Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
1. 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:
Specific deficiency #1 - 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. In the instant case, the file size is listed in kilobytes rather than in bytes (should be 46,581 bytes).
Specific deficiency #2 – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). In the instant case, the sequences at [0256], Table 2 are not shown with sequence identifiers.
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.
2. Applicant's election without traverse of Group III and species of bispecific antibody “DQN0344xx/DZN0385ee” in Applicant’s amendment and response filed 2/21/25 is acknowledged. The CDRs of the DQN0385ee arm of the bispecific antibody are SEQ ID NO:2-4 and 18-20, and the VH and VL sequences correspond to SEQ ID NO: 1 and 17, respectively, while the heavy and light chain constant regions are SEQ ID NO: 34 and 35, respectively. The CDRs of the DQN0344xx arm of the bispecific antibody are SEQ ID NO: 10-12 and 26-28, and the VH and VL sequences correspond to SEQ ID NO: 9 and 25, respectively, while the heavy and light chain constant regions are SEQ ID NO: 33 and 35, respectively. Applicant states that the elected bispecific antibody binds to a complex formed by HLA-DQ2.5 and a hordein 2 peptide and does has substantially no binding activity to HLA-DQ2.2 or to a complex of HLA-DQ2.5 and a salmonella peptide comprising the sequence of SEQ ID NO: 51. However, evidentiary reference Okura et al. (Nat. Comm. 2023) teaches the bispecific antibody having the arms derived from antibodies DQN0344xx and DQN0385ee that were humanized and mutated for optimization and termed “DONQ52” binds/cross-reacts to/with multiple gluten epitopes besides hordein 2 with limited binding to irrelevant peptides (appearing to be the ones recited in instant base claim 17) (see entire reference, especially second paragraph on page 2, paragraph bridging pages 2-3, first full paragraph on page 3, Figure 2a). It is therefore not clear if an antibody comprising the two arms before humanization and mutational optimization also bind to the breadth of the celiac disease related epitopes as well.
Upon consideration of the prior art, search and examination has been extended to the species of bispecific antibody comprising the arms consisting of or comprising the antibodies DQN0429 cc (e.g., recited at part “(ii)” of dependent claim 40, and comprising the VH/VL and cognate set of CDRs disclosed at Table I at [0105] of the specification at the second entry therein) and DQN0344xx. Search and examination is also being extended to the species recited in instant claims 51-53, the irrelevant no binding activity peptides recited at parts “(a)”-“(f)” of instant base claim 1, the HLA-molecules recited in claim 33, and HLA-DQ2.5 complexes comprising peptides from 33mer gliadin, alpha 1 gliadin alpha 1b gliadin, alpha 2 gliadin, omega 1 gliadin, omega 3 gliadin, secalin 1, secalin 2, or hordein.
Claims 17, 32-40 and 51-53 read upon the elected species and the species noted above and are presently being examined.
Note that the Examiner of this application has changed.
3. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the Examiner on form PTO-892, they have not been considered.
4. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which Applicant may become aware in the specification.
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 17, 32-36, 38, 39 and 51-53 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). "Compliance with the written description requirement is essentially a fact-based inquiry that will ‘necessarily vary depending on the nature of the invention claimed.' " Enzo Biochem, 323 F.3d at 963, 63 USPQ2d at 1612. An invention described solely in terms of a m ethod of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. See MPEP 2163 I.A.
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). "Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." See MPEP 2163 II.3.
