DETAILED ACTION
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/30/2025 has been entered.
Notice of Pre-AIA or AIA Status
2. The present application is being examined under the pre-AIA first to invent provisions.
3. No claims 69-70 have been added. Claims 48-70 are pending. Claims 1-47 are canceled. Claims 48, 49, 51, 53, 55, 58, 60 and 62 have been amended.
4. Claims 48-70 are under examination.
Rejections Maintained
Claim Rejections - 35 USC § 112
5. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
6. Claims 48-68 and new claims 79-80 remain/are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Note: part 1 of the rejection has been withdrawn in view of applicant’s amendments to the claims. The following is part 2 of the rejection modified in view of applicant’s amendments.
The instant claims recite “an antigen that exists in both aggregated and unaggregated forms in plasma in vivo”. The claims are rejected because the specification does not adequately describe all the species encompass by the genus of antigens that exist in both aggregated and unaggregated forms in plasma in vivo”. Specifically the aggregated form of the antigens in plasma in vivo has not been adequately described.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members.
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
Lastly, even if a selection procedure is disclosed that was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision.
The instant claims require using “an unaggregated form of an antigen in plasma in vivo” and “an aggregated form of the antigen in plasma in vivo” in an assay to select antigen binding domains that have a binding activity to the aggregated form of the antigen that is higher than its binding activity to the unaggregated form of the antigen. The specification does not adequately describe all the species encompassed by the genus of antigens in aggregated form in plasma in vivo. The specification discloses “aggregated antigen refers to a molecule in a state at which two or more of a molecule (monomer) present in a normal biological fluid have become aggregated or multimerized. An aggregated antigen may be a molecule in which monomers having the same three-dimensional structure (protein secondary structure or tertiary structure) are aggregated or multimerized as compared to antigens normally present in in biological fluid, or it may be a molecule in which partially or totally degenerated molecules as compared to the monomer are aggregated or multimerized. Furthermore, an aggregated antigen may be a molecule in which a mixture of two is aggregated or multimerized. In the aggregated antigens, another type of antigen that does not bind to the antigen-binding molecule may also be present.” (emphasis added)
Given the broadest reasonable interpretation of the claims in light of the specification, the claims encompass using unaggregated antigens and their aggregated antigens in assays to screen antigen binding domains that have a binding activity to the aggregated antigens that is higher than its binding activity to their unaggregated antigens (emphasis added). Claim 65 and new claim 69 recite “wherein the antigen is any one of huntingtin, ataxin-1, ataxin-2, Ca channel alA, ataxin-7, TATA binding protein, Machado-Joseph disease (MJD) protein, Dentatorubral Pallidoluysian Atrophy (DRPLA) protein, androgen receptor, al- antitrypsin, al-antichymotrypsin, neuroserpin, C1 inhibitor, antithrombin III, A3, immunoglobulin light chain (L-ch), transthyretin, Serum amyloid A (SAA), beta-2 microglobulin (p2M), immunoglobulin heavy chain (H-ch), cystatin C, a synuclein, amylin, hemoglobin, crystallin, IgA, Tau protein, TAR DNA-binding protein 43kDa (TDP-43), Superoxide dismutase (SOD1), FUS (Fused in Sarcoma), Prion, paired-like homeobox 2B (PHOX2B), Aristaless- related homeobox, X-linked (ARX) protein, poly-adenylate binding protein nuclear 1 (PABPN1), dysferlin, desmin, Glial fibrillary acidic protein (GFAP) or keratin 5/14”.
While the specification has adequate written description for the above antigens in unaggregated form, it does not have written description for their corresponding aggregated antigens that exit in plasma in vivo.
The specification discloses one aggregated antigen, which is an aggregated hIgA (Example 2, page 165). The specification discloses that aggregated hIgA was prepared using the crosslinking agent SPDP. After crosslinking reaction the macromolecular component was fractioned by gel filtration chromatography to obtain aggregated hIgA (page 165). The molecular weight of the aggregated hIgA is 780 kDa (page 165). However, the disclosed aggregated hIgA is not an aggregated form of IgA in plasma in vivo (emphasis added) as it is prepared using the crosslinking agent SPDP in vitro. Therefore, the specification does not disclose a representative number of species for the genus because the genus encompasses aggregates of any antigens that exist in plasma in vivo, including those recited in instant claim 65.
