delivered to 4-5 litters, resulting in −20 transgenic mice, of whom half will reach 3 months of age. Based on extensive experience with this strain, this cohort size allows to detect significant changes of 25% in amyloid levels. Small sub-cohorts on non-transgenic littermates at 4 weeks old are harvested to evaluate transduction and tropism.
[0206] At 3 months, the age at which substantial plaque formation is typically observed in these mice, one hemibrain is fixed and stained for amyloid immunoreactivity burden with anti-pan-Aβ antibody, Aβ5-biotin, and Thio-S. The other hemibrain is fractionated and Aβ levels are quantified by ELISA from RIPA-soluble fraction, SDS-soluble, and SDS-insoluble, formic acid-soluble fractions. Astrogliosis and microgliosis are evaluated using glial fibrillary acid protein (GFAP) and ionized calcium-binding molecule-1 (IBA-1) antibodies, respectively. Image analysis is done following scanning whole slides with the Aperio System and analysis of immunoreactivity burden by ImageScope program (Aperio, CA). Neuron counts in specific areas of the hippocampus and cortex where neurodegenerative may be observed by gross H&E analysis are also assessed quantitatively using NeuN antibody and determined by double-blinded quantification. Detailed calculations of mouse numbers are presented in the Vertebrate animals section. Control groups were injected with a non-specific CPR, anti-pan Aβ alone, and GFP. It is expected that each CPR has a differential effect on Aβ.
[0207] Based on these results the most effective anti-AβCPR agent can be pinpointed. To test whether CPRs are functional in a therapeutic paradigm, one or two of the most promising CPR from prevention study, and the appropriate controls, are administered intraocularly or into the tail vein into 4 month old CRND8 mice. At 4 months of age CRND8 mice have moderate levels of deposits, by 6 months they have significant amyloid accumulation. Amyloid burden and Aβ levels are assessed at 2 months post injection and compared to the non-specific CPR control group. These controls are designed to test whether non-specific activation of astrocytes is beneficial in targeting amyloid pathology. Additionally, control groups are injected with scFv's alone and GFP.
[0208] Given the above-described positive preliminary results and the demonstrated success in performing all the methods, experiments to assess the effect on prevention of aggregation and clearance of existing pathology are ongoing. CPRs activate astrocytes and microglia and it is possible that the non-specific CPR may have an effect on amyloid pathology. Nevertheless, the role of phagocytosis in amyloid clearance and the specific CPR domain may become better understood. Experiments are ongoing to optimize the CPRs of the disclosure to induce minimal off-target effects.
Example 2
[0209] CPRs May Bind AD or Tau when Expressed in Microglia or Monocytes and Alter the Proteinopathy in Ex Vivo Brain Slice Culture Models or In Vivo Following Transplantation of the CPR Expressing Microglia/Monocytes into the Brain of the Appropriate Proteinopathy Mouse Model.
[0210] This experiment evaluated whether the CPRs enhance microglial phagocytosis of amyloid plaques and tau aggregates. Multiple genetic association studies have identified numerous loci that harbor genes that encode proteins of known immune function that alter the risk of developing AD and other neurodegenerative proteinopathies (35). Microglial cells are the primary immune cells of the central nervous system and function as macrophages. They respond to foreign material or cellular debris by changing their morphology, becoming activated, migrating to the site of damage, clearing the foreign material and cellular debris through phagocytosis, and secreting signals to increase response to the insult (36). Activated microglia have been described as a common feature of many neurodegenerative diseases (37-39). To enhance microglial activity, microglia are transduced with CPRs (i.e., by AAV vectors encoding the CPRs). Transducing microglia in vivo remains a technical challenge, but a novel mutant capsid has been developed that transduces microglial cells in culture and ex vivo brain slices (FIGS. 9A and 9B). This allows testing of the approach of CPRs in a BSC model of model of tauopathy and to engineer microglial cells ex vivo and transplant into AD mouse model to increase phagocytic clearance of amyloid.
