DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application is being examined under the pre-AIA first to invent provisions.
2. Applicant’s reply filed on 5/1/2026 is acknowledged. New claims 71-74 have been added. Claims 48-64 and 66-74 are pending. Claims 1-47 and 65 are canceled. Claims 48, 52 and 66-69 have been amended.
3. Claims 48-64 and 66-74 are under examination.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on 5/1/2026 has been considered by the examiner.
Objections Withdrawn
5. All objections are withdrawn in view of applicant’s amendments and persuasive arguments.
Rejections Maintained
Claim Rejections - 35 USC § 112
6. 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.
7. Claims 48-64, 66-70 and new claims 71-74 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.
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 69 recites “wherein the antigen is any one of Ca channel α1A, TATA binding protein, Machado-Joseph disease (MJD) protein, al-antitrypsin, al-antichymotrypsin, C1 inhibitor, antithrombin III, Ap, immunoglobulin light chain (L-ch), Serum amyloid A (SAA), beta-2 microglobulin (β2M), immunoglobulin heavy chain (H-ch), cystatin C, amylin, hemoglobin, crystallin, 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).
New claim 71 is rejected as the term “comprise two or more of the antigens” encompasses dimers, oligomers, aggregates having high molecular weight and misfolded protein aggregates which are insoluble. Furthermore, the term “comprises” is open, and does not exclude the presence of other proteins in the aggregates. The specification does not disclose which aggregates are useful for antibody screening.
New claim 72 is rejected as the term “comprise two or more of the antigens” encompasses aggregates having high molecular weight which are insoluble. Furthermore, the term “comprises” is open, and does not exclude the presence of other proteins in the aggregates. The specification does not disclose which aggregates are useful for antibody screening.
New claim 73 is rejected because the limitation “comprises two or more monomers of the antigen that are partially degenerated forms of the unaggregated form of the antigen” encompasses aggregates having high molecular weight and misfolded protein aggregates which are insoluble. Furthermore, the term “comprises” is open, and does not exclude the presence of other proteins in the aggregates. The specification does not disclose which aggregates are useful for antibody screening.
New claim 74 is rejected because the claim encompasses insoluble aggregates e.g. hemoglobin aggregates and larger Aβ fibrillr aggregates. The specification does not disclose which aggregates are useful for antibody screening.
Applicant’s Arguments
The response states that the Office action somewhat mischaracterizes the claims, saying at page 5: "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...." While claim 48 does say that the antigen "exists in both aggregated and unaggregated forms in plasma in vivo," that language is simply a description of the antigen. The claim does not require using either form of the antigen while it is "in plasma in vivo." Independent claim 48 is not directed to aggregated antigens per se. Rather, it is directed to a method of producing an antibody. In this method, antigen-binding molecules are selected from a library based on defined binding properties toward aggregated and unaggregated forms of an antigen, and then nucleic acid molecule(s) encoding an antibody comprising the antigen- binding domain of a selected antigen-binding molecule is/are then introduced into a cell that is cultured to produce the antibody.
The Federal Circuit's recent decision in Teva Pharmaceuticals International GmbH v. Eli Lilly and Company, No. 2024-1094 (Fed. Cir. Apr. 16, 2026), is very much on point here. (A copy of the opinion is attached as Exhibit A, for the Office's convenience.) In Teva, the Federal Circuit reversed the district court's finding of invalidity under 35 U.S.C. §112, holding that the district court incorrectly assumed that the written description and enablement standards appropriate for a composition claim would also apply to compositions used in a claimed method. Instead, according to the court, where a method claim uses a known genus as part of an invention, the specification need not describe the genus as though the applicant were claiming the genus per se.
Applicant asserts that the present rejection is based on the same faulty reasoning as applied by that district court. The Office action treats the claims as though applicant were claiming the genus of aggregated antigens themselves, and faults the specification for allegedly failing to describe a representative number of species within that genus. But claim 48 does not claim aggregated antigens. Claim 48 claims a method for producing antibodies, in which aggregated and unaggregated forms of an antigen are used as binding targets in defined selection steps. Under Teva, the proper inquiry is whether the specification reasonably conveys possession of the claimed antibody-production method, in view of the specification and the knowledge in the art.
