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 that there are peptides from gliadin that bind to HLA-DQ2.5 from gliadin, but does not disclose their sequences (e.g., [0260], Figs. 1 and 7) (these gluten derived peptides, “in particular 33mer gliadin peptide, alpha 1 gliadin peptide, alpha 2 gliadin peptide, omega 1 gliadin peptide, alpha 3 gliadin peptide, alpha 1b gliadin peptide, avenin 1 peptide, avenin 2 peptide, avenin 3 peptide, hordein 1 peptide, secalin 1 peptide, secalin 2 peptide”). One of Applicant’s elected species, the antibody designated “DQN0344xx” has binding activity to HLA-DQ2.5 and one of these peptides, but not when the peptide is one of the irrelevant ones tested ([0260]). Applicant’s other elected species designated “DQN0385ee” has binding activity to HLA-DQ2.5 when it is in the form of a complex with one of several gluten peptides, i.e., 33mer gliadin peptide, alpha 1 gliadin peptide, alpha 2 gliadin peptide, gamma 1 gliadin peptide, gamma 2 gliadin peptide, omega 1 gliadin peptide, omega 2 gliadin peptide, BC hordein peptide, alpha 3 gliadin peptide, alpha 1b gliadin peptide, gamma 4b gliadin peptide, avenin 1 peptide, avenin 2 peptide, hordein 1 peptide, hordein 2 peptide, secalin 1 peptide, secalin 2 peptide, 14mer1 peptide, and 26mer gliadin peptide, but not with an irrelevant peptide tested ([0261. Figs 2 and 8). These are true for the bispecific version comprising both said antibodies ([0263], [0273]). Neither of these said antibodies displays binding to an HLA-DQ2.5 positive PBMC B cell ([0270]).
As pertains to claims 51 and 53, it would take undue experimentation to determine antibodies that bind to a same epitope as another antibody.
Evidentiary reference Anderson et al. (J. Clin.Microbiol., 1986, 23(3): 475-480) teaches identification of epitopes on RSV proteins by competitive binding immunoassay. However, Anderson et al. teach “Although competitive binding can distinguish between competing and non-competing MAbs, it does not necessarily identify which MAbs react at which epitopes and antigenic sites…For example, two-way blocking between two MAbs suggests but does not prove that they react at the same or overlapping epitopes…Similarly, the lack of blocking between two MAbs suggests, but does not prove that they react at distinct epitopes or antigenic sites…” (paragraph spanning pages 478-479).
Similarly, the method of differential antigen disruption taught by evidentiary reference Shi et al. (J. Immunol. Methods., 2006, 314: 9-20) also suffers from the same deficiencies as the method taught by Anderson et al., i.e., “if the...antibodies are found to share a binding profile with a ligand in the differential antigen disruption experiment, very likely, their epitopes overlap with the ligand-binding site, thereby infringing ligand-binding". That is, given this teaching and a general concordance with the competition assay method also taught by Anderson et al, the method suggests but does not prove that the antibodies react with the same epitope. Thus the evidentiary references underscore unpredictability in the art of identifying, and therefore making, antibodies that bind to the same epitope, even if they compete.
Instant claims 32 and 52 are included in this rejection because they depend upon claim 17, and the experimentation is undue regarding making and/or using the claimed antigen-binding molecule recited in base claim 17, and the determination of a blocking antibody as recited in claim 32 or one that competes with a specific antibody as recited in claim 52 also constitute undue experimentation.
There is insufficient guidance in the specification as to how to make and/or use the instant invention. Undue experimentation would be required of one skilled in the art to practice the instant invention. See In re Wands 8 USPQ2d 1400 (CAFC 1988).
8. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
9. Claims 34, 37 and 40 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
a) Claim 34 is indefinite in the recitation of “which has enhanced binding activity to a complex formed by HLA-DQ2.5 and a gluten peptide” because it is not clear what is meant by the said limitation in the absence of a limiting definition therefore or by the recitation of a comparative binding activity.
b) Claim 37 recites “The antigen-binding molecule of claim 17, wherein the molecule is any one of (1) to (3) below”. This limitation lacks antecedent basis in instant base claim 17 since the antigen-binding molecule of claim 17 is bispecific or multispecific, whereas the antigen-binding molecule of dependent claim 37 is monospecific.
c) Claim 40 recites “The antigen-binding molecule of claim 37” that is either of two bispecific antigen-binding molecules. This limitation lacks antecedent basis in instant base claim 17 since the antigen-binding molecule of claim 17 is bispecific or multispecific, whereas the antigen-binding molecule of dependent claim 37 is monospecific.
10. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
11. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
12. Claims 17, 32-36, 38 and 39 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO 2019/158602 A2 (priority to 2/13/2018, IDS reference) or CA 3091055 (note that the equivalent of this application is the WO 2019/158602 A2 document).
WO 2019/158602 A2 teaches a bispecific antibody or antibody-like molecule that has an antigen binding region comprising one arm that specifically binds to HLA-DQ2.5:DQ2.5glia-a1a (an immunodominant wheat gluten epitope) and another that binds to HLA-DQ2.5:-glia-a2 (an immunodominant wheat gluten epitope) or to CD3 (paragraph spanning pages 83-84, page 73 at lines 20-35, page 84 at lines 3-20). WO 2019/158602 A2 teaches that the CLIP2 peptide used in the studies is MATPLLMQALPMGAL (e.g., page 178 at lines 21-22) and that the monospecific antibodies exemplified preferentially bind to HLA-DQ2.5:DQ2.5glia-a1a or to HLA-DQ2.5:DQ2.5glia-a2 and not to HLA-DQ2.5 in complex with the irrelevant CLIP2 peptide (e.g., page 162 at Figure 1 text, page 167 at Figure 14 text, example 1, example 2, page 176 at lines 1-5). WO 2019/158602 A2 teaches that antibodies were affinity-matured and showed improved off-rates as compared to the mother clones (page 191 at lines 7-16, Table Z spanning pages 196-197). WO 2019/158602 A2 teaches that the antibodies can block the interaction between T cells bearing TCRs specific for the peptides and human HLA-DQ2.5 positive B cells loaded with the requisite exogenous cognate peptide (Example 9) (and note that there is no limiting definition in the specification for the limitation “blocks”) (and also implying that there is no reactivity of the TCR positive cells or the antibody with B cells not loaded with the cognate peptide). WO 2019/158602 A2 teaches humanized versions of such antibodies comprising the same CDRs as the non-human antibodies (e.g., page 74 at lines 5-20). WO 2019/158602 A2 teaches that these antibodies did not react with HLA-DQ2.2 (Figure 3, page 163 at lines 6-16). WO 2019/158602 A2 teaches that up to 50% of gluten-reactive CD4+ TH cells in an active CD lesion may be focused on either of the immunodominant HLA-DQ2.5:DQ2.5glia-a1a or HLA-DQ2.5:-glia-a2 epitopes and that selectively blocking dominating epitopes in HLA-driven diseases has been shown to ameliorate disease (page 176 at lines 33-37). See entire reference.
CA 3091055 contains these same teachings as the equivalent of this application is the WO 2019/158602 A2 document above.
Although the art reference does not explicitly disclose that the antibodies do not react with the CLIP peptide having the sequence consisting of that of SEQ ID NO: 45 (i.e., KLPKPPKPVSKMRMATPLLMQALPMGALP, see part “(a)” of instant base claim 17), the art reference does teach that the antibodies do not react with the CLIP peptide having the sequence MATPLLMQALPMGAL, and that the core sequence for binding is PLLMQALP (page 161 at line 15 of the art reference); thus more likely than not, the antibodies would not react with the peptide of instantly recited SEQ ID NO: 45. Also, the art reference teaches that specificity to the human HLA-DQ2.5 positive B cells is predicated to endogenous loading with the cognate immunodominant peptide (this pertains to part “(f)” recited in instant base claim 17. In addition, although the art reference does not teach that the antibodies do not have substantial binding activity to each of the HLA molecules recited in dependent claim 33, the art reference does teaches that the antibodies do not binding to the first alternative in the said claim HLA-DQ2.2. Therefore, the claimed antigen-binding molecule the claimed appears to be the same as the antigen-binding molecule of the prior art absent a showing of differences. Since the Patent Office does not have the facilities for examining and comparing the antigen-binding molecule of the instant invention to those of the prior art, the burden is on Applicant to show a distinction between the product of the instant invention and that of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977).
Instant dependent claim 34 is included in this rejection because as is stated above in this rejection, the limitation recited therein is indefinite in the recitation of enhanced binding activity to a complex formed by HLA-DQ2.5 and a gluten peptide or the recitation of a comparative binding activity. The art reference teaches antibodies with acceptable affinities as well as better affinity-matured antibodies of the parental clones.