The “aggregated antigens” encompass any protein aggregates that exist in plasma in vivo and may comprise partially or totally degenerated proteins. The aggregated antigens include soluble oligomers as well as insoluble aggregates. The specification has not disclosed a genus of circulating protein aggregates that can be used in the claimed method. Applicant has not obtained any antigens in aggregated form from plasma.
Adiutori et al (Brain Communications 2021, 1-16) teaches that circulating protein aggregates separated by ultracentrifugation are visible as electron-dense macromolecular particles appearing as either large globular or as small filamentous formations. Analysis by mass spectrometry revealed that circulating protein aggregates obtained from patients are enriched with proteins involved in the proteasome system, possibly reflecting the underlying basis of dysregulated proteostasis seen in the disease, while those from healthy controls show enrichment of proteins involved in metabolism (abstract). Unbiased proteomics revealed that a total of 4973 proteins were commonly detected in circulating protein aggregates (abstract). Adiutori et al. teaches detecting proteins in the aggregates (page 4). However they do not disclose isolating and structural analysis of any specific protein aggregate.
Pedersen et al (Anal Chem, 2013, 85: 4215-4227, PTO-892 dated 4/4/2025) teaches that it is important to realize that protein aggregation is a highly complex process where a single technique cannot give a complete characterization of the entire chain of events. Each step of the protein aggregation process is also by itself very heterogeneous and may give rise to oligomeric species with a distribution of size and conformational properties which are not readily resolved and quantitatively estimated using any of the present techniques. Thus, the applicability of specific analytical techniques varies along the protein aggregation pathway (page 4217, last para).
Schuster et al. (J Pharm Sci., 2021, 110: 3103-3110) teaches that studies on in vivo protein aggregation and fragmentation are scarce presumably due to analytical challenges (Title, abstract and page 3104, column 1, para 3). Schuster et al. teaches that changes in pH, composition, osmolality, and temperature may be key factors contributing to protein aggregation (page 3104, column 1, para 4). Regarding in vivo aggregation and precipitation of therapeutic proteins, Schuster et al. teaches that thousands of different macromolecules present in human body fluids may alter the properties of administered proteins and impact their stability by e.g., heteroaggregation or other interactions such as enzymatic modification or cleavage. Pathologic conditions such as a pro-inflammatory environment found in some patients may accelerate aggregation, precipitation, and oxidation (page 3104, column 1, para 5). Biological fluids are highly complex and contain numerous endogenous proteins with concentrations often considerably exceeding those of administered therapeutic proteins (e.g., endogenous vs. therapeutic IgG). Subvisible particle (SbVP) analysis in biological fluids remains a challenge due to the plethora of matrix components covering a wide
size range. For example, whole blood contains molecules covering a size range between 1 and 1000 nm (e.g., proteins, peptides, small molecules, lipids, exosomes), 1-5 mm (apoptotic vesicles), and 2−20 mm (platelets and cells). Biological fluids require a controlled carbon dioxide environment to maintain the physiologic pH and avoid incubation under non-physiologic conditions, which may not be representative of events occurring in patients. Endogenous molecules of biological fluids may degrade under non-physiologic conditions, which in turn can trigger degradation of the protein of interest (page 3106, last para). Substituting biological fluids with surrogate buffers may compromise the physiologic relevance of an in vitro model to an extent that it may not allow to monitor protein aggregation and/or fragmentation (page 3109, para 1).
While protein aggregates can be detected in blood, actual isolation and characterization of protein aggregates from blood is extremely difficult because protein aggregates are usually unstable, and exist as heterogenous mixtures (oligomers, protofibrils, fibrils and complexed with lipids, metals, immunoglobulins and complement factors). Standard chromatographic techniques (e.g., size exclusion or affinity chromatography) can inadvertently disrupt aggregate structures or fail to separate them from high-molecular-weight complexes.
Maintaining the native conformations that define aggregation-specific epitopes is critical for downstream antibody screening but is easily disturbed by purification steps that involve changes in pH, ionic strength, or denaturing conditions. Loss of key structural features can obscure the very epitopes used to differentiate aggregates from monomers.