Applicant has broadly claimed:
an antigen-binding molecule that comprises at least two antigen-binding domains, wherein one or more the of the antigen-binding domains have binding activity to one or more complexes formed between HLA-DQ2.5 and an immune dominant peptide related to celiac disease, wherein one or more of the antigen-binding domains have substantially no binding activity to at least one of the HLA-DQ2.5 complexes recited at parts (a)-(e) or an HLA-DQ2.5 positive PBMC B cell, wherein the antigen binding molecule is a bispecific or multispecific antigen-binding molecule (as is recited in instant base claim 17);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule blocks the interaction between an HLA-DQ2.5/gluten peptide complex and an HLA-DQ2.5/gluten peptide-restricted CD4+ T cell (dependent claim 32);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule has substantially no binding activity to each of the HLA-DQ molecules recited in the claim (Applicant’s elected species is HLA-DQ2.2) (dependent claim 33);
the antigen-binding molecule of claim 17, which has enhanced binding activity to a complex formed by HLA-DQ2.5 and a gluten peptide (dependent claim 34);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule has stronger binding activity to at least two of the HLA-DQ2.5/peptide complexes recited in the claim at parts (i)-(xix) as compared to its binding activity to at least one of the HLA-DQ2.5/peptide complexes recited at parts (a)-(f) therein (dependent claim 35);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule, wherein the antigen[binding molecule has stronger binding activity to at least two of the HLA-DQ2.5/peptide complex alternatives recited at parts (i)-(xviii) as compared to its binding activity to at least one of the HLA-DQ2.5/peptide complexes recited at parts (a)-(f) (dependent claim 36);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule is a bispecific antigen-binding molecule (dependent claim 38);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule is a bispecific antibody (dependent claim 39);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule binds to the same epitope bound by any one of the antigen-binding molecules recited at parts (1)-(3) (dependent claim 51);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule competes with any one of the antigen binding molecules recited at parts (1)-(3) for binding to a complex formed by HLA-DQ2.5 and a gluten peptide (dependent claim 52);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule binds to the same epitope bound by either (a) an antigen-binding molecule comprising the alternatives recited at parts (i) and (iii), or (b) an antigen-binding molecule comprising the alternatives recited a parts (ii) and (iii).
The specification does not disclose a representative number of species of such antigen-binding molecule comprising at least two-antigen binding domains, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function.
The antigen-binding molecule of instant base claim 17 that comprises at least two-antigen-binding domains is a bispecific or multispecific antigen-binding molecule that must possess the functional property of having binding activity to one or more HLA-DQ2.5 complexes and a generic non-defined immune dominant peptide related to celiac disease while also possessing the functional property of having substantially no binding activity to at least one of the HLA-DQ2.5/peptide complexes recited at parts (a)-(e) (defined peptides) or to an HLA-DQ2.5 positive PBMC B cell (i.e., having a multiplicity of endogenously loaded peptides that may differ from individual to individual).
Relative to instant independent claim 17, the antigen-binding molecules recited in the dependent claims must also possess additional functional properties as follows.
The antigen-binding molecule of claim 32 must also in addition possess the functional property of blocking the interaction between some generic HLA-DQ2.5/generic gluten peptide complex and an HLA-DQ2.5/gluten peptide-restricted CD4+ T cell (that is, a CD4+ T cell that is cognate for the said complex or is cross-reactive therewith). The antigen-binding molecule of claim 33 must also possess the functional property of having no substantial binding activity to each of the recited HLA molecules (presumably with any bound peptide in its peptide binding groove or to the HLA molecules themselves). The antigen-binding molecule of claim 34 must also possess the functional property of enhanced binding activity to a complex formed by HLA-DQ2.5 and a generic gluten peptide. The antigen-binding molecule of claim 35 must possess at least two and up to nineteen additional functional properties in the form of having stronger binding activity to at least two of the HLA-DQ2.5 complexes with a peptide from one of the at least two to nineteen recited proteins. The antigen-binding molecule of claim 36 must also possess the functional property of having stronger comparative binding to at least two to eighteen of the HLA-DQ2.5 complexes with a peptide from the recited proteins versus its binding activity to at least one of the HLA-DQ2.5 complexes with a defined peptide recited at parts (a)-(e) or to an HLA-DQ2.5 positive PBMC B cell (i.e., having a multiplicity of endogenously loaded peptides that may differ from individual to individual). The antigen-binding molecule of claim 51 must also possess the functional property of binding to the same epitope that is bound by any one of the three antigen-binding molecules at parts (1)-(3) that are defined by their cognate six CDRs. The antigen-binding molecule of claim 52 must also possess the functional property of competing with the same epitope that is bound by any one of the three antigen-binding molecules at parts (1)-(3) that are defined by their cognate six CDRs. The antigen-binding molecule of claim 53 must also possess the functional property of binding to two of the recited antigen-binding molecules (i.e, i and iii, or ii and iii).