13. Claims 17 and 32-40 are re rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2023/0118024 A1.
The applied reference has a common inventor and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
US 2023/0118024 A1 discloses an antibody of the invention, including a bispecific or multispecific antibody, having activity to HLA-DQ2.5 but substantially no binding activity to HLA-DQ8, HLA-DQ5.1, HLA-DQ6.3, HLA-DQ7.3, HLA-DR, HLA-DP, or ta complex of the invariant chain and HLA-DQ2.5 in the presence of a gluten peptide such as gliadin, wherein the antibody has neutralizing activity against the binding between HLA-DQ2.5 and TCR, thus blocking the interaction between HLA-DQ2.5 and an HLA-DQ2.5-restricted CD4+ T cell (abstract, [0154]). US 2023/0118024 A1 discloses the antibody may be chimeric ([0159]), human ([0169]), or humanized ([0171]). US 2023/0118024 A1 discloses that the bound peptide may be from for example, 33mer gliadin, alpha 1 gliadin alpha 1b gliadin, alpha 2 gliadin, omega 1 gliadin, omega 3 gliadin, secalin 1, secalin 2, or hordein ([0205], [0206], [0165])) or US 2023/0118024 A1 exemplifies several such antibodies including DQN0344xx having the same HCRs and LCDRs, VH and VL as those of antibody DQN0344xx that is disclosed in the instant specification (see Table 1 at [0105] of the instant specification and Table 1 of the art reference at [0233]). US 2023/0118024 A1 discloses at Figure 30 (and [0133]), the binding specificities of this said antibody (HLA-DQ2.5 complexes comprising a peptide from gliadin 33mer, alpha 1, alpha 1b, alpha 2, mega 1, omega 2, secalin or secalin 2, while not binding to HLA-DQ2.5+ PBMCs (comprising B cells), CLIP peptide (SEQ ID NO: 103 of the art reference that is identical to instantly recited SEQ ID NO: 45), salmonella peptide (SEQ ID NO: 137 of the art reference that is identical to instantly recited SEQ ID NO: 51), mycobacterium bovis peptide (SEQ ID NO: 138 of the art reference that is identical to instantly recited SEQ ID NO: 53) or hepatitis B virus peptide (SEQ ID NO: 139 of the art reference that is identical to instantly recited SEQ ID NO: 50). Several other antibodies also have this binding/non-substantial binding pattern (see [0377]). US 2023/0118024 A1 discloses antibodies that additionally do not have binding activity to HLA-DQ2.2 ([0380]), and of these the antibodies having both said binding profiles are DQN-0344xx, 0334bb, 0225dd, 0271hh, 0324hh and 0370hh. US 2023/0118024 A1 discloses the range of Kd of these antibodies ([0244]). See entire reference. See entire reference.
Instant dependent claims 34 and 37 are included in this rejection due to the indefiniteness of these claims as enunciated above in this office action.
14. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
15. Claims 17, 32-36, 38 and 39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11,739,153 (issued from 17/477,651). Although the claims at issue are not identical, they are not patentably distinct from each other because these said claims are drawn to a bispecific antibody comprising two arms, one that is a variant of antibody DQN0344 and one that is a variant of antibody DQN0385, wherein these said variants appear to be CDR1 and CDR2 variants of the parental antibodies. The specification of US 11,739,153 evidences that these antibodies have substantially no binding activity to HLA-DP, HLA-DR, HLA-DQ5.1, 6.3, 7.3, 7.5 or 8 (column 4 at lines 4-7) or to complexes of HLA-DQ2.5 with irrelevant peptides such as a CLIP peptide HBV 1 peptide, Salmonella peptide, M. Bovis peptide, and thyroperoxidase peptide (paragraph spanning columns 3-4, column 3 at lines 57-63), but do have binding to any one or more of the same immunodominant gluten peptides that are recited in the instant claims (e.g., column 3 at lines 8-56), and the specification evidences their dissociation constants (column 26 at lines 19-25). The specification of 11,739,153 also evidences that the irrelevant peptides are the same as those that are recited in the instant claims (paragraph spanning columns 111-112). The specification also discloses that the antibody blocks the binding between the complex and a cognate CD4+ T cell (column 4 at lines 8-14 and examples).