However, there are no objective evidences of administering astrocyte expressing any chimeric receptor wherein the claimed method can treat that include prevention of any and all subject, including but are not limited to, apes; chimpanzees; orangutans; humans; monkeys; domesticated animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and other animals such as mice, rats, guinea pigs, and hamsters having diagnosed with any and all possible amyloid-related neurodegenerative disease, disorder or condition.
Chen et al (of record, Science 391: 1006-1018, 2016; PTO 892) teaches that astrocytes are known to play essential roles in regulating neuronal activity and, like microglia, may contribute to synaptic pruning through their phagocytic function. However, owing to limitations of the current disease model, it remains unclear whether direct manipulation of astrocytes using our CAR system could lead to adverse effects from enhanced phagocytic activity. Despite clear reductions inamyloid pathology, behavioral outcomes—particularly in the late-stage Adu-Dectin1 cohort-did not show corresponding improvement. It re-mains unclear whether signaling from CAR intracellular domains, especially Dectin1, further amplifies activation of amyloid-primed glia, thereby disrupting synapse maintenance and neuronal function and offsetting the benefits of plaque reduction. Consistent with this possibility, CAR-A treatment in this cohort failed to rescue amyloid-associated synapse loss to the same extent observed in the early-intervention group. Together, these findings indicate that optimization of CAR-A signaling design, dosing strategies, and treatment timing will be essential to achieve cognitive benefit and underscore the need for systematic evaluation of potential side effects across multiple disease models and with more comprehensive behavioral testing. Future work should also assess how CAR-A compares with other gene- and cell-based approaches and whether combination strategies, including astrocyte-targeted metabolic therapies, can further enhance functional recovery, see p. 11, left col, in particular.
As such, it would take undue trials and errors to practice the claimed invention.
Applicant's arguments filed on August 28, 2026 have been fully considered but they are not persuasive.
Applicant has amended the claims as described above. Applicant submits that one of skill would be able to make and use the chimeric receptor as set forth in amended claims 1-6, 13, 15, 17, 18, and 21 based on the disclosure in the present application without undue experimentation. Applicant further submits that one of skill would be able to determine how to treat a subject with an amyloid-related neurodegenerative disease, as recited in claim 57 and 58, without undue experimentation, given the high level of skill in the art and the guidance provided in the application.
Accordingly, withdrawal of the rejections of claims 1, 3-6, 13, 15, 17, 18, 21, 41, 57, and 58 under 35 U.S.C. § 112 is respectfully requested.
In response, the amendment to claims 1, 3, 17, 57, and 58 is acknowledged.
Contrary to applicant’s assertion that one of skill would be able to make and use the chimeric receptor as set forth in amended claims 1-6, 13, 15, 17, 18, and 21 based on the disclosure in the present application without undue experimentation, enablement is not commensurate in scope with the claims as how to make and use because of the following reasons.
First, the specification does not teach the structure of any and all possible single-chain variable antibody fragment (scFv) antibodies having affinity for any amyloid beta peptide encompassed by the claimed chimeric receptor (claim 2). The specification does not teach the structure, e.g., amino acid sequences of heavy chain variable domain and light chain variable domain of a sufficient number of species of the genus of scFvs that having affinity for any amyloid beta peptide encompassed by the claimed chimeric receptors. The specification does not disclose the structure-identifying information about the claimed chimeric receptor, nor describe a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can make and use the actual claimed chimeric receptor themselves without undue experimentation.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. newly cited, Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (newly cited, J Mol Biol. 2003 Nov 14;334(1): 103-118, PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Even a single CDR substitution can disrupt antigen binding as evidenced by Rudikoff et al. (of record, Proc Natl Acad Sci USA Vol 79 page 1979, 1982; PTO 892). Rudikoff et al. 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.
Ito et al (of record, FEBS Letters 309(1): 85-88, 1992; PTO 892) teaches substitution of histidine at various positions in an anti-lysozyme antibody. The L3A mutant contained a histidine in place of tyrosine in CDR3 of the light chain and the resulting mutant antibody lost its ability to bind to lysozyme antigen in an ELISA assay, see section spanning left and right column of page 86.
