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 and 4-21 are pending.
Applicant’s election of Group I in the reply filed on January 29, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 21 is withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1 and 4-20, drawn to a method of treating a motor neuron degenerative disorder in a subject in needed thereof, are being acted upon in this Office Action.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on August 1, 2025 and April 28, 2023 have been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
The listing of references in the specification at page 36 is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings filed on April 28, 2023 are acceptable.
Specification
The specification is objected to because it contains disclosures of amino acid sequences that are not accompanied by SEQ ID NOS, at least with respect to the sequences shown in Figure 12B. While it appears those sequences are included in the sequence listing, a sequence identifier (SEQ ID NO) must accompany each sequence, either in the figure itself or in the Brief Description, each time it appears in the specification. 37 C.F.R. 1.821 (a) and (c); M.P.E.P. 2422.01-03.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objection
Claim 1 is objected to because of the following informality: the claim uses the abbreviation TREM1 without first defining it. To clarify the claim, applicant should first spell out the full term before using an abbreviation. Given the subject matter of the specification, the examiner presumes that "TREM1" stands for "Triggering receptors expressed on myeloid cells-1". Appropriate correction isrequired.
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 and 4-20 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 a method of treating any motor neuron degenerative disorder in a subject in need thereof, the method comprising systematically administering to the subject any antibody or antigen-binding fragment thereof that binds and neutralizes TREM1.
Claim 4 encompasses the method according to claim 1, wherein the antibody or antigen-binding fragment thereof prevents TREM1 interactions with one or more of its natural ligands.
Claim 5 encompasses the method according to claim 4, wherein said natural ligand is Peptidoglycan Recognition Protein 1 (PGLYRP 1).
Claim 6 encompasses the method according to claim 1, wherein said motor neuron degenerative disorder is amyotrophic lateral sclerosis (ALS).
Claim 7 encompasses the method according to claim 6, wherein said ALS is characterized by the presence of any mutation in SOD1 gene.
Claim 8 encompasses the method according to claim 1, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously or intravenously.
Claim 9 encompasses the method according to claim 1, wherein said antibody or antigen-binding fragment thereof binds to TREM1 with an affinity of at least 50 nM.
Claim 10 encompasses the method according to claim 1, wherein said treating reduces microglia neuronal uptake.
Claim 11 encompasses the method according to claim 1, wherein said treating inhibits the migration of microglia.
Claim 12 encompasses the method according to claim 11, wherein the migration is measured using a scratch wound assay.
Claim 13 encompasses the method according to claim 1, wherein said antibody or antigen-binding fragment thereof reduces the rate of phagocytosis in microglia.
Claim 14 encompasses the method according to claim 1, wherein said antibody or antigen binding fragment thereof is any monoclonal antibody or antigen-binding fragment thereof.
Claim 15 encompasses the method according to claim 1, wherein said antibody or antigen-binding fragment is any human, humanized or chimeric antibody or antigen-binding fragment thereof.
Claim 16 encompasses the method according to claim 1, wherein the antibody is a full length antibody.
Claim 17 encompasses the method according to claim 1, wherein said antibody or antigen-binding fragment comprises a human heavy chain constant region and a human light chain constant region.
Claim 18 encompasses the method according to claim 1, wherein said antibody is of the IgG isotype.
Claim 19 encompasses the method according to claim 1, wherein the antibody is an IgG1 or IgG4.
Claim 20 encompasses the method according to claim 1, wherein the anti-TREMI antibody or antigen- binding fragment is provided as a pharmaceutical composition comprising one or more of a pharmaceutically acceptable excipient, dilute or carrier.
Regarding motor neuron degenerative disorder, the specification define as follow:
[0056] The term “motor neuron disease” as used herein, refers to diseases that primarily (but not necessarily exclusively) affect motor neurons, neuromuscular input or signal transmission at the neuromuscular junction. The motor neuron diseases referred above include, but are not limited to, amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG), spinal muscular atrophy (SMA) or Charcot-Marie-Tooth disease (CMT).