16. Claims 17, 32-36, 38 and 39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/697,831. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of 18/697,831 are drawn to a formulation comprising a multispecific anti-HLA-DQ2.5/peptide antibody, wherein the said antibody comprises variants of the antibodies DQN0344xx and DQN0385 (including variations in the CDRs) that appear to have the functional properties that are recited in the instant claims (the specification of 18/697,831 evidences this, for example, at tables 2-3 through 2-6 and the figures).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
17. Claims 17, 32-36, 38 and 39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 19/234,516 in view of WO 2019/158602 A2 (priority to 2/13/2018, IDS reference) or CA 3091055 (note that the equivalent of this application is the WO 2019/158602 A2 document).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of 19/234,516 are drawn to anti-HLA-DQ2.5 antibody in the form of a peptide complex with a gluten peptide, at least one of a 33mer gliadin peptide, an alpha 1 or 1b gliadin peptide, an alpha 2 gliadin peptide, an omega 1 gliadin peptide, an omega 2 gliadin peptide, or a secalin 1 or 2 peptide, wherein the antibody blocks the interaction between the said complex and a cognate-restricted CD4+ T cell, wherein the antibody has substantially no binding activity to HLADQ5.1, 6.3 or 7.3 or to HLA-DR or HLA-DP and in one claim the antibody also has no substantial binding activity to HLA-DQ2.2, and wherein the antibody has substantially no binding activity to an HLA-DQ2.5/invariant chain peptide (CLIP) complex. The antibody has stronger binding activity to the said complex as compared to the complexes recited in claim 12 (i.e., a peptide the same source proteins, but not limited to the sequences recited in instant base claim 17). Claim 13 of 19/234,516 recites the antibody of the prior claims 1-7 that has specifically defined CDRs (that appear in Table [0147] of the specification of 19/234,5160.
The claims of 19/234,516 do not recite wherein the antibody is bispecific, nor what the identity of the invariant chain (CLIP) peptide is.
WO 2019/158602 A2 teaches a bispecific antibody or antibody-like molecule that has an antigen binding region comprising one arm that specifically binds to HLA-DQ2.5:DQ2.5glia-a1a (an immunodominant wheat gluten epitope) and another that binds to HLA-DQ2.5:-glia-a2 (an immunodominant wheat gluten epitope) or to CD3 (paragraph spanning pages 83-84, page 73 at lines 20-35, page 84 at lines 3-20). WO 2019/158602 A2 teaches that the CLIP2 peptide used in the studies is MATPLLMQALPMGAL (e.g., page 178 at lines 21-22) and that the monospecific antibodies exemplified preferentially bind to HLA-DQ2.5:DQ2.5glia-a1a or to HLA-DQ2.5:DQ2.5glia-a2 and not to HLA-DQ2.5 in complex with the irrelevant CLIP2 peptide (e.g., page 162 at Figure 1 text, page 167 at Figure 14 text, example 1, example 2, page 176 at lines 1-5). WO 2019/158602 A2 teaches that antibodies were affinity-matured and showed improved off-rates as compared to the mother clones (page 191 at lines 7-16, Table Z spanning pages 196-197). WO 2019/158602 A2 teaches that the antibodies can block the interaction between T cells bearing TCRs specific for the peptides and human HLA-DQ2.5 positive B cells loaded with the requisite exogenous cognate peptide (Example 9) (and note that there is no limiting definition in the specification for the limitation “blocks”) (and also implying that there is no reactivity of the TCR positive cells or the antibody with B cells not loaded with the cognate peptide). WO 2019/158602 A2 teaches humanized versions of such antibodies comprising the same CDRs as the non-human antibodies (e.g., page 74 at lines 5-20). WO 2019/158602 A2 teaches that these antibodies did not react with HLA-DQ2.2 (Figure 3, page 163 at lines 6-16). WO 2019/158602 A2 teaches that up to 50% of gluten-reactive CD4+ TH cells in an active CD lesion may be focused on either of the immunodominant HLA-DQ2.5:DQ2.5glia-a1a or HLA-DQ2.5:-glia-a2 epitopes and that selectively blocking dominating epitopes in HLA-driven diseases has been shown to ameliorate disease (page 176 at lines 33-37). See entire reference.
CA 3091055 contains these same teachings as the equivalent of this application is the WO 2019/158602 A2 document above.
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have made a bispecific version of the antibody of the claims of 19/234,516 as is taught by the cited art reference, including from those recited in the claims of ‘516 and/or those taught by the art reference, and to additionally have used the CLIP peptide taught by said art reference as the negative control.
One of ordinary skill in the art would have been motivated to do this in order to increase avidity and to take advantage of different binding characteristics of individual antibodies.