Piche-Nicholas et al (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Second, regarding intracellular phagocytic signaling domain (claims 1, 3, 4, 5, 6, 21), the specification discloses human FCERG comprises the amino acid sequence of SEQ ID NO: 11, human MRC1 comprises the amino acid sequence of SEQ ID NO: 12, mouse FCERG comprises the amino acid sequence of SEQ ID NO: 18, mouse MRC1 comprises the amino acid sequence of SEQ ID NO: 19, dual human FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 15, dual human MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 16, mouse dual FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 24 and mouse MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 25.
Other than the particular intracellular phagocytic signaling domains above, the specification does not teach the structure-identifying information about the claimed intracellular phagocytic signaling domain (claims 1, 3, 4, 5, 6, 21); the specification does not teach a representative number of species falling within the scope of the genus or structure common to the members of the genus so the one of skill in the art can make and use the claimed chimeric receptor for treating neurodegenerative disease or disorder.
Even assuming the intracellular phagocytic signaling domain is derived from TREM2 (triggering receptor expressed on myeloid cells 2) receptor, the term “derived” encompasses addition, substitution, deletion or a combination thereof (claim 2 in the event of rejoinder). The specification discloses just human TREM2.
However, the specification does not teach where and what amino acid within the full-length sequence of any TREM2 (triggering receptor expressed on myeloid cells 2) receptor to be deleted, added, substituted or a combination thereof such that the derivative still maintains intracellular phagocytic signaling.
Third, regarding treating a subject diagnosed with any amyloid-related neurodegenerative disorder that encompassed prevention.
Regarding treatment, the specification discloses:
[0035] The terms “ameliorate” and “treat” are used interchangeably and include both therapeutic and prophylactic treatment. Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a neurodegenerative disease or disorder described herein).
Regarding “disease”, the specification discloses:
[0045] “Disease” means any condition or disorder that damages or interferes with the normal function of a cell, tissue, organ or organism. Exemplary diseases of the disclosure are neurodegenerative diseases.
Regarding “subject”, the specification discloses:
[0049] The term “subject” includes organisms which are capable of suffering from a disorder as described herein or who could otherwise benefit from the administration of a compound of the present disclosure, such as human and non-human animals. Preferred humans include human patients suffering from or prone to suffering from diseases or disorders as discussed above, as described herein. Mammalian species that may benefit from the disclosed methods of treatment include, but are not limited to, apes; chimpanzees; orangutans; humans; monkeys; domesticated animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and other animals such as mice, rats, guinea pigs, and hamsters. A “subject in need of treatment” includes a subject diagnosed, e.g., by a medical or veterinary professional, as suffering from or susceptible to a neurodegenerative disease, disorder or condition described herein.
However, there are insufficient in vivo working example. It is unpredictable administering to a subject such as apes; chimpanzees; orangutans; humans; monkeys; domesticated animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and other animals such as mice, rats, guinea pigs, or hamsters a modified astrocyte comprising which undisclosed chimeric receptor is effective for preventing which amyloid-related neurodegenerative disease, disorder, or condition.
Chen et al (of record, Science 391: 1006-1018, 2016; PTO 892) teaches that astrocytes are known to play essential roles in regulating neuronal activity and, like microglia, may contribute to synaptic pruning through their phagocytic function. However, owing to limitations of the current disease model, it remains unclear whether direct manipulation of astrocytes using our CAR system could lead to adverse effects from enhanced phagocytic activity. Despite clear reductions inamyloid pathology, behavioral outcomes—particularly in the late-stage Adu-Dectin1 cohort—did not show corresponding improvement. It re-mains unclear whether signaling from CAR intracellular domains, especially Dectin1, further amplifies activation of amyloid-primed glia, thereby disrupting synapse maintenance and neuronal function and offsetting the benefits of plaque reduction. Consistent with this possibility, CAR-A treatment in this cohort failed to rescue amyloid-associated synapse loss to the same extent observed in the early-intervention group. Together, these findings indicate that optimization of CAR-A signaling design, dosing strategies, and treatment timing will be essential to achieve cognitive benefit and underscore the need for systematic evaluation of potential side effects across multiple disease models and with more comprehensive behavioral testing. Future work should also assess how CAR-A compares with other gene- and cell-based approaches and whether combination strategies, including astrocyte-targeted metabolic therapies, can further enhance functional recovery, see p. 11, left col, in particular.