Regarding subject, the specification defines subject as follow:
[0055] A “subject,” “individual” or “patient” is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, rats, simians, humans, farm animals, sport animals, and pets.
Regarding anti-TREM1 antibody or antigen binding fragment thereof, the specification discloses: anti-mouse TREM1 (MAB1187, R&D System). Said Anti-TREM1 Antibody Reduces Migratory Capacity of Microglia In Vitro, see Example 4. The Anti-TREM1 Antibody Reduces Spinal Cord Microglial Phagocytosis in SOD1-G93A Mice, see Example 9. The effects of a TREM1 antibody on brain inflammation in SOD1-G93A mice were assessed using a mass cytometry approach. SOD1-G93A mice (100 days of age) were injected with either isotype (IgG2A, MAB006, R&D Systems) antibody or anti-mouse TREM1 (MAB1187, R&D Systems) antibody (two I.P. injections 48 hours apart). 24 hours after the second injection, mice were anaesthetized and perfused with 1×HBSS (10 U/ml heparin) for 5 mins, see Example 10. The same commercially available anti-mouse TREM1 antibody can penetrate the brain of SOD1-G93A mice, see Example 11. The epitope to which the anti-mouse TREM1 (MAB1187) binds was mapped to residues L45, M46, K47, N50, Q71, R72, P73, T75, R76, P77, S78, S92, and E93 (the positions correspond to the SEQ ID NO: 2 from mouse TREM1). The following corresponding epitope residues in human TREM1 have been identified (the positions correspond to SEQ ID NO: 1): L45, E46, K47, S50, E71, R72, P73, K75, N76, S77, H78, D92, and H93.
However, the specification does not describe the structure-identifying information, e.g., amino acid sequences of heavy and light chain variable regions for any antibody or antigen-binding fragment thereof that binds and neutralizes any Triggering receptors expressed on myeloid cells-1 (TREM1) from any mammalian species for treating any and all motor neuron degenerative diseases including, but are not limited to, amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG), spinal muscular atrophy (SMA) or Charcot-Marie-Tooth disease (CMT) in all mammalian subject. The disclosure does not describe a representative number of species of antibody and antigen binding fragment thereof falling with 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 anti-TREM1 antibody or antigen binding fragment thereof that would be effective for treating any subject having any motor neuron degenerative diseases.
Although the claims recite some functional characteristics, the claims lack written description because there is no disclosure of a correlation between function, e.g., binding and neutralizing TREM1 (claim 1), preventing any natural ligands from interacting with TREM1 (claim 4), any ligand such as peptidoglycan Recognition Protein 1 (PGLYRP1, claim 5), binding with an affinity of at least 50 nM (claim 9), reduces microglia neuronal uptake (claim 10), inhibiting the migration of microglia (claim 11), reducing the rate of phagocytosis in microglia (claim 13) and structure, e.g., amino acid sequence of the heavy and light chain variable domains of the antibody beyond the anti-mouse TREM1 MAB1187. The specification has not adequately described the genus of antibodies that specifically bind “TREM1” that would be effective to treat motor neuron degenerative disorder that include, but are not limited to, amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG), spinal muscular atrophy (SMA) or Charcot-Marie-Tooth disease (CMT). One of skill in the art would not immediately envision or recognize which antibodies would have the requisite ability to be effective to treat which motor neuro degenerative disorder from those that would merely bind TREM1.
Mere idea or function, e.g., binding is insufficient for written description; isolation and characterization at a minimum are required. A description of what a material does, rather than what it is, usually does not suffice. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
It is well-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 over 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 (Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g.. Discussion).
Poosarla et al. (Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
The state of the art at the time the invention was made recognized that antibody that binds to protein from one species may not bind to the same protein from another species.