As such, the antigen-binding molecule may be any antigen-binding molecule comprising at least two of any in the broad genus of antigen-binding domains (with the exception of dependent claim 39 that is a bispecific antibody), it must possess the functional property of binding to a complex of the human MHC class II molecule HLA-DQ2.5 and a generic immune-dominant peptide related to celiac disease while also possessing the functional property of having substantially no binding activity to a complex formed by HLA-DQ2.5 and a defined peptide (partes (a)-(e) or to one or more complexes formed by HLA-DQ2.5 and an endogenously loaded peptide on a B cell from peripheral blood (PBMC) (i.e., the antigen-binding molecule as well as its at least two antigen-binding domains is functionally claimed by its binding and non-binding activities).
Also note that definitions in the instant specification also impart additional functional properties upon the claimed antigen-binding molecule and its antigen-binding domains.
The specification at [0060] discloses that binding activity can be rephrased as “specific activity”, and that anti-HLA-DQ2.5 antibodies of the invention have a Kd of 5 x 10-7 M or less to 2 x 10-9 M or less for binding to one or more complexes formed and a gluten peptide described herein. Thus, the definition in the instant specification for “binding activity” also imparts the functional property of having a specific range of dissociation constants upon the claimed antigen-binding molecules and its at least two antigen-binding domains (i.e., is a functional subgenus).
The specification discloses at [0026] that the phrase “substantially no binding activity” as used herein refers to activity of an antibody to bind to an antigen of no interest at a level of binding that includes no-specific or background binding but does not include specific binding. In other words, such an antibody has “no specific/significant binding activity” towards the antigen of no interest.”
The specification discloses at [0012] that the term “anti-HLA-DQ2.5 antibody” refers to an antibody that is capable of binding to HLA-DQ2.5 or one or more complexes formed by HLA-DQ2.5 and a gluten peptide with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting HLA-DQ2.5. Thus, this said definition in the specification also imparts the functional property of having some undisclosed sufficient affinity that makes the antibody useful as a diagnostic and/or therapeutic agent (note the disclosure of sufficient “affinity” which is applicable to individual antigen-binding domains, rather than ‘avidity’, the latter being a composite sum of affinities that would be applicable to a multispecific antibody).
The recitation of what antigen (the HLA-DQ2.5/peptide complex) an antigen-binding molecule binds does not provide adequate written description for the structure of an antigen-binding molecule (and its comprised antigen-binding domains).
With respect to structure and function, the skilled artisan was aware that it is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites.
For example, evidentiary reference Kim et al. (Trends. Pharm. Sci., 2023, 44(3): 175-189) teaches that antibodies comprise six CDRs, highly variable sequences, and frameworks of conserved sequences. Kim et al. teach that the 3D structure of the antibody determines how it interacts with an antigen and governs its binding properties. Kim et al. teach that it remains to be seen if various advances underlying protein structure and sequence-based design can be consolidated for antibody generation without degradation in the performance. (See entire reference, especially Figure 1 and first paragraph on page 177.)
Evidentiary reference D' Angelo et al. (Front. Immunol. 2018, 9, article 395, pages 1-13) teaches that “the same HCCDR3 can be generated by many different rearrangements, but that specific target binding is an outcome of unique rearrangements and VL pairing: the HCDR3 is necessary, albeit insufficient for specific antibody binding” (see entire reference, especially abstract).
Evidentiary reference Lloyd et al. (Protein Engineering, Eng. Design & Selection, 2009, 22(3): 159-168) teaches that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding. Lloyd et al. further teach that in their studies, of the 841 unselected and 5,044 selected antibodies sequenced, all but one of the 49 functional VH gene segments was observed, and that there are on average about 120 different antibodies generated per antigen. Lloyd et al. also teach that a wide variety of VH and VL pairings further increase diversity. (See entire reference.)
Evidentiary reference Edwards et al. (JMB, 2003, 334: 103-118) teaches that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lamda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well.