As such, it would take undue trials and errors to practice the claimed invention.
For these reasons, the rejection is maintained.
New ground of rejection necessitated by the amendment filed August 28, 2026
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-6, 13, 15, 18 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over US20200345774 (of record, Getts hereafter, published November 5, 2020, claimed earliest priority to 62/841,190, filed April 30, 2019, PTO 892) in view of Golde et al (newly cited, WO2021016316 publication, published January 28, 2021; PTO 892) and U.S. Patent No. 12,344,662 (of record, filed February 11, 2019, claimed earliest priority to 62/628,632, filed February 9, 2018; PTO 892).
Claim 1 recites a chimeric receptor comprising:(i) an intracellular phagocytic signaling domain, (ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta peptide, tau protein or a-synuclein protein, and (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, wherein the scFv comprises an amino acid sequence having at least 99% sequence identity to any of SEQ ID NO: 1 (elected species).
Claim 3 recites the chimeric receptor comprising:(i) a first intracellular phagocytic signaling domain, (ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta peptide, tau protein or a-synuclein protein, (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, and (iv) a second intracellular phagocytic signaling domain fused to the first intracellular phagocytic signaling domain.
Claim 4 recites the chimeric receptor of claim 2, wherein the scFv comprises an amino acid sequence having at least 99% sequence identity to any of SEQ ID NO: 1.
Claim 5 recites the chimeric receptor of claim 1, wherein the transmembrane domain comprises a hinge domain.
Claim 6 recites the chimeric receptor of claim 1, wherein the transmembrane domain is covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain by one or more linkers.
Claim 13 recites the chimeric receptor of claim 1, wherein the first intracellular phagocytic signaling domain comprises a FCERIγ (or FCERG) signaling domain (elected species).
Claim 18 recites the chimeric receptor of claim 1, wherein the chimeric receptor comprises a second extracellular binding domain.
Claim 21 recites the chimeric receptor of claim 1, wherein the transmembrane domain is a CD8 transmembrane domain (elected specie).
Regarding claims 1, 3-5, 21, Getts teaches a chimeric phagocytic receptor comprising an extracellular domain (ECD) that binds to CD5 (see para. [0325]), a hinge region of a CD8 receptor (see para. [0327]), a CD8 transmembrane region (see para. [0328]) or TREM transmembrane domain that trimerizes with DAP12 transmembrane domains (see para. [0322]) one or more intracellular domains (ICD), e.g., phagocytic signaling domains, e.g., TREM2 (para. [0322]), FcγR, FcαR or FcεR, see para. [0039], [0075], [0076], [0078], [0329], FIG 6A below.
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Examples of intracellular phagocytic signaling domain is CD206 (aka MRC1), see para. [0096]. The chimeric phagocytic receptor comprises an antigen binding domain, the transmembrane domain comprises a hinge domain as per claim 5, see FIG. 6A above. Examples of phagocytosis signaling domain comprises an intracellular signaling domain derived from a phagocytic receptor, e.g., CD206 (aka MRC1 signaling domain) as per claim 15, see para. [0093], [0111], TYROBP (DAP12, see para. [0111], signaling domain comprises a PI3-kinase (PI3K) recruitment domain. In some embodiments, the proinflammatory signaling domain comprises a sequence with at least 90% sequence identity to SEQ ID NO: 4, see para. [0078].
Regarding claims 13, 15 and 21, Getts teaches examples of transmembrane domain include DAP12 (see para. [0109]), TREM2 intracellular domain and transmembrane domain, see para. [0115], in particular.
Getts teaches that targeting cell, e.g., human primary macrophage cells expressing phagocytic receptor is expected to enhanced phagocytosis of such cells thereby clearing diseased cells, see para. [0008] to [0010], [0027], [0029].
Getts does not teach the single-chain antibody (scFv) having affinity for an amyloid beta peptide wherein the scFv comprises an amino acid sequence having at least 99% identity to SEQ ID NO: 1 as per claims 1, 3 and 4.