For example, Yu et al. (Investigative Ophthalmology & Visual Science 49(2): 522-527, February 2008; PTO 892) teach bevacizumab, which is a humanized anti-human VEGF-A mAb A.4.6.1 binds specifically to human VEGF-A, the same antibody does not bind to mouse VEGF-A (see page 522, right col., page 523, Figure 1, in particular).
Further, computational and machine learning approaches for sequence-based prediction of paratope-epitope interactions are accumulating, but “it remains unclear whether antibody-antigen binding is predictable” (Akbar et al., Cell Reports 34 (11): 108856, Mar. 16, 2021 at p. 2, col. 2, para. 2 (PTO 892)).
While the specification discloses discontinue epitope to which the anti-mouse TREM1 binds, the current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See e.g., Lo et al., “Conformational epitope matching and prediction based on protein surface spiral features,” BMC Genomics 22 (Suppl 2): 116, 2021, PTO 892) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
Regarding treating any motor neuron degenerative disorder in any mammalian subject, Applicants have provided insufficient evidence or nexus that would lead the skilled artisan to predict which antibody is effective for treating which motor neuron degenerative disorder that include, but are not limited to, amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG), spinal muscular atrophy (SMA) or Charcot-Marie-Tooth disease (CMT).
Even assuming the method limits to treating amyotrophic lateral sclerosis (ALS) using SOD1-G93A mice model, the data disclosed in the application simply show that a commercial anti-mouse-TREM1 antibody can penetrate to some extent into brain tissue (examples 11 and 14) and reduces spinal cord microglial phagocytosis in SOD1-G93A mice (example 9) as well as the levels of co-stimulatory molecules and activation markers (example 10).
However, neither the art nor the specification show these mechanisms correlate with ameliorating amyotrophic lateral sclerosis (ALS) symptoms. Thus, the specification does not disclose a representative number of species of antibody that binds to TREM1 to be administered in the claimed method, nor sufficient structure/function relationship correlative to the recited functional properties.
Regarding mutation in SOD1 gene (claim 7), the term mutation encompasses germline mutations, and somatic mutation that encompass deletion, substitution, addition and a combination thereof. The specification does not describe what kind of mutations are characteristics of ALS in SOD1 gene that the claimed method can treat.
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.
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).
Although one of skill in the art could: make a mAb against human TREM1, screen for antibody that binds to epitope L45, E46, K47, S50, E71, R72, P73, K75, N76, S77, H78, D92, and H93 where the positions correspond to SEQ ID NO: 1, test candidates, and produce a corresponding antibody, note that:
“Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Equally note that adequate written description of a newly characterized antigen alone is not adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional. Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017).
Therefore, only a method of reducing spinal cord microglial phagocytosis in a subject in need thereof, the method comprising systemically administering to the subject an antibody or antigen-binding fragment thereof that binds to L45, M46, K47, N50, Q71, R72, P73, T75, R76, P77, S78, S92, and E93 of SEQ ID NO: 2, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 1 and 4-20 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 a method of reducing spinal cord microglial phagocytosis in a subject in need thereof, the method comprising systemically administering to the subject an antibody or antigen-binding fragment thereof that binds to L45, M46, K47, N50, Q71, R72, P73, T75, R76, P77, S78, S92, and E93 of SEQ ID NO: 2, does not reasonably provide enablement for a method of treating any neuro degenerative disease in any subject by systemically administering to the subject any antibody or antigen-binding fragment thereof that binds and neutralizes any TREM1 as set forth in claims 1 and 4-20. 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 a method of treating any motor neuron degenerative disorder in a subject in need thereof, the method comprising systematically administering to the subject any antibody or antigen-binding fragment thereof that binds and neutralizes TREM1.
Claim 4 encompasses the method according to claim 1, wherein the antibody or antigen-binding fragment thereof prevents TREM1 interactions with one or more of its natural ligands.