Neither the specification nor the prior art teaches the structures of the broadly encompassed aggregated antigens of plasma that can be used in the claimed method. Applicant has not disclosed any relevant, identifying characteristics, such as structure or other physical and/or chemical properties, sufficient to show possession of the claimed genus of aggregated antigens. Mere idea or function 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. Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
In the absence of structural characteristics that are shared by members of the genus, and absence of a representative number of species to describe the genus, one of ordinary skill in the art would conclude that the applicant was not in possession of the claimed method of using unaggregated antigens and their corresponding aggregated antigens to select antigen binding domains that have a binding activity to the aggregated antigens that is higher than its binding activity to their corresponding unaggregated antigens.
It is noted that, “[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Applicant’s Arguments
The response states that an aggregated antigen contains multiple copies of a given antigen monomer, associated together. Because the structures of the unaggregated antigens covered by the claims have been adequately described (as acknowledged by the Examiner), the structures of the corresponding aggregates of those antigens are likewise adequately described by the specification's saying that an aggregate contains multiple copies of the antigen monomers. This simple description provides the "relevant, identifying characteristics, such as structure or other physical and/or chemical properties" that the Office action asserts (at page 12) is lacking. The specification's description is certainly "sufficient to distinguish infringing methods from non-infringing methods," as stated in the University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886, 1984 (CAFC 2004) case cited in the Office action at pages 12-13. The Office has not provided any rational basis for asserting otherwise. And applicant fails to see the relevance of the Eli Lilly case cited at page 12 of the Office action as saying, "definition by function ... does not suffice to define the genus," given that the claims recite no such "function" for the aggregates. The aggregates are quite simply defined solely by their structure. Applicant submits that generating or isolating the aggregates would not provide further description of the aggregates that is relevant to the present claims. Applicant wishes to clarify the record with respect to a statement made in the Office action that suggests a possible misinterpretation of the term "aggregate." The Office action asserts at page 10 that "the aggregated antigens are generally insoluble at neutral pH." It appears that the Office may be interpreting the term "aggregated" as necessarily meaning "insoluble." While some aggregated antigens, such as the aggregates described by Pedersen et al. that accumulate as deposits in the brain and are associated with certain neurodegenerative diseases, can be considered to be insoluble, that doesn't mean that all aggregated antigens are insoluble. And, as discussed by Pedersen et al., even the insoluble deposits in the brain form from monomers in a gradual process that begins with soluble aggregated oligomeric species. See Pedersen et al., page 4217, column 2, to page 4221, column 2, where the authors refer to "soluble oligomeric precursors to neuropathological amyloid" and go on describe several analytical techniques useful for aggregates that are soluble (or at least suspended) in fluids. To clarify the intended scope of the claims, independent claim 48 has been amended to specify that the antigen is one that exists in aggregated and unaggregated forms in plasma in vivo. Because plasma circulates in vivo, any aggregate present in it would be either soluble or suspended in the plasma.
Applicant asks that the rejection for lack of written description be withdrawn.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive. The claims encompass using any aggregated proteins of plasma in the claimed method. However, the specification fails to describe a structure of any specific aggregated proteins that exist in plasma. The term aggregated antigen is not limited to a dimer or oligomer of an antigen. Aggregated proteins often exist as a heterogeneous mixture of species, ranging from small oligomers to insoluble fibrils. It broadly encompasses any misfolded protein aggregates. Aggregated proteins differ structurally from their monomeric forms and are often present at extremely low abundance, making it difficult to isolated them without altering their native state. For example, oligomeric forms of misfolded proteins in neurodegenerative disease are ephemeral and vary in size, hydrophobicity, and structural conformation, complicating both their biochemical isolation and accurate quantification in body fluids such as blood or cerebrospinal fluid (CSF). Maintaining the native conformations that define aggregation-specific epitopes is critical for downstream antibody screening but is easily disturbed by purification steps that involve changes in pH, ionic strength, or denaturing conditions. Because aggregated proteins differ structurally from their monomeric forms, description of an antigen in monomeric form is insufficient for description of the antigen in aggregated form. Since aggregated antigens of plasma are specifically required in the claimed method, they must be adequately described.