In Abbvie Deustschland Gmbh & Co KG, Abbvie Bioresearch Center, Inc., and Abbvie Biotechnolo-, Ltd., v. Janssen Biotech In. And Centocor Biologics, LLC, Case No. 2013-1338 and 2013-1346, C.A. Fed (“Abbvie”), the Federal Circuit reiterates the inherent unpredictability of protein engineering in Abbvie. For example, functionally defined genus claims can be inherently vulnerable to invalidity challenges for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbot Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem., Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002). However, the record here does not indicate such an established correlation. Instead, AbbVie used a trial and error approach to modify individual amino acids in order to improve the IL-12 binding affinity.
Thus, there is no structure-function relationship for the identity of an antigen with a cognate an antigen-binding molecule. As pertains to (i) the genus of antigen-binding molecules that possess the functional property of binding to the same epitope as an antigen binding molecule comprising for a bispecific molecule two (2) sets of six (6) fully defined CDRs or (ii) that possess the functional property of competing with such an antigen binding molecule (the latter having the functional property of binding to the same epitope or sterically hindering binding to the same epitope), there is no structure-function relationship (except in both instances, potentially antibodies that have the same set of cognate CDRs).
There is no evidence for a representative number of species of such antigen-binding molecules with its at least two antigen-binding domains and the required functional properties thereof.
The specification at [0013] discloses that the term “antigen-binding molecule” as used herein refers to any molecule that comprises an antigen-binding site or any molecule that has binding activity to an antigen, and may further refer to molecules such as a peptide or protein having a length of about five amino acids or more, and may be derived from a living organism, be a naturally occurring polypeptide, or be an artificially designed sequence…the terms “antigen-binding molecule” and “antibody” herein are used in the broadest sense and encompass various antibody structures.
The specification at [0017] discloses that the term “celiac (coeliac) disease” refers to a hereditary autoimmune disease caused by damages in the small intestine upon ingestion of gluten contained in food.
The specification discloses at [0025] that in celiac disease, gluten peptides are antigenic peptides recognized by T cells that cause the disease and that immune dominance is the phenomenon where immune response is mainly triggered by a relatively small number of antigenic peptides called “immune dominant peptides”. In celiac disease, such immune dominant peptides include, for example alpha 1 gliadin and alpha 2 gliadin (both of which are included in the sequence of 33mer gliadin), and omega 1 gliadin, omega 2 gliadin, and BC hordein (five peptides in total). Alternatively, the immune peptides include alpha 1 gliadin, alpha 2 gliadin, omega 1 gliadin, omega 2 gliadin, BC hordein, gamma 1 gliadin, and gamma 2 gliadin (seven peptides in total), but are not limited thereto. “Herein, such immune dominant peptides may be called “immune dominant peptides related to celiac disease”. As long as they are dominantly related to celiac disease, the types and total number of the peptides are not particularly limited.”
It is clear that the genus of immune dominant peptides related to celiac disease and/or those derived from specific proteins involved in celiac disease are not limited to those few fully-defined peptides disclosed in the specification. It is also clear that the few species of antibodies (with their fully defined set of CDRs) disclosed in the specification that are specific for one of a few HLA-DQ2.5/defined peptide complexes (e.g., Table 1 at [0105], Table 3) are not representative of the genus of antibodies that possess binding activity to a complex of HLA-AQ2.5 with generic immune dominant peptide related to celic disease and binding with a specific range of affinity (and including wherein it has stronger comparative binding activity to an incompletely defined or fully defined HLA-DQ2.5/peptide complex) while possessing the functional property of not binding to various complexes of HLA-DQ2.5 with an irrelevant, fully defined peptide or a set of HLA-DQ2.5 complexes displaying endogenously loaded peptides that are expressed on a B cell from peripheral blood. These few said species of antibody are also not representative of the breadth of “antigen-binding molecule(s)” that are not/do not comprise antibodies. It is also clear that the specification does not disclose a representative number of species of antigen-binding molecules that possess the functional property of binding to the same epitope as an antigen binding molecule comprising for a bispecific molecule having 2 sets of 6 fully defined CDRs or that possess the functional property of competing with such an antigen binding molecule. These few said species of antibody are also not representative of the breadth of the antigen-binding molecule of claim 17, wherein the antigen-binding molecule has substantially no binding activity to each of the HLA-DQ2.5/defined peptide complexes recited in dependent claim 33.