Claim 5 encompasses the method according to claim 4, wherein said natural ligand is Peptidoglycan Recognition Protein 1 (PGLYRP 1).
Claim 6 encompasses the method according to claim 1, wherein said motor neuron degenerative disorder is amyotrophic lateral sclerosis (ALS).
Claim 7 encompasses the method according to claim 6, wherein said ALS is characterized by the presence of any mutation in SOD1 gene.
Claim 8 encompasses the method according to claim 1, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously or intravenously.
Claim 9 encompasses the method according to claim 1, wherein said antibody or antigen-binding fragment thereof binds to TREM1 with an affinity of at least 50 nM.
Claim 10 encompasses the method according to claim 1, wherein said treating reduces microglia neuronal uptake.
Claim 11 encompasses the method according to claim 1, wherein said treating inhibits the migration of microglia.
Claim 12 encompasses the method according to claim 11, wherein the migration is measured using a scratch wound assay.
Claim 13 encompasses the method according to claim 1, wherein said antibody or antigen-binding fragment thereof reduces the rate of phagocytosis in microglia.
Claim 14 encompasses the method according to claim 1, wherein said antibody or antigen binding fragment thereof is any monoclonal antibody or antigen-binding fragment thereof.
Claim 15 encompasses the method according to claim 1, wherein said antibody or antigen-binding fragment is any human, humanized or chimeric antibody or antigen-binding fragment thereof.
Claim 16 encompasses the method according to claim 1, wherein the antibody is a full length antibody.
Claim 17 encompasses the method according to claim 1, wherein said antibody or antigen-binding fragment comprises a human heavy chain constant region and a human light chain constant region.
Claim 18 encompasses the method according to claim 1, wherein said antibody is of the IgG isotype.
Claim 19 encompasses the method according to claim 1, wherein the antibody is an IgG1 or IgG4.
Claim 20 encompasses the method according to claim 1, wherein the anti-TREMI antibody or antigen- binding fragment is provided as a pharmaceutical composition comprising one or more of a pharmaceutically acceptable excipient, dilute or carrier.
Regarding motor neuron degenerative disorder, the specification discloses:
[0056] The term “motor neuron disease” as used herein, refers to diseases that primarily (but not necessarily exclusively) affect motor neurons, neuromuscular input or signal transmission at the neuromuscular junction. The motor neuron diseases referred above include, but are not limited to, amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG), spinal muscular atrophy (SMA) or Charcot-Marie-Tooth disease (CMT).
Regarding subject, the specification defines subject as follow:
[0055] A “subject,” “individual” or “patient” is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, rats, simians, humans, farm animals, sport animals, and pets.
Regarding anti-TREM1 antibody or antigen binding fragment thereof, the specification discloses anti-mouse TREM1 (MAB1187, R&D System). Said Anti-TREM1 Antibody Reduces Migratory Capacity of Microglia In Vitro, see Example 4. The Anti-TREM1 Antibody Reduces Spinal Cord Microglial Phagocytosis in SOD1-G93A Mice, see Example 9. The effects of a TREM1 antibody on brain inflammation in SOD1-G93A mice were assessed using a mass cytometry approach. SOD1-G93A mice (100 days of age) were injected with either isotype (IgG2A, MAB006, R&D Systems) antibody or anti-mouse TREM1 (MAB1187, R&D Systems) antibody (two I.P. injections 48 hours apart). 24 hours after the second injection, mice were anaesthetized and perfused with 1×HBSS (10 U/ml heparin) for 5 mins, see Example 10. The same commercially available anti-mouse TREM1 antibody can penetrate the brain of SOD1-G93A mice, see Example 11. The epitope to which the anti-mouse TREM1 (MAB1187) binds was mapped to residues L45, M46, K47, N50, Q71, R72, P73, T75, R76, P77, S78, S92, and E93 (the positions correspond to the SEQ ID NO: 2 from mouse TREM1). The following corresponding epitope residues in human TREM1 have been identified (the positions correspond to SEQ ID NO: 1): L45, E46, K47, S50, E71, R72, P73, K75, N76, S77, H78, D92, and H93.