Claim Rejections - 35 USC § 112
7. Claims 48-68 and new claims 69-70 remain/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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The rejection has been modified in view of applicant’s amendments.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
''Factors to be considered in determining whether a disclosure would
require undue experimentation have been summarized by the board in Ex
parte Forman. They include (1) the quantity of experimentation necessary,
(2) the amount of direction or guidance presented, (3) the presence or
absence of working examples, (4) the nature of the invention, (5) the state
of the prior art, (6) the relative skill of those in the art, (7) the predictability
or unpredictability of the art, and (8) the breadth of the claims.''
The nature of the invention
Independent claim 48 is drawn to a method for producing an antibody, the method comprising:
(1) providing a library comprising a plurality of antigen-binding molecules comprising antigen-binding domains having diverse amino acid sequences, each antigen-binding domain comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 and a light chain variable region comprising CDR1, CDR2, and CDR3, wherein one or more of the antigen-binding molecules comprise, in a CDR of a heavy chain variable region or a CDR of a light chain variable region, at least one amino acid residue that has metal-chelating activity or is a histidine;
(2) carrying out the following series of selection steps (a)-(c), in any order, to select from the library an antigen-binding molecule comprising an antigen-binding domain that binds to an antigen that exists in both aggregated and unaggregated forms in plasma in vivo:
(a) selecting one or more of the antigen-binding molecules, each comprising an antigen- binding domain that binds both to the aggregated form of the antigen and the unaggregated form of the antigen;
(b) selecting one or more antigen-binding molecules, each comprising an antigen-binding domain that binds to the aggregated form of the antigen with a binding activity according to any of (i), (ii), or (iii) below:
(i) a binding activity that varies depending on calcium ion concentration, the antigen-binding domain having a KD (3 µM Ca)/KD (2 mM Ca) value, defined as the ratio of (KD for the aggregated form at a calcium ion concentration of 3 µM) to (KD for the aggregated form at a calcium ion concentration of 2 mM), of 2 or more, or
(ii) a binding activity that varies depending on pH, the antigen- binding domain having a KD (pH 5.8)/KD (pH 7.4) value, defined as the ratio of (KD for the aggregated form at pH 5.8) to (KD for the aggregated form at pH 7.4), of 2 or more, or
(iii) a binding activity that varies depending on both pH and calcium ion concentration, the antigen-binding domain having a KD (pH 5.8)/KD (pH 7.4) value of 2 or more and a KD (3 µM Ca)/KD (2 mM Ca) value of 2 or more,
wherein each KD (pH 5.8)/KD (pH 7.4) value is determined using a surface plasmon resonance technique in which the antigen binding molecule is immobilized, the aggregated form of the antigen serves as analyte, and the following conditions are used: 0.05% polyoxyethylene (20) sorbitan monolaurate,20 mmol/1 ACES, 150mM NaCl, and 1.2 mM CaCl2, at 37 °C and at the appropriate pH;
wherein each KD (3 µM Ca)/KD (2 mM Ca) value is determined using a surface plasmon resonance technique in which the antigen binding molecule is immobilized, the aggregated form of the antigen serves as analyte, and the following conditions are used: 0.05% polyoxyethylene (20) sorbitan monolaurate,20 mmol/1 ACES, 150mM NaCl, and the appropriate concentration of CaCl2, at 37 °C and pH 7.4;
(c) selecting one or both of (A) and (B):
(A) one or more antigen-binding molecules having a binding activity to the aggregated form of the antigen that is higher than its binding activity to the unaggregated form of the antigen;
(B) one or more antigen-binding molecules, each comprising an antigen- binding domain characterized in that a test antibody comprising that antigen- binding domain complexed with the aggregated antigen has a binding activity to an Fc receptor that is higher than the binding activity to the Fc receptor of a complex comprising the test antibody and the unaggregated form of the antigen, wherein the Fc receptor is human FcRn or a human Fc[Symbol font/0x67] receptor;
(3) introducing into a cell one or more nucleic acid molecules encoding an antibody comprising the selected antigen-binding domain of the antigen-binding molecule selected in of step (2) and an Fc region; and
(4) culturing the cell to produce the encoded antibody of step (3).