The facts of Teva illustrate the point. The claims at issue there were directed to methods of treating headache using humanized anti-CGRP antagonist antibodies. The Federal Circuit emphasized that "[the] claimed invention is the use of anti-CGRP antagonist antibodies, or humanized versions thereof, to treat headache-not such antibodies themselves." Id. at 12 (emphasis in original). Although the specification disclosed only one humanized anti-CGRP antagonist antibody, it also disclosed several murine anti-CGRP antagonist antibodies and prior- art methods of humanization, against the backdrop that anti-CGRP antagonist antibodies and methods of making and humanizing antibodies were known in the art. See id. at 13-14. The court held that these disclosures were sufficient to support a finding that the specification disclosed a representative number of species, particularly because a skilled artisan would have understood that the whole class of humanized anti-CGRP antagonist antibodies would function similarly in the claimed method of treating headache. See id. at 14. The Federal Circuit also rejected Lilly's argument that distinguishing between claims to a method of using antibodies and claims to the antibodies themselves was merely "semantic," emphasizing that the distinction was supported by precedent. See id. at 16-17. In particular, the court distinguished University of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004), and Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010) (en banc), because those cases involved claims where the compounds or molecules usable in the claimed methods were not disclosed and were not shown to be known in the art. In contrast, in Teva, relevant antibodies were known in the art and some were even disclosed in the specification.
The same reasoning applies here. The pending claims are not directed to aggregated antigens per se. Rather, they are directed to a method for producing antibodies using selection steps in which the aggregated and unaggregated forms of an antigen serve as binding targets. As in Teva, the relevant genus, aggregated forms of antigens, is not itself the invention. Rather, the aggregated forms of antigens are a known genus used in a novel claimed method for selecting and producing antibodies with desired binding properties.
It is certainly well known in the art that many antigens can form aggregates in plasma in vivo. To illustrate this, applicant lists below (and provides in the presently filed IDS) several publications, each published prior to the May 30, 2012 priority date of the present application, reporting examples of aggregated forms of various proteins in plasma. These examples include aggregated forms of proteins recited in claim 70 and amended claim 69, such as IgA, immunoglobulin light chain (L-ch), beta-2 microglobulin, amyloid-3 (A3), and hemoglobin.
IgA: Sancho et al., Clin Exp Immunol, 1981, 47:327-335, describes finding "polymeric" IgA (i.e., IgA aggregates) in sera from patients with alcoholic liver disease. See, page 329.
Immunoglobulin light chain: Abraham et al, Clin Chem, 2002 Oct, 48(10):1805-1811, reports the presence of trimolecular aggregates of lambda light chain dimers in the serum. See, Abstract.
beta-2 microglobulin: Vincent et al., Biochem J, 1994, 298:181-187, reports dimers of this protein (i.e., aggregates) in plasma. See, Abstract.
Aβ: Xia et al., Arch Neurol, 2009 Feb, 66(2):190-199, discloses that monomers and "oligomeric assemblies" (i.e., aggregates) of A(3 can be found in human plasma. See, Abstract.
Hemoglobin: Kapralov et al., J Biol Chem, 2009 Oct 30, 284(44):30395-30407, discusses hemoglobin/haptoglobin aggregates found in plasma. See, Abstract.
The articles cited above demonstrate that the art was aware that protein aggregates exist in plasma. Furthermore, it is relevant to note the holding in Teva that, because methods of humanizing antibodies were known in the art, the existence in the art of non-humanized anti- CGRP antibodies provided written description support for Teva's claim limitation specifying humanized CGRP antibodies. This has a corollary to the present facts, where the Office concedes that the structures of the antigens listed in claim 69 were known in the art. Since aggregates of those antigens are made up of copies of the antigens (or portions thereof), one of ordinary skill in the art would understand the basic amino acid sequences making up the aggregates. Thus, it is unnecessary for the specification or the art to have disclosed precise structures of the aggregates themselves in order to satisfy the standard as set out in Teva.
Applicant also points out that methods for analyzing aggregated forms of antigens were well established in the art.. See, for example, Pedersen et al. (Anal Chem, 2013, 85: 4215-4227), a review article published in 2013 (and cited in the Office action) that describes known techniques for detecting, separating, and characterizing soluble oligomers and higher-order aggregate species. Such art-recognized methods serve as further confirmation that aggregated forms of antigens were not an unknown or newly invented class of materials, but rather a known genus that a person of ordinary skill in the art would have understood could be used as targets in binding and selection assays.
Accordingly, under the framework articulated in Teva, the present specification, together with what is known in the art, discloses a representative number of species for the known genus of aggregated forms of antigens that can be used in the claimed antibody production method. The written description requirement does not require applicant to isolate, structurally characterize, and describe in detail every aggregated form of every antigen encompassed by the claims, particularly where the claims are directed to a method using such aggregates as binding targets, rather than to the aggregates themselves.