However, the specification does not teach the structure-identifying information, e.g., amino acid sequences of heavy and light chain variable regions for any antibody or antigen-binding fragment thereof that binds and neutralizes any Triggering receptors expressed on myeloid cells-1 (TREM1) from any mammalian species for treating any and all motor neuron degenerative diseases including, but are not limited to, amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG), spinal muscular atrophy (SMA) or Charcot-Marie-Tooth disease (CMT) in all mammalian subject. The specification does not enable one of skilled in the art to make and use without undue experimentation.
Although the claims recite some functional characteristics, there is no correlation between structure, e.g., e.g., amino acid sequence of the heavy and light chain variable domains of the antibody or antigen-binding fragment thereof that binds TREM1 and function, e.g., binding and neutralizing TREM1 (claim 1), preventing any natural ligands from interacting with TREM1 (claim 4), any ligand such as peptidoglycan Recognition Protein 1 (PGLYRP1, claim 5), binding with an affinity of at least 50 nM (claim 9), reduces microglia neuronal uptake (claim 10), inhibiting the migration of microglia (claim 11), reducing the rate of phagocytosis in microglia (claim 13) beyond the anti-mouse TREM1 MAB1187. The specification does not teach how to predict which antibody from the genus of antibodies that specifically bind “TREM1” and would be effective to treat motor neuron degenerative disorder that include, but are not limited to, amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG), spinal muscular atrophy (SMA) or Charcot-Marie-Tooth disease (CMT) in all mammalian subject.
It is well-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 over 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 (Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g.. Discussion).
Poosarla et al. (Biotechn Bioeng 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Further, the state of the art at the time the invention was made recognized that antibody that binds to protein from one species may not bind to the same protein from another species.
For example, Yu et al. (Investigative Ophthalmology & Visual Science 49(2): 522-527, February 2008; PTO 892) teach bevacizumab, which is a humanized anti-human VEGF-A mAb A.4.6.1 binds specifically to human VEGF-A, the same antibody does not bind to mouse VEGF-A (see page 522, right col., page 523, Figure 1, in particular).
Further, computational and machine learning approaches for sequence-based prediction of paratope-epitope interactions are accumulating, but “it remains unclear whether antibody-antigen binding is predictable” (Akbar et al., Cell Reports 34 (11): 108856, Mar. 16, 2021 at p. 2, col. 2, para. 2 (PTO 892)).
While the specification discloses discontinue epitope to which the anti-mouse TREM1 binds, the current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See e.g., Lo et al., “Conformational epitope matching and prediction based on protein surface spiral features,” BMC Genomics 22 (Suppl 2): 116, 2021, PTO 892) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
Regarding treating any motor neuron degenerative disorder in any mammalian subject, Applicants have provided insufficient evidence or nexus that would lead the skilled artisan to predict which antibody is effective for treating which motor neuron degenerative disorder that include, but are not limited to, amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG), spinal muscular atrophy (SMA) or Charcot-Marie-Tooth disease (CMT).
Even assuming the method limits to treating amyotrophic lateral sclerosis (ALS) using SOD1-G93A mice model, the data disclosed in the application simply show that a commercial anti-mouse-TREM1 antibody can penetrate to some extent into brain tissue (examples 11 and 14) and reduces spinal cord microglial phagocytosis in SOD1-G93A mice (example 9) as well as the levels of co-stimulatory molecules and activation markers (example 10).
However, neither the art nor the specification show these mechanisms correlate with ameliorating ALS symptoms.