Claims 64 is drawn to the method of claim 48, wherein, when the encoded antibody of step (4) is introduced into a subject whose blood contains both the aggregated and unaggregated forms of the antigen, the ratio of clearance of the aggregated form of the antigen from the blood of the subject in the presence of the antibody to clearance of the aggregated form of the antigen from the blood of the subject in the absence of the antibody is at least 1.5 times the ratio of clearance of the unaggregated form of the antigen from the blood of the subject in the presence of the antibody to clearance of the unaggregated form of the antigen from the blood of the subject in the absence of the antibody.
Claim 65 is drawn to the method of claim 48, wherein the antigen is any one of huntingtin, ataxin-1, ataxin-2, Ca channel alA, ataxin-7, TATA binding protein, Machado-Joseph disease (MJD) protein, Dentatorubral Pallidoluysian Atrophy (DRPLA) protein, androgen receptor, al- antitrypsin, al-antichymotrypsin, neuroserpin, C1 inhibitor, antithrombin III, A3, immunoglobulin light chain (L-ch), transthyretin, Serum amyloid A (SAA), beta-2 microglobulin (p2M), immunoglobulin heavy chain (H-ch), cystatin C, a synuclein, amylin, hemoglobin, crystallin, IgA, Tau protein, TAR DNA-binding protein 43kDa (TDP-43), Superoxide dismutase (SOD1), FUS (Fused in Sarcoma), Prion, paired-like homeobox 2B (PHOX2B), Aristaless- related homeobox, X-linked (ARX) protein, poly-adenylate binding protein nuclear 1 (PABPN1), dysferlin, desmin, Glial fibrillary acidic protein (GFAP) or keratin 5/14.
The nature of the inventions is a method of producing an antibody that binds to an aggregated form of an antigen with a binding activity higher than the unaggregated form of the antigen.
The invention is in a class of invention, which the CAFC has characterized as ''the unpredictable arts such as chemistry and biology.'' Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The breadth of the claims
The instant claims require using “unaggregated form of an antigen” and “aggregated form of the antigen” in an assay to select antigen binding domains that have a binding activity to the aggregated form of an antigen that is higher than its binding activity to the unaggregated form of the antigen. The specification discloses “aggregated antigen refers to a molecule in a state at which two or more of a molecule (monomer) present in a normal biological fluid have become aggregated or multimerized. An aggregated antigen may be a molecule in which monomers having the same three-dimensional structure (protein secondary structure or tertiary structure) are aggregated or multimerized as compared to antigens normally present in in biological fluid, or it may be a molecule in which partially or totally degenerated molecules as compared to the monomer are aggregated or multimerized. Furthermore, an aggregated antigen may be a molecule in which a mixture of two is aggregated or multimerized. In the aggregated antigens, another type of antigen that does not bind to the antigen-binding molecule may also be present.” (emphasis added)
Given the broadest reasonable interpretation of the claims in light of the specification, the claims encompass using unaggregated antigens and their aggregated antigens in assays to screen antigen binding domains that have a binding activity to the aggregated antigens that is higher than its binding activity to their unaggregated antigens. Claim 65 recites “wherein the antigen is any one of huntingtin, ataxin-1, ataxin-2, Ca channel alA, ataxin-7, TATA binding protein, Machado-Joseph disease (MJD) protein, Dentatorubral Pallidoluysian Atrophy (DRPLA) protein, androgen receptor, al- antitrypsin, al-antichymotrypsin, neuroserpin, C1 inhibitor, antithrombin III, A3, immunoglobulin light chain (L-ch), transthyretin, Serum amyloid A (SAA), beta-2 microglobulin (p2M), immunoglobulin heavy chain (H-ch), cystatin C, a synuclein, amylin, hemoglobin, crystallin, IgA, Tau protein, TAR DNA-binding protein 43kDa (TDP-43), Superoxide dismutase (SOD1), FUS (Fused in Sarcoma), Prion, paired-like homeobox 2B (PHOX2B), Aristaless- related homeobox, X-linked (ARX) protein, poly-adenylate binding protein nuclear 1 (PABPN1), dysferlin, desmin, Glial fibrillary acidic protein (GFAP) or keratin 5/14”.