However, Golde teaches scFv antibody that binds to amyloid beta including scFv’s against beta peptide 9 (aka Aβ9 scFv), see para. [0027], [0230], FIG. 6A-6E, [0232], in particular. The reference Aβ9 scFv comprises the amino acid sequence of SEQ ID NO: 108, which is 100% identical to the claimed SEQ ID NO: 1 as per claims 1, 3 and 4.
Query Match 100.0%; Score 1317; Length 945;
Best Local Similarity 100.0%;
Matches 246; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVTLKESGPGILQPSQTLSLTCSFSGFSLNTFGMGVSWIRQPSGKGLEWLAHIFWDDDKH 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 690 QVTLKESGPGILQPSQTLSLTCSFSGFSLNTFGMGVSWIRQPSGKGLEWLAHIFWDDDKH 749
Qy 61 YNPSLKSRLTISKDTSNNQVFLKITTVDTADTATYYCVRYGFDGFPYWGQGTLVTVSAGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 750 YNPSLKSRLTISKDTSNNQVFLKITTVDTADTATYYCVRYGFDGFPYWGQGTLVTVSAGG 809
Qy 121 GGSGGGGSGGGGSDVVMTQTPLSLPVSLGDQASISCRSNQSLVHSNGNTYLHWYLQKPGQ 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 810 GGSGGGGSGGGGSDVVMTQTPLSLPVSLGDQASISCRSNQSLVHSNGNTYLHWYLQKPGQ 869
Qy 181 SPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGFYFCSQSTRVPWTFGGGT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 870 SPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGFYFCSQSTRVPWTFGGGT 929
Qy 241 KLELKR 246
||||||
Db 930 KLELKR 935
Regarding claim 18, the Golde teaches chimeric receptor comprises one or more extracellular binding domain such as scFv that binds to Tau for targeting amyloid plaque in CRND8 transgenic mice that overexpress amyloid precursor protein (APP) and human Alzheimer’s disease, see para. [0027] to [0028].
Golde teaches that the Aβ9 scFv fusion protein comprising a cell signaling domain, e.g., Triggering receptor expressed on myeloid cells 2 (hsTREM2) as per claim 15, see para. [00187], reference SEQ ID NO: 75, in particular. Golde teaches that the Aβ9 scFv fusion protein is useful for reducing amyloid plaque deposition in the brains of CRDN8 mice, see para. [00233].
Likewise, the ‘662 patent teaches chimeric antigen receptor comprising scFv that binds to aberrant amyloid beta for treating a neurodegenerative disease, see entire document, col. 73, line 3-16, col. 12, in particular. Example of scFv antibody DG01 that has affinity for amyloid beta comprises the amino acid sequence of SEQ ID NO:1, which is 96.4% sequence identity the claimed SEQ ID NO: 3 as per claims 1 and 4, see col. 4, lines 53-54, col. 9, see sequence alignment below:
OTHER INFORMATION: DG01 SCFV
Query Match 96.4%; Score 1283.5; Length 266;
Best Local Similarity 99.6%;
Matches 246; Conservative 0; Mismatches 0; Indels 1; Gaps 1;
Qy 2 QVQLVESGGGVVQPGRSLRLSCAASGFAFSSYGMHWVRQAPGKGLEWVAVIWFDGTKKYY 61
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 20 QVQLVESGGGVVQPGRSLRLSCAASGFAFSSYGMHWVRQAPGKGLEWVAVIWFDGTKKYY 79
Qy 62 TDSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARDRGIGARRGPYYMDVWGKGTTV 121
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 80 TDSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARDRGIGARRGPYYMDVWGKGTTV 139
Qy 122 TVSS-GGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKP 180
|||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 140 TVSSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKP 199
Qy 181 GKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 200 GKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGG 259
Qy 241 GTKVEIK 247
|||||||
Db 260 GTKVEIK 266
The ‘662 patent teaches that chimeric antigen receptors (CARs) may comprise a hinge sequence between the antigen binding (AB) domain and a transmembrane (TM) domain. One of the ordinary skill in the art will appreciate that a hinge sequence is a short sequence of amino acids that facilitates flexibility, a transmembrane domain (TM domain), one or more intracellular signaling domain (ICS). Typically, the TM domain denotes a single transmembrane α helix of a transmembrane protein, also known as an integral protein.