Therefore, it appears that the instant specification does not adequately disclose the breadth of the antigen-binding molecule comprising at least two-antigen binding domains that is recited in the instant claims. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such antigen-binding molecules at the time the instant application was filed.
7. Claims 17, 32-36, 38, 39 and 51-53 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 specification does not disclose how to make and/or use the instant invention:
an antigen-binding molecule that comprises at least two antigen-binding domains, wherein one or more the of the antigen-binding domains have binding activity to one or more complexes formed between HLA-DQ2.5 and an immune dominant peptide related to celiac disease, wherein one or more of the antigen-binding domains have substantially no binding activity to at least one of the HLA-DQ2.5 complexes recited at parts (a)-(e) or an HLA-D!2.5 positive PBMC B cell, wherein the antigen binding molecule is a bispecific or multispecific antigen-binding molecule (as is recited in instant base claim 17);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule blocks the interaction between an HLA-DQ2.5/gluten peptide complex and an HLA-DQ2.5/gluten peptide-restricted CD4+ T cell (dependent claim 32);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule has substantially no binding activity to each of the HLA-DQ molecules recited in the claim (Applicant’s elected species is HLA-DQ2.2) (dependent claim 33);
the antigen-binding molecule of claim 17, which has enhanced binding activity to a complex formed by HLA-DQ2.5 and a gluten peptide (dependent claim 34);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule has stronger binding activity to at least two of the HLA-DQ2.5/peptide complexes recited in the claim at parts (i)-(xix) as compared to its binding activity to at least one of the HLA-DQ2.5/peptide complexes recited at parts (a)-(f) therein(dependent claim 35);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule, wherein the antigen[binding molecule has stronger binding activity to at least two of the HLA-DQ2.5/peptide complex alternatives recited at parts (i)-(xviii) as compared to its binding activity to at least one of the HLA-DQ2.5/peptide complexes recited at parts (a)-(f) (dependent claim 36);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule is a bispecific antigen-binding molecule (dependent claim 38);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule is a bispecific antibody (dependent claim 39);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule binds to the same epitope bound by any one of the antigen-binding molecules recited at parts (1)-(3) (dependent claim 51);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule competes with any one of the antigen binding molecules recited at parts (1)-(3) for binding to a complex formed by HLA-DQ2.5 and a gluten peptide (dependent claim 52);
the antigen-binding molecule of claim 17, wherein the antigen-binding molecule binds to the same epitope bound by either (a) an antigen-binding molecule comprising the alternatives recited at parts (i) and (iii), or (b) an antigen-binding molecule comprising the alternatives recited a parts (ii) and (iii).
The specification has not enabled the breadth of the claimed invention because the claims encompass any in the broad genus of antigen-binding molecules comprising any in the broad and structurally diverse genus of genus of at least two antigen-binding domains having binding activity (including its defined range of affinity) to one or more complexes of the human MHC class II molecule HLA-DQ2.5 and a generic, undefined, immune dominant peptide related to celiac disease while having substantially no binding activity to a least one of the fully defined HLA-DQ2.5/peptide complexes recited in instant base claim 17 or to one or more HLA-DQ2.5/non-defined endogenous peptides that are present on the surface of a B cell from peripheral blood, or those that bind to a same epitope or compete with another antibody as is detailed below in this rejection.
The state of the art is such that it is unpredictable in the absence of appropriate evidence whether the claimed compositions can be made and/or used without undue experimentation over the breath of the claims.
The specification at [0013] discloses that the term “antigen-binding molecule” as used herein refers to any molecule that comprises an antigen-binding site or any molecule that has binding activity to an antigen, and may further refer to molecules such as a peptide or protein having a length of about five amino acids or more, and may be derived from a living organism, be a naturally occurring polypeptide, or be an artificially designed sequence…the terms “antigen-binding molecule” and “antibody” herein are used in the broadest sense and encompass various antibody structures.
Thus, the specification discloses a broad genus for the limitation “antigen-binding molecule” that includes, but is not limited to an antibody.
The specification further discloses at [0012] that the term “anti-HLA-DQ2.5 antibody” refers to an antibody that is capable of binding to HLA-DQ2.5 or one or more complexes formed by HLA-DQ2.5 and a gluten peptide with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting HLA-DQ2.5.