The “aggregated antigens” encompass any protein aggregates that exist in plasma in vivo and may comprise partially or totally degenerated proteins. The aggregated antigens include soluble oligomers as well as insoluble aggregates.
The quantity of experimentation
The quantity of experimentation is extremely large in view of the breadth of the claims and unpredictability of making and using antibodies that have a binding activity to the aggregated form of an antigen that is higher than its binding activity to the unaggregated form of the antigen.
Working examples and guidance in the specification
The specification discloses making one aggregated antigen, which is an aggregated hIgA (Example 2, page 165). The specification discloses that aggregated hIgA was prepared using the crosslinking agent SPDP. After crosslinking reaction the macromolecular component was fractioned by gel filtration chromatography to obtain aggregated hIgA (page 165). The molecular weight of the aggregated hIgA is 780 kDa (page 165). However, the disclosed aggregated hIgA is not an aggregated form of IgA in plasma in vivo (emphasis added) as it is prepared using the crosslinking agent SPDP in vitro
The specification does not teach how to isolate/make the broadly encompassed circulating protein aggregates useful in the claimed method. The specification has not obtained aggregated form of the antigens recited in claim 65. There is no evidence indicating that applicant has made any antigen binding molecules that have a binding activity to the aggregated form of an antigen that is higher than its binding activity to the unaggregated form of the antigen, and introduced such antigen binding molecules into a subject as required by instant claim 64.
The specification does not provide guidance on making the broadly encompassed circulating aggregated antigens useful in the claimed method.
The unpredictability of the art and the state of the prior art
Adiutori et al (Brain Communications 2021, 1-16) teaches that circulating protein aggregates separated by ultracentrifugation are visible as electron-dense macromolecular particles appearing as either large globular or as small filamentous formations. Analysis by mass spectrometry revealed that circulating protein aggregates obtained from patients are enriched with proteins involved in the proteasome system, possibly reflecting the underlying basis of dysregulated proteostasis seen in the disease, while those from healthy controls show enrichment of proteins involved in metabolism (abstract). Unbiased proteomics revealed that a total of 4973 proteins were commonly detected in circulating protein aggregates (abstract). Adiutori et al. teaches detecting proteins in the aggregates (page 4). However they do not disclose isolating and structural analysis of any specific protein aggregate.
Pedersen et al (Anal Chem, 2013, 85: 4215-4227, PTO-892 dated 4/4/2025) teaches that it is important to realize that protein aggregation is a highly complex process where a single technique cannot give a complete characterization of the entire chain of events. Each step of the protein aggregation process is also by itself very heterogeneous and may give rise to oligomeric species with a distribution of size and conformational properties which are not readily resolved and quantitatively estimated using any of the present techniques. Thus, the applicability of specific analytical techniques varies along the protein aggregation pathway (page 4217, last para).
Schuster et al. (J Pharm Sci., 2021, 110: 3103-3110) teaches that studies on in vivo protein aggregation and fragmentation are scarce presumably due to analytical challenges (Title, abstract and page 3104, column 1, para 3). Schuster et al. teaches that changes in pH, composition, osmolality, and temperature may be key factors contributing to protein aggregation (page 3104, column 1, para 4). Regarding in vivo aggregation and precipitation of therapeutic proteins, Schuster et al. teaches that thousands of different macromolecules present in human body fluids may alter the properties of administered proteins and impact their stability by e.g., heteroaggregation or other interactions such as enzymatic modification or cleavage. Pathologic conditions such as a pro-inflammatory environment found in some patients may accelerate aggregation, precipitation, and oxidation (page 3104, column 1, para 5). Biological fluids are highly complex and contain numerous endogenous proteins with concentrations often considerably exceeding those of administered therapeutic proteins (e.g., endogenous vs. therapeutic IgG). Subvisible particle (SbVP) analysis in biological fluids remains a challenge due to the plethora of matrix components covering a wide
size range. For example, whole blood contains molecules covering a size range between 1 and 1000 nm (e.g., proteins, peptides, small molecules, lipids, exosomes), 1-5 mm (apoptotic vesicles), and 2−20 mm (platelets and cells). Biological fluids require a controlled carbon dioxide environment to maintain the physiologic pH and avoid incubation under non-physiologic conditions, which may not be representative of events occurring in patients. Endogenous molecules of biological fluids may degrade under non-physiologic conditions, which in turn can trigger degradation of the protein of interest (page 3106, last para). Substituting biological fluids with surrogate buffers may compromise the physiologic relevance of an in vitro model to an extent that it may not allow to monitor protein aggregation and/or fragmentation (page 3109, para 1).