Regarding mutation in SOD1 gene (claim 7), the term mutation encompasses germline mutations, and somatic mutation that encompass deletion, substitution, addition and a combination thereof. The specification does not describe what kind of mutations are characteristics of ALS in SOD1 gene that the claimed method can treat.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by Lloyd, Poosarla, Yu, Akbar, and Lo, and the insufficient working examples, undue experimentation would be required to practice the claimed methods commensurate with the scope of the claims.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 4-11 and 13-20 are rejected under 35 U.S.C. 102 (a)(1)as being anticipated by Pincetic et al (WO2017152102, published September 8, 2017; PTO 892) as evidence by Gurney et al (Science 264: 1772-1775, 1994; PTO 892).
Claim 1 encompasses a method of treating any motor neuron degenerative disorder in a subject in need thereof, the method comprising systematically administering to the subject any antibody or antigen-binding fragment thereof that binds and neutralizes TREM1.
Claim 4 encompasses the method according to claim 1, wherein the antibody or antigen-binding fragment thereof prevents TREM1 interactions with one or more of its natural ligands.
Claim 5 encompasses the method according to claim 4, wherein said natural ligand is Peptidoglycan Recognition Protein 1 (PGLYRP 1).
Claim 6 encompasses the method according to claim 1, wherein said motor neuron degenerative disorder is amyotrophic lateral sclerosis (ALS).
Claim 7 encompasses the method according to claim 6, wherein said ALS is characterized by the presence of any mutation in SOD1 gene.
Claim 8 encompasses the method according to claim 1, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously or intravenously.
Claim 9 encompasses the method according to claim 1, wherein said antibody or antigen-binding fragment thereof binds to TREM1 with an affinity of at least 50 nM.
Claim 10 encompasses the method according to claim 1, wherein said treating reduces microglia neuronal uptake.
Claim 11 encompasses the method according to claim 1, wherein said treating inhibits the migration of microglia.
Claim 13 encompasses the method according to claim 1, wherein said antibody or antigen-binding fragment thereof reduces the rate of phagocytosis in microglia.
Claim 14 encompasses the method according to claim 1, wherein said antibody or antigen binding fragment thereof is any monoclonal antibody or antigen-binding fragment thereof.
Claim 15 encompasses the method according to claim 1, wherein said antibody or antigen-binding fragment is any human, humanized or chimeric antibody or antigen-binding fragment thereof.
Claim 16 encompasses the method according to claim 1, wherein the antibody is a full length antibody.
Claim 17 encompasses the method according to claim 1, wherein said antibody or antigen-binding fragment comprises a human heavy chain constant region and a human light chain constant region.
Claim 18 encompasses the method according to claim 1, wherein said antibody is of the IgG isotype.
Claim 19 encompasses the method according to claim 1, wherein the antibody is an IgG1 or IgG4.
Claim 20 encompasses the method according to claim 1, wherein the anti-TREMI antibody or antigen- binding fragment is provided as a pharmaceutical composition comprising one or more of a pharmaceutically acceptable excipient, dilute or carrier.
Regarding claims 1, 6, 8, Pincetic teaches a method of treating motor neuron disease, e.g., amyotrophic lateral sclerosis (ALS, para. [0411], [0413]) or Parkinson’s disease (para. [0408] to [0410]), Huntington’s disease (para. [0414] to [0415]) by administrating (para. [0298]) to an individual in need thereof, e.g., a human subject (para. [0379]) an anti-TREM1 antibody or antigen binding fragment thereof, e.g., Fab, F(ab’)2 (para. [0108]) that binds to human and mouse TREM1 (Table 6) to reduce the risk, and/or treat such disease, see entire document. The route of administration includes intravenous (aka systemically), subcutaneous, see para. [0379].
Regarding claims 4-5, Pincetic teaches that the TREM1 antibody or antigen binding fragment thereof inhibits the interaction between human TREM1 and hPGLYRP1 (one of its natural ligands), see para. [0186], [0190], [0478], Example 5.