Thus, the specification discloses that for an antigen-binding molecule that comprises an antibody, the binding activity is associated with an undisclosed affinity, just that it is useful as a diagnostic and/or therapeutic agent in targeting HLA-DQ2.5, however, the specification does later disclose an affinity range but just for an antibody that binds to one or more complexes of HLA-DQ2.5 and a generic gluten peptide.
The specification at [0060] discloses that binding activity can be rephrased as “specific activity”, and that anti-HLA-DQ2.5 antibodies of the invention have a Kd of 5 x 10-7 M or less to 2 x 10-9 M or less for binding to one or more complexes formed and a gluten peptide described herein.
The specification discloses at [0025] that in celiac disease, gluten peptides are antigenic peptides recognized by T cells that cause the disease and that immune dominance is the phenomenon where immune response is mainly triggered by a relatively small number of antigenic peptides called “immune dominant peptides”. In celiac disease, such immune dominant peptides include, for example alpha 1 gliadin and alpha 2 gliadin (both of which are included in the sequence of 33mer gliadin), and omega 1 gliadin, omega 2 gliadin, and BC hordein (five peptides in total). Alternatively, the immune peptides include alpha 1 gliadin, alpha 2 gliadin, omega 1 gliadin, omega 2 gliadin, BC hordein, gamma 1 gliadin, and gamma 2 gliadin (seven peptides in total), but are not limited thereto. “Herein, such immune dominant peptides may be called “immune dominant peptides related to celiac disease”. As long as they are dominantly related to celiac disease, the types and total number of the peptides are not particularly limited.”
The specification clearly discloses that although some immunodominant peptides related to celiac disease derive from a subset of specific proteins, such immunodominant peptides that bind to HLA-DQ2.5 related to celiac disease are not limited to these.
The specification discloses at [0026] that the phrase “substantially no binding activity” as used herein refers to activity of an antibody to bind to an antigen of no interest at a level of binding that includes no-specific or background binding but does not include specific binding. In other words, such an antibody has “no specific/significant binding activity” towards the antigen of no interest.”
The specification at [0017] discloses that the term “celiac (coeliac) disease” refers to a hereditary autoimmune disease caused by damages in the small intestine upon ingestion of gluten contained in food.
The genus of such antigen-binding molecules is broad, encompassing antigen-binding domains from the genus of antigen-binding domains, including antibodies, that have binding activity (including within a specific affinity range) to a broad genus of HLA-DQ2.5/peptide complexes comprising (in claims 17, 32, 33, 38, 39) an undefined, generic peptide from the genus of immune dominant peptides related to celiac disease, or a generic, undefined peptide from specific recited proteins, while not binding to at least one of a complex of HLA-DQ2.5 and a defined irrelevant peptide or to one or more HLA-DQ2.5/endogenous peptide complexes presented on a B cell from peripheral blood, including in claim 32, wherein the antigen binding molecule blocks the interaction between some HLA-DQ2.5/undefined gluten peptide complex and a cognate or cross-reactive HLA-DQ2.5/undefined gluten peptide complex-restricted CD4+ T cell, or including in claim 33, wherein the antigen-binding molecule has substantially no binding activity to each of the HLA class II molecules or subgenus of HLA class II molecules recited in the claim (presumably not to those nominal molecules or to complexes of those molecules in complex with a peptide), or including in claim 34, wherein the antigen-binding molecule has an enhance binding activity to a complex formed by HLA-DQ2.5 and a generic, undefined gluten peptide, or including in claim 35, wherein the antigen-binding molecule has stronger binding activity to at least two of nineteen different HLA-DQ2.5/undefined peptides from specific recited proteins as compared to binding activity to at least one of a complex of HLA-DQ2.5 and a defined irrelevant peptide or to one or more HLA-DQ2.5/endogenous peptide complexes presented on a B cell from peripheral blood, or including in claim 36, wherein the antigen binding molecule has stronger binding activity to at least two of eighteen different complexes of HLA-DQ2.5/undefined peptides from specific recited proteins as compared to binding activity to at least one of a complex of HLA-DQ2.5 and a defined irrelevant peptide or to one or more HLA-DQ2.5/endogenous peptide complexes presented on a B cell from peripheral blood, or including in claims 51 and 53 wherein the antigen-binding molecule binds to the same epitope bound by any one of the recited antigen-binding molecules comprising a cognate set of six fully defined CDRs, or including in claim 52, wherein the antigen-binding molecule competes with any one of a antigen-binding molecules comprising a cognate set of six fully defined CDRs.