While protein aggregates can be detected in blood, actual isolation and characterization of protein aggregates from blood is extremely difficult because protein aggregates are usually unstable, and exist as heterogenous mixtures (oligomers, protofibrils, fibrils and complexed with lipids, metals, immunoglobulins and complement factors). Standard chromatographic techniques (e.g., size exclusion or affinity chromatography) can inadvertently disrupt aggregate structures or fail to separate them from high-molecular-weight complexes.
Maintaining the native conformations that define aggregation-specific epitopes is critical for downstream antibody screening but is easily disturbed by purification steps that involve changes in pH, ionic strength, or denaturing conditions. Loss of key structural features can obscure the very epitopes used to differentiate aggregates from monomers.
Level of skill in the art
The level of skill in the art is deemed to be high.
Conclusion
Thus given the broad claims in an art whose nature is identified as unpredictable, the unpredictability of the art, the large quantity of research required to define these unpredictable variables, the lack of guidance provided in the specification, the absence of a working example on making and using the broadly encompassed aggregated antigens in screen assays, and the negative teachings in the prior art balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of ordinary skill in the art to perform the methods as broadly claimed.
Applicant’s Arguments
The response states that applicant established above that even the Pedersen et al. publication cited by the Office does not support the Office's apparent belief that all aggregates are insoluble. Rather, Pedersen et al. explains that some aggregates (referred to as "oligomers" or the like) are soluble or at least suspended in fluids and can be assayed by standard methods that are described in some detail in that reference. Claim 48 now recites that the antigen "exists in both aggregated and unaggregated forms in plasma in vivo," so excludes aggregated forms of the antigen that cannot exist in plasma in vivo. The Office has suggested no reason that assaying the presently claimed aggregated forms of the antigen would require undue experimentation.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive. The claims encompass using any aggregated proteins of plasma to screen for antibodies. However, the specification does not teach how to make the broadly encompassed circulating protein aggregates. The term aggregated antigen is not limited to a dimer or oligomer of an antigen. Aggregated proteins often exist as a heterogeneous mixture of species, ranging from small oligomers to insoluble fibrils. It broadly encompasses any misfolded protein aggregates. Aggregated proteins differ structurally from their monomeric forms and are often present at extremely low abundance, making it difficult to isolated them without altering their native state. For example, oligomeric forms of misfolded proteins in neurodegenerative disease are ephemeral and vary in size, hydrophobicity, and structural conformation, complicating both their biochemical isolation and accurate quantification in body fluids such as blood or cerebrospinal fluid (CSF). Maintaining the native conformations that define aggregation-specific epitopes is critical for downstream antibody screening but is easily disturbed by purification steps that involve changes in pH, ionic strength, or denaturing conditions. The specification has not teach how to make the broadly encompassed protein aggregates of plasma. For example, the specification does not teach the structures of aggregated form of antigens of claim 65, and how to make them. It would require undue experimentation for one of ordinary skill in the art to perform the method as broadly claimed.
New Grounds of Objection
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
8. Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
9. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code, see pages 46 and 50, for example. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
10. Claim 48 is objected to for reciting a phrase “to select from the library an antigen-binding domain” in lines 9-10 (lines 1-2 of part (2)). The phrase should be changed to “to select from the library one or more antigen-binding molecules” to be consistent of parts (a)-(c).
Claim 48 is objected to for reciting a phrase “the antigen-binding domain of the antigen-binding molecules” in line 2 of part (3). The phrase should be changed to “the antigen-binding domain of the one or more antigen-binding molecules” to be consistent of parts (a)-(c).
Claim 57 is objected to for missing a word “that” after “residues” in line 2. The term “and” in line 2 should be deleted.
Claims 66 and 67 are objected to for reciting “Fc region’s” in line 4
Conclusion
11. No claims are allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
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/HONG SANG/Primary Examiner, Art Unit 1646