Examples of ICS include common FcRγ (FCER1G), FcεRI (aka FCERG signaling domain), DAP10, and DAP12, see col. 29, lines 5-6, col. 31, line 41-46, col. 51, line 11-17, in particular.
Regarding claim 6, the ‘662 patent teaches various flexible linker, e.g., Gly/Ser linker, see col. 29, line 28-40.
Regarding claim 13, the ‘662 patent teaches examples of cytoplasmic signaling sequence include, but not limited to common FcRγ (FCER1G), FcεRI (aka FCERG signaling domain, col. 31, line 45), or DAP12, see col. 29, lines 5-6, col. 31, line 41-46, col. 51, line 11-17, in particular.
Regarding claim 18, the ‘662 patent teaches chimeric receptor comprises one or more extracellular binding domain as per claim 18 (see col. 24, lines 39-42).
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of Getts, Golde and the ‘662 patent by substituting the scFv in the chimeric phagocytic receptor of Getts for Golde’s scFv9 that has affinity for amyloid beta peptide 9 wherein the chimeric phagocytosis receptor having one or more intracellular phagocytic signaling domain such as TREM2 signal domain of Golde or FCER1G and/or DAP12 as taught by the ‘662 patent to arrive at the claimed invention with a reasonable expectation success, i.e., chimeric phagocytic receptor arrange from N- to C-terminus comprising extracellular binding domain comprising a single-chain antibody having affinity for an amyloid beta peptide, a transmembrane domain covalently linked to an intracellular phagocytic signaling domain wherein the scFv comprises the amino acid sequence having at least 100% identical to the claimed SEQ ID NO: 1.
One of ordinary skill in the art would have had an expectation of success at the time the invention was made to have substituted a known scFv that binds to CD5 of Getts for another, e.g., scFv that binds to amyloid beta peptide 9 and/or Tau of Golde in the chimeric phagocytic receptor because Golde teaches such bispecific antibody is useful for treating human Alzheimer’s Disease patient and Getts teaches that targeting cell expressing phagocytic receptor to amyloid plaque is expected to enhanced phagocytosis of such thereby clearing aberrant amyloid beta (see para. [0008] to [0010]).
One of ordinary skill in the art would have been motivated to do so because Golde teaches that the Aβ9 scFv fusion protein is useful for reducing amyloid plaque deposition in the brains of CRDN8 mice, see para. [00233].
One would have been motivated, with a reasonable expectation of success to do this for targeting cell expressing chimeric phagocytic receptor to engulf aberrant amyloid beta because Golde teaches scFv9 is specific for A beta and attenuate A.beta. deposition in old CRND8 mice, see para. [0025].
One of ordinary skill in the art would have been motivated to do so because the ‘662 patent teaches that chimeric antigen receptor (CAR) which comprises scFv that targets at least one aberrant protein, e.g., Aβ peptides is useful for treating neurodegenerative disease or condition (see Summary, in particular) and Getts teaches that cell expressing chimeric phagocytic receptor is able to clear disease cells.
Further, the simple substitution of one known element for another to obtain predictable results is one of the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143 as a rationale supporting obviousness.
In addition, the claims would have been obvious because "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Finally, applying known technique of making chimeric phagocytic receptor to a known product would be ready for making another chimeric phagocytic receptor to a known product in the same way.
“The test of obviousness is not express suggestion of the claimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Claims 41, 57 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over US20200345774 (of record, Getts hereafter, published November 5, 2020, claimed earliest priority to 62/841,190, filed April 30, 2019, PTO 892) in view of Golde et al (newly cited, WO2021016316 publication, published January 28, 2021; PTO 892) and U.S. Patent No. 12,344,662 (of record, filed February 11, 2019, claimed earliest priority to 62/628,632, filed February 9, 2018; PTO 892) as applied to claims 1-6, 13, 15, 18, and 21 mentioned above and further in view of Rosenthal (of record, US20180186855, published July 5, 2018; PTO 892) and Jung et al (newly cited, Biomolecules & Therapeutics 26(4): 350-357, 2018; PTO 892).