It is clear that the genus of immune dominant peptides related to celiac disease and/or those derived from specific proteins involved in celiac disease are not limited to those few fully-defined peptides disclosed in the specification. It is also clear that the few species of antibodies (with their fully defined set of CDRs) disclosed in the specification that are specific for one of a few HLA-DQ2.5/defined peptide complexes (e.g., Table 1 at [0105], Table 3) are not representative of the genus of antibodies that possess binding activity to a complex of HLA-AQ2.5 with a generic immune dominant peptide related to celic disease and binding within a specific range of affinity (and including wherein it has stronger comparative binding activity to an incompletely defined or fully defined HLA-DQ2.5/peptide complex) while not binding to various complexes of HLA-DQ2.5 with an irrelevant, fully defined peptide or a set of HLA-DQ2.5 complexes displaying endogenously loaded peptides that are expressed on a B cell from peripheral blood. It is also apparent that these the few said species of antibody disclosed in the specification are narrower than the breadth of “antigen-binding molecule(s)” that are not and/or do not comprise antibodies. The art also recognizes that making an antibody that binds to a same epitope (excluding ones that comprise a same cognate set of CDRs such as humanized, human or chimeric antibodies) is an unpredictable event.
Evidentiary reference Frick, R. (2019, Engineering TCR-like Antibodies, Doctoral Thesis, Depts. Biosicences, Immunology, and Pharmacology, University of Oslo, pages 1-65) teaches that there are several examples of TCR-like antibodies against MHC class II complexes (1.3.2). Frick teaches that Celiac disease (CeD)is an inflammatory condition of the small intestine with symptoms triggered by dietary uptake of gluten from wheat, barley, or rye. Frick further teaches that antibodies against TG2 (transglutaminase enzyme) is an autoimmune feature of the condition. Frick teaches that more than 90% of patients with CeD express HLA-DQ2.5 (1.4). Frick teaches immunodominant HLA-DQ2.5-restricted gliadin epitopes in Table 1.1 as reproduced below:
Table 1.1: Immunodominant HLA-DQ2.5 restricted gliadin epitopes
Epitope 9mer core sequence∗
DQ2.5-glia-_1a PFPQPELPY
DQ2.5-glia-_2 PQPELPYPQ
DQ2.5-glia-!1 PFPQPEQPF
DQ2.5-glia-!2 PQPEQPFPW
Frick also teaches that gluten reactive CD4+ T cells are found in the small intestine and in blood of both treated (on a gluten free diet) and untreated CeD patients, but not in healthy controls. Frick teaches that CeD patients have T cell responses to different gluten epitopes, but the majority have T cells specific for the alpha and omega-gliadin derived immunodominant epitopes shown above in Table 1.1 (1.4.2).
Frick teaches selection of antibodies specific for deamindated DQ2.5-glia-a1a in complex with HLA-DQ2.5 from a human naïve scFv phage library (section 3 on page 23). Frick also teaches an antibody specific for the second immunodominant epitope derived from alpha-gliadin, termed DQ2.5-glia-a2, selected from a human naïve scFv phage library that was characterized by a low affinity and a high off-rate, necessitating implementation of strategies for affinity maturation using a semi-rational library design strategy in concert with a fully random strategy for one of the specificities. The targeted strategy was based on computational docking models, choosing poorly interacting CDR loops for randomization, followed by selection of antibodies from these second generation libraries using phage display (section 3 on page 24, page 34 at section 5.1). Frick teaches that computational modeling and docking of antibodies can be used on a limited basis to gain insight into structural reasons for improved antibody affinities, however, these methodologies come with limitations and cannot provide the same certainty as crystal structures, and are not expected to be accurate in all instances (section on page 26).