Applicant further submits that new dependent claims 71-74 also satisfy the written description requirement. New claims 71-73 are based on the specification's description of "aggregated antigen" and provide further structural characterizations for the aggregated form of the antigens. See page 17, lines 11-18, of the as-filed application. New claim 74 specifies the subset of antigens for which applicant has submitted pre-priority-date publications disclosing the presence of corresponding aggregated forms in 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.
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).
Independent claim 48 recites
“(2) carrying out the following series of selection steps (a)-(c), in any order, to select from the library one or more antigen-binding molecules comprising an antigen-binding domain that binds to an antigen that exists in both aggregated and unaggregated forms in plasma in vivo”;
“(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)”;
“(i) a binding activity that varies depending on calcium ion concentration…”;
“(ii) a binding activity that varies depending on pH…”, and
“(iii) a binding activity that varies depending on both pH and calcium ion concentration…”.
As one can see, the aggregated form of the antigen is required in the screening assays to select the antibodies with certain binding activities. The screening assays are performed in solution under varying calcium ion concentrations and/or pH values. The claims encompass using a genus of aggregated antigens that exist in plasma to select antigen binding molecules with certain binding activities. The recited screening assays require the aggregated antigens be soluble or be solubilized. The specification does not disclose which aggregates are useful for antibody screening.
The references submitted by applicant (Sancho et al., Abraham et al, Vincent et al., Kapralov et al. and Xia et al.) have been carefully considered but are not sufficient to overcome the rejection. Xia et al. teaches detecting soluble Aβ oligomer (detected Aβ oligomer in supernatant). Abraham et al. teaches detecting λ light chain dimers (which is soluble). Sancho et al. teaches detection of monomeric and polymeric IgA (which is soluble). Vincent et al. teaches detecting β2-microglobulin dimers (generally soluble under physiological condition). Kapralov et al. detected hemoglobin-haptoglobin complex (which is either soluble or was solubilized for SDS-PAGE and HPLC). However, the term aggregated antigen is not limited to a soluble dimer or soluble Aβ oligomer. As indicated in the previous office action, 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).
The Federal Circuit's recent decision in Teva Pharmaceuticals International GmbH v. Eli Lilly and Company, No. 2024-1094 (Fed. Cir. Apr. 16, 2026) does not apply to instant case. Methods of making humanized antibodies were well known. However, methods of isolating insoluble protein aggregates from blood are not. 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). Although methods of detecting soluble protein dimer or soluble Aβ oligomer were known in the art , 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 solubilization and chromatographic techniques (e.g., size exclusion or affinity chromatography) can inadvertently disrupt aggregate structures or fail to separate them from high-molecular-weight complexes. The art known soluble dimers and soluble Aβ oligomer are not a representative number of species for the genus as the genus includes small oligomers to insoluble aggregates, and misfolded protein aggregates. 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 that is useful for antibody screening. Since aggregated antigens are required for the claimed method, they must be adequately described.
For the foregoing reasons, the rejection is deemed proper and is therefore maintained.
Claim Rejections - 35 USC § 112
8. Claims 48-64, 66-70 and new claims 71-74 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.
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 one or more antigen-binding molecules 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 one of the one or more antigen-binding molecules 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.
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 69 recites “wherein the antigen is any one of Ca channel α1A, TATA binding protein, Machado-Joseph disease (MJD) protein, al-antitrypsin, al-antichymotrypsin, C1 inhibitor, antithrombin III, Ap, immunoglobulin light chain (L-ch), Serum amyloid A (SAA), beta-2 microglobulin (β2M), immunoglobulin heavy chain (H-ch), cystatin C, amylin, hemoglobin, crystallin, 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 69. 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.
New claim 71 is rejected as the term “comprise two or more of the antigens” encompasses dimers, oligomers, aggregates having high molecular weight and misfolded protein aggregates which are insoluble. Furthermore, the term “comprises” is open, and does not exclude the presence of other proteins in the aggregates. The specification does not teach how to obtain/isolate and use aggregates having high molecular weight and misfolded protein aggregates in the claimed method.
New claim 72 is rejected as the term “comprise two or more of the antigens” encompasses aggregates having high molecular weight which are insoluble. Furthermore, the term “comprises” is open, and does not exclude the presence of other proteins in the aggregates. The specification does not teach how to obtain/isolate and use aggregates having high molecular weight in the claimed method.