The combine teachings of Getts, Golde and the ‘662 patent have been discussed supra.
The references above do not teach that a modified cell comprising said chimeric antigen receptor wherein the cell is an astrocyte as per claim 41, a method of treating a subject is diagnosed with or at risk of developing a neurodegenerative disease, disorder, or condition, the method comprising: administering to the subject the modified astrocyte and a method of treating a neurodegenerative disease, disorder, or condition, the method comprising: administering to a subject the modified astrocyte as per claim 58.
However, Rosenthal teaches a chimeric receptor comprising an extracellular binding domain, e.g., anti-amyloid beta chain-chain variable fragment (scFv) domain (see para. [0009], [0017]), a CD8 hinge domain, a CD8 transmembrane domain, an intracellular signaling domain, e.g., a common FcR gamma (FCERIG, para. [0102]), DAP12 intracellular domain, see para. [0009], [0102], [0104].
Regarding cells, Rosenthal teaches that cells include astrocytes, see para. [0009], [0014], [0018]. Rosenthal teaches that signaling through DAP12 or TCR3Zeta receptor ITAM intracellular domains leads to downstream signaling events such as Syk kinase activation, which promotes survival, functionality, phagocytosis, and proliferation in cells, e.g., astrocytes, see para. [0105]. TREM2, an endogenous receptor that signals through DAP12, is protective in human and in mouse models of Alzheimer's disease and multiple sclerosis, see para. [0105].
Regarding claims 57 and 58, Rosenthal teaches administering astrocytes containing the chimeric receptor (para. [0167], [0286]) to an individual diagnosed with dementia induces clearance or phagocytosis of disease-associated protein or cells, see para. [0286], thereby treating or preventing neurodegenerative disease, e.g., Alzheimer’s disease, dementia, see para. [0290] to [0300].
Jung teaches that astrocytes are the most abundant cell type in the brain and constitute approximately 40% of brain cells, see p. 351, right col. Jung teaches that glial phagocytosis Astrocyte- and microglia mediated phagocytosis play various roles under different physiological conditions. In normal and healthy conditions, glial phagocytosis involves in regulation of neural circuit remodeling by eliminating unwanted synapses and neurites. Furthermore, glia mediates removal of apoptotic cells and neuronal debris in maintaining brain homeostasis. In pathological conditions, astrocytes and microglia phagocytose protein aggregates, such as A, Htt, and α-Syn to clear accumulated proteins in the brains with neurodegenerative diseases, see p. 354, left col. caption under Fig 2, in particular.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to substitute the cell that expressing the chimeric receptor of Getts, Golde and the ‘662 patent for another, e.g., astrocyte that highly expressed in the brain as taught by Rosenthal and Jung to arrive at the claimed invention with a reasonable expectation of success, e.g., a astrocytes expressing a chimeric engulfment receptor (CER) comprising a single chain scFv that binds to beta amyloid peptide 9; a CD8 hinge, a CD8 or TREM2 transmembrane domain, a first engulfment signaling domain, e.g., TREM2, FcεR1 or MRC1 (CD206) signaling domain and a second engulfment signaling domain, e.g., FcεR1 and/or MRC1 for clearance of protein aggregates, Aβ as taught by Jung.
One would have been motivated, with a reasonable expectation of success to do this because Jung teaches that astrocytes are the most abundant cell type in the brain and Rosenthal teaches administering astrocytes containing the chimeric receptor (para. [0167], [0286]) to an individual diagnosed with dementia is expected to induce clearance or phagocytosis of disease-associated protein or apoptotic cells, see para. [0286], thereby treating neurodegenerative disease, e.g., Alzheimer’s disease, dementia, see para. [0290] to [0300].
Further, the simple substitution of one known element for another to obtain predictable results is one of the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143 as a rationale supporting obviousness.
“The test of obviousness is not express suggestion of the claimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Allowable Subject Matter
SEQ ID NO: 2, 11-12, 15-16, 24-35, 42-43 are free of prior art.
Conclusion
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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