Thus, Frick teaches that although most CeD patients have T cells specific for the alpha and omega-gliadin derived immunodominant epitopes shown above in Table 1.1, CeD patients have T cells specific for other epitopes from gluten. Frick also evidences that although TcR like antibodies can be made, the process is labor-intensive, including for selecting lead molecules and further work to affinity mature the antibodies for sufficient affinity is required, either through implementation of semi-rational library design or design based upon computational docking models in some limited instances.
Evidentiary reference Frick et al. (Science Immunology, 8/20/2021, 6, eabg4925, pages 1-16) teaches that antibodies with specificity for peptide/MHC (pMHC) are called TCR-like antibodies, and as soluble agents have increased stability and higher affinity than do TCRs. Frick et al. teach that celiac disease (CeD) is an inflammatory autoimmune-like condition caused by CD4+ T cells that recognize deamidated gluten protein peptides in the context of the HLA-DQ molecules HLA-DQ2.5, HLA-DQ2.2 and HLA-DQ8, with HLA-DQ2.5 being the most strongly associated with CeD and detected in about 90% of patients with CeD compared with about 20% in healthy controls. Frick et al. teach that a range of gluten T cell epitopes have been characterized, but four immunodominant epitopes derived from a-gliadin and w-gliadin are particularly prominent in the context of HLA-DQ2.5 (introduction section). Frick et al. teach the generation of TCR-like antibodies specific for a complex of HLA-DQ2.5 with the peptide DQ2.5-glia-a2. Frick et al. teach that it was necessary to screen on a phage display selection of a fully human naive antibody (Ab) library with multiple rounds of competition and thermostability screenings and selections, resulting in binding Abs with low binding affinity, followed by secondary complementary determining region (CDR)-targeted optimization in order to obtain highly specific binders with picomolar monomeric affinities towards the said complex. Frick et al. teach that the lead candidate Ab (Fab 3.C11) displayed a similar docking geometry with respect to the said complex similar to prototypic CeD patient-derived TCRs having the same specificity, a docking geometry that was different from the other clones. See entire reference.
Evidentiary reference Okura et al. (Nat. Comm. 2023) teaches that more than 80% of HLA-DQ2.5+ CeD patients (celiac disease patients) are responsive to multiple gluten epitopes other than DQ2.5-glia-a1a and DQ2.5-glia- a 2, and that in HLA-DQ2.5+ CeD, there are five distinct immunodominant epitopes found in wheat or barley. In addition more than thirty gluten epitopes with different amino acid sequences are known or predicted to be presented on HLA-DQ2.5, and conceivably, the T cell response to all these epitopes drive pathology in CeD. Okura et al. further teach that even among the five immunodominant epitopes, the sequence homology is low. Okura et al. teach that a bispecific antibody having the arms DQN0344xx and DQN0385ee that were humanized followed by extensive mutational optimization of the heavy and light chains to improve the properties of each of the two original antibodies, with the resulting bispecific antibody termed “DONQ52” that binds/cross-reacts to/with multiple gluten epitopes with limited binding to irrelevant peptides (see entire reference, especially second paragraph on page 2, paragraph bridging pages 2-3, first full paragraph on page 3, Figure 2a). Note that Okura et al. teach that structural analysis demonstrated that the paratopes of CONQ52 contain an unusually high number of Tyr residues and these multiple Tyr residues flexibly recognize the Pro and Gln-rich motifs common to pathogenic gluten epitopes, regardless of the amino acids adjacent to each Pro and Gln.
Evidentiary reference Hoydahl et al. (Antibodies, 2019, 8(2): 32, pages 1-21) teaches that monoclonal antibodies targeting MHC/peptide complexes (pMHC) are often referred to as “TCR-like” antibodies or “T cell mimic antibodies” (TCRm), as pMHC complexes are generally recognized by TCRs (abstract and introduction). Hoydahl et al. teach that TCRm antibody production via hybridoma technology is challenging (section 3.1). Hoydahl et al. further teach that TCRm antibodies isolated from naïve phage display libraries have been of low affinity, necessitating affinity maturation or use of immune phage display libraries (section 3.2). Hoydahl et al. teach that one TCRm antibody has been isolated using yeast display libraries (section 3.3).
The instant specification discloses a 33-mer gliadin peptide that binds to HLA-DQ2.5 (e.g., example 1). The specification discloses tha