New claim 73 is rejected because the limitation “comprises two or more monomers of the antigen that are partially degenerated forms of the unaggregated form of the antigen” encompasses aggregates having high molecular weight and misfolded protein aggregates which are insoluble. Furthermore, the term “comprises” is open, and does not exclude the presence of other proteins in the aggregates. The specification does not teach how to obtain/isolate and use aggregates having high molecular weight and misfolded protein aggregates in the claimed method.
New claim 74 is rejected because the claim encompasses insoluble aggregates e.g. hemoglobin aggregates and larger Aβ fibrillr aggregates. The specification does not teach how to obtain/isolate and use aggregates having high molecular weight and misfolded protein aggregates in the claimed method.
Applicant’s Arguments
The response states that independent claim 48 is not directed to aggregated antigens per se. Rather, claim 48 is directed to a method for producing an antibody, in which aggregated and unaggregated forms of an antigen are used as binding targets in defined selection steps, followed by introduction of nucleic acid molecules encoding an antibody comprising the selected antigen-binding domain into a cell and culturing the cell to produce the antibody. The enablement inquiry must therefore be commensurate with the actual scope of the claimed method, not with an unclaimed genus of aggregated antigens standing alone.
The Federal Circuit's reasoning in Teva is instructive. In addressing enablement, the court explained that Lilly's "research assignment" argument might have greater force if the claims had been directed to the genus of humanized anti-CGRP antagonist antibodies themselves. But because the asserted claims were not directed to the antibodies per se, and instead claimed the use of such antibodies for the limited purpose of treating headache, the relevant question was whether the specification enabled the claimed use. The court held that, because the relevant antibodies and methods of making them were known, humanization was routine, and the specification taught that the antibodies worked for the claimed method, finding or making every species within the genus was "more akin to extra credit than a necessary research assignment left to others to complete." Teva, at 21-24.
The same reasoning applies here. The Office action appears to frame the alleged undue experimentation as the need to "make the broadly encompassed circulating protein aggregates." (Office Action, p. 20). But the present claims do not require applicant to make, isolate, or structurally characterize every circulating aggregate. The claims require using an antigen that exists in both aggregated and unaggregated forms in plasma in vivo as a target in selection steps to screen a library to identify antigen-binding molecules having the recited binding properties. The relevant "research assignment," therefore, is not the discovery or manufacture of every aggregated protein in plasma, but the performance of the claimed antibody-production method using such aggregated and unaggregated antigen forms, a process for which the specification provides extensive guidance.
Moreover, a skilled artisan would not have been required to engage in undue
experimentation to obtain aggregated forms of the antigens. As discussed above in connection with written description, publications demonstrate that aggregated forms of many antigens were known to exist in plasma before the priority date, including aggregated forms of A(3, immunoglobulin light chain, beta-2 microglobulin, immunoglobulin heavy chain, hemoglobin, and IgA. In addition, methods for detecting, separating, and characterizing protein aggregates, including soluble oligomers and higher-order aggregate species, were known in the art. Thus, as in Teva, the claimed method uses a known class of materials as part of a different invention; it does not claim that class of materials per se. The fact that different antigens, or different aggregated forms of an antigen, may vary in size, conformation, or oligomeric state does not mean that undue experimentation is required to carry out the claimed method, particularly where the claim itself defines the relevant functional selection criteria and the specification teaches how to measure them.
Accordingly, when the enablement inquiry is properly focused on the claimed antibody-production method, rather than on an unclaimed genus of aggregated antigens per se, the specification enables the full scope of the present claims. Withdrawal of the rejection is requested.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive. The claims encompass using any aggregated antigens that exist in blood to screen for antibodies with certain binding activities. The aggregated antigens are specifically required to perform the claimed method. However, the specification does not teach how to isolate/obtain and use the broadly encompassed protein aggregates. As discussed above, the term aggregated antigen is not limited to soluble dimers and soluble Aβ oligomer. 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 Federal Circuit's recent decision in Teva Pharmaceuticals International GmbH v. Eli Lilly and Company, No. 2024-1094 (Fed. Cir. Apr. 16, 2026) does not apply to instant case. Methods of making humanized antibodies were well known. However, methods of isolating insoluble protein aggregates from blood are not. 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). Although methods of detecting soluble protein dimer or soluble Aβ oligomer were known in the art, 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 solubilization and chromatographic techniques (e.g., size exclusion or affinity chromatography) can inadvertently disrupt aggregate structures or fail to separate them from high-molecular-weight complexes. Because the specification does not teach how to isolate/obtain the broadly encompassed protein aggregates, one of ordinary skill in the art would not be able to perform the claimed method without undue experimentation.
Conclusion
9. No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
10. 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
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