Regarding claim 7, evidentiary reference Gurney teaches that amyotrophic lateral sclerosis (ALS) is characterized by the presence of mutation in superoxide dismutase (SOD) gene, e.g., (G93A) in humans and mice, see p. 1772, left col.
Regarding claim 9, Pincetic teaches that the anti-TREM1 antibody or antigen binding fragment thereof binds to TREM1 with high affinity, e.g., about 1010 M-1 to 1011 M-1 or higher, which is at least 50 nM, see para. [0119].
Claims 10-11 are included because the reference anti-TREM1 antibody or antigen binding fragment thereof inherently reduces microglia neuronal uptake and migration of microglia, see para. [0188], [0189], [0249].
“Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Since the Patent Office does not have the facilities for examining and comparing the antibodies of the instant invention to those of the prior art. the burden is on applicant to show that the prior art antibody is different from the claimed antibody. See In re Best. 562 F2d 1252. 195 USPQ 430(CCPA 1977).
Regarding claim 13, Pincetic teaches that the anti-TREM1 antibody may induce clearance and/or phagocytosis after binding to a TREM1 protein expressed in a cell of one or more of apoptotic neurons, neuro tissue debris of the nervous system, non-nerve tissue debris of the nervous system, see para. [0290], or microglia, see para. [0293].
Regarding claims 14-15, Pincetic teaches that the anti-TREM1 antibody is a monoclonal antibody, humanized, chimeric, human antibody or antigen binding fragment thereof, e.g., Fab, Fab'-SH, Fv, scFv, and F(ab')2), see para. [0300], in particular.
Regarding claim 16, Pincetic teaches that the anti-TREM1 antibody is a full-length antibody, see para. [0106].
Claim 17 is included because the reference human antibody (para. [0116], [0206]) inherently has a human heavy chain constant region and a human light chain constant region.
Regarding claims 18-19, Pincetic teaches that the anti-TREM1 antibody is human IgG1 or IgG4, see para. [0124], [0125].
Regarding claim 20, Pincetic teaches that the anti-TREM1 antibody or antigen-binding fragment thereof is provided in a pharmaceutical composition comprising one or more pharmaceutically acceptable carrier, e.g., distilled water, buffered water, physiological saline, PBS, see para. [0134], [0138], [0369, [0370].
Thus, the reference teachings anticipate the claimed invention.
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).
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Pincetic et al (WO2017152102, published September 8, 2017; PTO 892) in view of Rajapakse (US20100113415, published May 6, 2010; PTO 892).
The teachings of Pincetic have been discussed supra.
Pincetic does not teach the method wherein the migration is measured using a scratch wound assay as per claim 12.
However, Rajapakse teaches following damage to the CNS, different cell types respond in different ways. Neurons typically attempt to regenerate their connections, and largely fail. Astrocytes and microglial cells proliferate, migrate and become hypertrophic, see para. [0007]. Rajapakse teaches scratch wound assays are commonly used to assess the effect of drugs and drug candidates on the cellular proliferation and/or migration associated with wound closing, see para. [0386], 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 combine the teachings of Pincetic and Rajapakse by using scratch wound assays of Rajapakse to assess the anti-TREM1 antibody or antigen binding fragment thereof of Pincetic for inhibition of migration of microglia.
One of ordinary skill in the art would have been motivated to do so, with a reasonable expectation of success, because Rajapakse teaches scratch wound assays are commonly used to assess the effect of drugs and drug candidates on the migration of microglia associated with wound closing, see para. [0386], in particular.
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 Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 4-9 and 14-20 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 31 and 33 of copending Application No. 18/558,686 (Reference) as evidence by Gurney et al (Science 264: 1772-1775, 1994; PTO 892). Although the conflicting claims are not identical, they are not patentably distinct from each other because copending claims anticipate instant claims.