Although the art reference does not explicitly disclose that the antibodies do not react with the CLIP peptide having the sequence consisting of that of SEQ ID NO: 45 that is recited in instant base claim 17 (i.e., KLPKPPKPVSKMRMATPLLMQALPMGALP, see part “(a)” of instant base claim 17), the art reference does teach that the antibodies do not react with the CLIP peptide having the sequence MATPLLMQALPMGAL, and that the core sequence for binding is PLLMQALP (page 161 at line 15 of the art reference); thus more likely than not, the antibodies would not react with the peptide of instantly recited SEQ ID NO: 45. Therefore, the antibody of the instant claims appears to be similar to the antigen-binding molecule of the prior art absent a showing of unobvious differences. Since the Patent Office does not have the facilities for examining and comparing the antigen-binding molecule of the instant invention to those of the claims of 19/234,516 in view of the said art, the burden is on Applicant to show an unobvious distinction between the antigen binding molecule of the instant invention and that of the claims of 19/234,516 in view of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977).
18. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 18/595,973 case as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 17, 32-36, 38 and 39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-27 of copending Application No. 18/595,973 in view of WO 2019/158602 A2 (priority to 2/13/2018, IDS reference) or CA 3091055 (note that the equivalent of this application is the WO 2019/158602 A2 document).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 16 and 17 of 18/595,973 are drawn to an antibody comprising any one of the alternatives recited in base claim 16, or to an antibody that binds to the same epitope or competes for binding with any one of the alternatives recited in base claim 117.
Claim 18 of 18/595,973 is drawn to a nucleic acid encoding an anti HLA-DQ2.5/8 antibody that has substantially not binding activity to HLA-DR and to HLA-DP or to a complex of invariant chain (CLIP) peptide and HLA-DQ2.5.
Claims 19-24 of 18/595,973 are drawn to a method of screening for an antibody.
Claim 25 of 18/595,973 is drawn to a method of preparing a pharmaceutical composition.
Claims 26 and 27 of 18/595,973 are drawn to a method for treating a patient having an autoimmune disease associated with presentation of an antigen peptide fragment by HLA-DQ2.5 to a cognate CD4+ T cell comprising administering the antibody to the patient.
The claims of 18/595,973 do not recite wherein the antibody is a bispecific antibody, nor the identity of the invariant chain (CLIP) peptide.
The specification of 18/595,973 at the Examples evidences that these antibodies have binding activity to HLA-DQ2.5/gliadin 33mer peptide complexes, (i.e., from alpha 2 gliadin that contains epitopes from alpha 1a, alpha 1b and alpha 2 gliadin as is evidenced by Schalk et al. (Nature.com/scientific reports, 2017, 7: 45092/DOI:10.1038/srep45092, pages 1-12, see entire reference, especially first paragraph of reference).
The claims of 18/595,973 do not recite wherein the antibody is a bispecific antibody, nor the particular subsequence of the invariant chain peptide.
WO 2019/158602 A2 teaches a bispecific antibody or antibody-like molecule that has an antigen binding region comprising one arm that specifically binds to HLA-DQ2.5:DQ2.5glia-a1a (an immunodominant wheat gluten epitope) and another that binds to HLA-DQ2.5:-glia-a2 (an immunodominant wheat gluten epitope) or to CD3 (paragraph spanning pages 83-84, page 73 at lines 20-35, page 84 at lines 3-20). WO 2019/158602 A2 teaches that the CLIP2 peptide used in the studies is MATPLLMQALPMGAL (e.g., page 178 at lines 21-22) and that the monospecific antibodies exemplified preferentially bind to HLA-DQ2.5:DQ2.5glia-a1a or to HLA-DQ2.5:DQ2.5glia-a2 and not to HLA-DQ2.5 in complex with the irrelevant CLIP2 peptide (e.g., page 162 at Figure 1 text, page 167 at Figure 14 text, example 1, example 2, page 176 at lines 1-5). WO 2019/158602 A2 teaches that antibodies were affinity-matured and showed improved off-rates as compared to the mother clones (page 191 at lines 7-16, Table Z spanning pages 196-197). WO 2019/158602 A2 teaches that the antibodies can block the interaction between T cells bearing TCRs specific for the peptides and human HLA-DQ2.5 positive B cells loaded with the requisite exogenous cognate peptide (Example 9) (and note that there is no limiting definition in the specification for the limitation “blocks”) (and also implying that there is no reactivity of the TCR positive cells or the antibody with B cells not loaded with the cognate peptide). WO 2019/158602 A2 teaches humanized versions of such antibodies comprising the same CDRs as the non-human antibodies (e.g., page 74 at lines 5-20). WO 2019/158602 A2 teaches that these antibodies did not react with HLA-DQ2.2 (Figure 3, page 163 at lines 6-16). WO 2019/158602 A2 teaches that up to 50% of gluten-reactive CD4+ TH cells in an active CD lesion may be focused on either of the immunodominant HLA-DQ2.5:DQ2.5glia-a1a or HLA-DQ2.5:-glia-a2 epitopes and that selectively blocking dominating epitopes in HLA-driven diseases has been shown to ameliorate disease (page 176 at lines 33-37). See entire reference.
CA 3091055 contains these same teachings as the equivalent of this application is the WO 2019/158602 A2 document above.
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have made a bispecific version of the antibody of the claims of 18/959,973 as is taught by the cited art reference, including from those recited in the claims of 18/595,973 and/or those taught by the art reference, and to additionally have used the CLIP peptide taught by said art reference as the negative control.
One of ordinary skill in the art would have been motivated to do this in order to increase avidity and to take advantage of different binding characteristics of individual antibodies.
Although the art reference does not explicitly disclose that the antibodies do not react with the CLIP peptide having the sequence consisting of that of SEQ ID NO: 45 that is recited in instant base claim 17 (i.e., KLPKPPKPVSKMRMATPLLMQALPMGALP, see part “(a)” of instant base claim 17), the art reference does teach that the antibodies do not react with the CLIP peptide having the sequence MATPLLMQALPMGAL, and that the core sequence for binding is PLLMQALP (page 161 at line 15 of the art reference); thus more likely than not, the antibodies would not react with the peptide of instantly recited SEQ ID NO: 45. As regards instant dependent claim 33, although the claims of 18/595,973 do not recite that the antibody has substantially no binding activity to HLA-DQ2.2, DQ.6, DQ7.5, or DQ7.3, they do recite that it has substantially no binding activity to HLA-DR and HLA-DP. Therefore, the antibody of the instant claims appears to be similar to the antigen-binding molecule of the prior art absent a showing of unobvious differences. Since the Patent Office does not have the facilities for examining and comparing the antigen-binding molecule of the instant invention to those of the claims of 18/595,973 in view of the said art, the burden is on Applicant to show an unobvious distinction between the antigen binding molecule of the instant invention and that of the claims of 19/234,516 in view of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977). Instant dependent claim 34 is included in this rejection due to the indefiniteness of this claim as enunciated above in this office action.
19. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 18/346,975 case as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 17, 32-36, 38 and 39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 48-77 of copending Application No. 18/346,975.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of 18/346,975 are drawn to a method of treating an individual who has celiac disease comprising administering an effective amount of a bispecific antibody that comprises a first arm that binds to a complex of HLA-DQ2.5 and a first gluten peptide, wherein the first arm comprises a first VH and a first VL that are at least 95% identical to a first reference VH and a first reference VL sequence, and a second arm that binds to a complex of HLA-DQ2.5 and a second gluten peptide, wherein the first arm comprises a second VH and a second VL that are at least 95% identical to a second reference VH and a second reference VL sequence that is recited in the claims.
Although the claims at issue are not identical, they are not patentably distinct from each other because these said claims are drawn to a bispecific antibody comprising two arms, one that is a variant of lead antibody DQN0344xx and one that is a variant of lead antibody DQN0385ee (e.g., Example 3 at [0312], wherein these said variants appear to be CDR1 and CDR2 variants of the parental antibodies (Tables 2-4 through 2-6). The specification of 18/346,975 evidences that these antibodies have substantially no binding activity to HLA-DP, HLA-DR, HLA-DQ5.1, 6.3, 7.3, 7.5 or 8 (page 5 at section [5]) or to complexes of HLA-DQ2.5 with irrelevant peptides such as a CLIP peptide HBV 1 peptide, Salmonella peptide, M. Bovis peptide, and thyroperoxidase peptide (page 5 at section [4-1]), but do have binding to any one or more of the same immunodominant gluten peptides that are recited in the instant claims (e.g., page 5 at sections [6-2], [8-1]). The specification of 18/346,975 also evidences that the irrelevant peptides are the same as those that are recited in the instant claims (page 151 at [0309]). The specification of 18/346,975 also discloses that the antibody blocks the binding between the complex and a cognate CD4+ T cell (page 5 at section [6]). Instant dependent claim 34 is included in this rejection due to the indefiniteness of this claim as enunciated above in this office action.
20. Wherein Applicant’s Forms 1449 list patent applications, only the originally filed specification, drawings, and claims have been reviewed.
21. No claim is allowed.
22. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641
Prosecution Insights