Copending claim 31 recites a method of treating or preventing a neurological disorder comprising administering a therapeutically effective amount of the antibody that binds to human TREM1, comprising: a light chain variable region comprising: a CDR-L1 comprising SEQ ID NO:11, a CDR-L2 comprising SEQ ID NO:12, and a CDR-L3 comprising SEQ ID NO:13; and a heavy chain variable region comprising: a CDR-H1 comprising SEQ ID NO: 14, a CDR-H2 comprising SEQ ID NO:15, and a CDR-H3 comprising SEQ ID NO:16 or a pharmaceutical composition comprising said antibody and a pharmaceutically acceptable adjuvant or carrier to a patient in need thereof (species), whereas instant claim 1 is generic with respect to the antibody or antigen binding fragment thereof (genus).
Copending claim 32 recites the method of claim 31, wherein said neurological disorder is amyotrophic lateral sclerosis (ALS) or Alzheimer's disease, which corresponds to instant claim 6.
Copending claim 2 recites the antibody according to claim 1, wherein said antibody inhibits or attenuates TREM1 binding to one or more of its natural ligands, which corresponds to instant claim 4.
Copending claim 3 recites the antibody according to claim 2, wherein said antibody inhibits or attenuates TREM1 binding to PGLYRPl, which corresponds to instant claim 5.
Copending claim 14 recites the antibody according to claim 1, wherein said antibody is an antibody fragment, which corresponds to instant claim 1.
Copending claim 15 recites the antibody according to claim 14, wherein said antibody fragment is Fab, Fab', F(ab')2, Fv, dsFv, scFv, or dsscFv.
Copending claim 16recites the antibody according to claim 1, wherein said antibody is a full length antibody, which corresponds to instant claim 16.
Copending claim 17 recites the antibody according to claim 16, wherein said antibody is an IgG1, IgG1 LALA, IgG4, IgG4P, or IgG4P FALA, which corresponds to instant claims 18-19.
The copending application also teaches the route of administration, e.g., intravenous, or subcutaneous as per claim 8, see para. [0452], [0454].
The copending application also teaches the antibody or antigen binding fragment thereof binds to human TREM1 with a KD of about any one of 100 nM, 50 nM, see para. [0312].
The copending application also teaches the antibody or antigen binding fragment thereof is a monoclonal antibody, see para. [0380], chimeric, humanized, fully human antibodies or whole antibody or antigen binding fragment thereof as per claims 14-17, see para. [0175], [0367] to [0371].
Claim 7 is included as evidentiary reference Gurney teaches that amyotrophic lateral sclerosis (ALS) is characterized by the presence of mutation in superoxide dismutase (SOD) gene, e.g., (G93A) in humans and mice, see p. 1772, left col.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Claims 10-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31-33 of copending Application No. 18/558,686 in view of Rajapakse (US20100113415, published May 6, 2010; PTO 892).
The copending application above have been discussed supra.
The copending application does not teach the method of treating a motor neuron degenerative disorder, wherein said treating reduces microglia neuronal uptake as per claim 10, wherein said treating inhibits the migration of microglia as per claim 11, or wherein the migration is measured using a scratch wound assay as per claim 12.
However, Rajapakse teaches following damage to the CNS, different cell types respond in different ways. Neurons typically attempt to regenerate their connections, and largely fail. Astrocytes and microglial cells proliferate, migrate and become hypertrophic, see para. [0007]. Rajapakse teaches scratch wound assays are commonly used to assess the effect of drugs and drug candidates on the cellular proliferation and/or migration associated with wound closing, see para. [0386], 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 combine the teachings of copending application and Rajapakse by using scratch wound assays of Rajapakse to assess the anti-TREM1 antibody or antigen binding fragment thereof of US20100113415 for inhibition of migration of microglia.
One of ordinary skill in the art would have been motivated to and had an expectation of success at the time the invention was made to assess the effect of anti-TREM1 on microglia migration because Rajapakse teaches scratch wound assays are commonly used to assess the effect of drugs and drug candidates on the migration of microglia associated with wound closing, see para. [0386], in particular.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641